Belzutifan and other Novel Therapies in Genitourinary Oncology 2023

By Rana McKay, MD - University of California San Diego

We're gonna start with kidney cancer and go through Belzutifan, Relatlimab, SRF-388 and the others that are listed here. Then we'll go into. And finally urothelial cancer. This is gonna  be a little bit of a whirlwind,  splash on each of these drugs where they're at. And then  tie it all up at the end.

Renal Cell Carcinoma 2023 Update

So we'll start with kidney cancer and first we'll talk about Belzutifan. and it's, I have to say it's been amazing taking care of kidney cancer patients and seeing the evolution of the treatment of this disease over the last decade because all of the drugs that we have to treat kidney cancer, We're based on Nobel prize level work, which is pretty quite remarkable. So we all know that in states of hypoxia or pseudo hypoxia, where a vhl gene is, mutated, h accumulates in the cell and actually results in angiogenesis and proliferation. and, Belzutifan is a small molecule inhibitor of, H two Alpha. these are the data from the LITESPARK-001 – Phase 1  trial.

This was a trial that was conducted in heavily pretreated clear cell RCC patients. There were 55 patients that were enrolled on the trial. The median number of lines of prior therapy was three, and you could see that the objective response rate was 25%. The progression-free survival. 14.5 months, and there's currently a large Phase 3 that's looking at the role of Belzutifan in the refractory setting in RCC.

This trial has completed accrual and we are all eagerly awaiting the results. Belzutifan already has an approval in kidney cancer for patients with vhl-. so associated disease, hereditary via cell. , but not yet for sporadic disease. There are other studies that are looking at Belzutifan in other combinations. There's LITESPARK-003, which looks at Belzutifan in combination with Cabozantinib.

Associated Renal Cell Carcinoma

There were two cohorts that enrolled onto this trial cohort. One was for treating naive patients. doing. Belzutifan with Cabozantinib and the Belzutifan dosing was at one 20 and Cabozantinib dosing was at 60. In the context of this clinical trial however, they have different, slightly different mechanisms of action with regards to their toxicity profile, you don't get that t k I talks with the Belzutifan. It's mainly anemia and shortness of breath. And then cohort two was in prior IO treated patients. And we can see top line data here for cohort one. That was the treatment Naive again was 57%. Cohort two was 31. this trial is continuing to accrue patients and so I think, you know, we'll see about different combination strategies in, RCC.

So there's a frontline trial Merck 012, that's also accruing patients. we've heard some data at the, early, late last year about cosmic 313, which looked like triple therapy. In metastatic RCC, there are other triple therapy combinations that are being explored. This trial uses the backbone of lenvatinib and pembrolizumab and then adds to.

Bone Belzutifan, so triple of Len Belzutifan and then LePen plus CTLA four inhibition. So that trial is currently ongoing and there's also another trial looking at Belzutifan lenvatinib in the second line setting that's also occurring. And so I, I, I actually think that one may have near completed accrual, but, so these are additional studies of Belzutifan.

I think this is probably the next kit on the block if I had to guess renal cell carcinomas. So, a very exciting agent. All right. We'll talk about  the different strategies to target the immune microenvironment. So there's stimulatory and inhibitory immune checkpoints. There's novel cytokine based therapies to activate T-cell response.

There's also targeting of immune metabolic pathways. so there's a lot of interesting and novel   IO based treatments to be explored. We'll talk a little bit about which, we all are familiar with the data in melanoma. This was a phase 2/3 study, double blind randomized trial previously unresected  Or, previously, untreated unresected melanoma with a primary endpoint of, PFS.

Combination of Relatlimab plus nivolumab versus nivolumab alone

This trial looked at the combination of Relatlimab plus nivolumab versus nivolumab alone was a positive study leading to an FDA approval of this agent. There is a, study called Fraction RCC, which is a multi-arm open-label trial looking at various IO combinations in. RCC and, and Relatlimab is being explored in that context we don't actually have any data yet, and I failed to highlight. Relatlimab is a first in class, basically lag three inhibitor that basically restores the effect function of exhausted cells. And so I think this is potentially another promising compound in RCC we'll talk about SRF-388. SRF-388 is a first in class anti IL-27  antibody.

We know that the immune regulatory cytokine IL-27  upregulates inhibitory immune checkpoint receptors such as PD-l1, and then downstream proinflammatory cytokines. There is a Phase 1 trial that's currently ongoing, a Phase 1 first in hand with this agent. There's been some, there's multiple, That are enrolling on that study, but a little bit of a signal of some activity in the clear cell RCC dose expansion.

A hundred percent of patients had received prior IO and prior VEGF targeted therapy. And see some early signals of activity. So look for this agent. . And then, the other agent I wanted to highlight is ds, 6,000 a. this is a drug being made by Daichi Sanko, and I have to say there's a lot of excitement around there.

Cadherin 6

MADC pipeline. so this is a Cadherin 6 directed ADC, with three components. basically the monoclonal antibody that targets, CDH-6 and then your, cleavable linker. And then the payload here is a topo one  inhibitor. . so Cadherin 6 is involved in cell cell adhesion and epithelial mesenchymal transition.

Cadherin 6 is overexpressed in RCC and preclinical studies have demonstrated that its inhibition can lead to tor regression. And so this compound is  directed, right at this, target. And there's a Phase 1 study currently ongoing in RCC and ovarian. With some, again, early, very early preclinical data.

GU ASCO 2022

This is data that were presented at ASCO last year, and hopefully we'll continue to see updated data about this compound. . So I wanna talk a little bit about CA-9 and, we saw some data at GU ASCO just a couple of weeks ago that were presented regarding, imaging, with CA-9  with basically Ziron, Girentuximab.

There's also a therapeutic agent as well  that is in testing. So CA-9 is a cell surface transmembrane protein that's actually. Hypoxia and it's overexpressed in about 90% of clear cell RCCs and hypoxia and, and vhl laws can actually up-regulate CA-9 expression. It's very minimally expressed in normal tissue.

Ziron Trial

And, you know, it's expression can basically  well, it's, it's expression, like I said, is upregulated by  hypoxia. . So J Rituximab is a monoclonal antibody that basically binds to CA-9 and it's demonstrated safety in prior imaging and therapeutic studies. It's excreted through the hepatobiliary system and when it's linked to a zirconi payload, It can actually function like an imaging agent, you can imagine the zirconi. So this was a Phase 3 Ziron Trial  including 3000 patients demonstrating increased specificity and sensitivity for actual detection of small renal masses and being able to designate them as actually being, clear cell RCC. Now what's interesting is actually there's, you can, link the rituximab to Luteti and then it can actually function as a therapeutic agent, not just an imaging agent. And there are, two studies  that are actually currently ongoing here. I just highlighted. STARLITE 2. but, there's two studies that are currently ongoing with this agent given in combination with nivolumab in the second line setting and nivolumab Cabozantinib in the frontline setting, so I think that we're gonna see more about, rituximab, and its activity. There was previously some very old data that was presented like almost five or six years ago of rituximab and maybe Monty Pal, MD remembers the very old. Study that tested adjuvant during rituximab that just basically shut down.

But I, you know, I think that the dosing and, safety has been worked out and I think this is something to  be. , thinking about in the future, and I always get excited about the imaging here because, you know, you could imagine the role of, of more specific pet imaging tracer in the surveillance setting, for patients with, high risk of disease progression post nephrectomy, and, and, and could RCC evolve into an era like, like prostate cancer. I don. We'll see. All right, palbociclib. So palbociclib, you're probably familiar with it, since selective inhibitor of the Cyclin-dependent kinase 46, we know that the CDK 46 are canonically involved in, cell cycle, checkpoint control and dysregulation actually, may   and they're, they play have a dysregulated role in RCC and they could potentially serve as a therapeutic target.

Bill Kalan, MD and others

There's been some very elegant work that's been conducted by Bill Kalan, MD and his group, regarding the role of, CDK 4/6 in, inducing Lethal CDK 46 inhibition. In inducing synthetic lethality in RCC cell lines, specifically in vhl loss, models. And there's a phase two that's currently ongoing looking at palbociclib in combination with exit and nivolumab, for frontline, RCC, so more to come on the role of CDK4/6 inhibition and, and renal cell carcinomas, but certainly interesting. All right. So now we're gonna talk about prostate cancer. a lot of  interesting targets in prostate cancer. A lot of  interesting drugs. this is just like the tip of the iceberg of all the novel drugs that I think are.

Advanced Renal Cell Carcinoma

Being, looked at in prostate cancer. So just bear with me. so first we're gonna start with, continued targeting of the androgen receptor. So we know that ar alterations continue to be pretty relevant for people who have advanced disease, even in the setting of metastatic castration resistant disease, with regards to the genomic alterations that are seen, we can see ar amplifications in about 60% of individuals with metastatic castration. Resistant disease. There are splice variants where you basically lose the ligand binding domain and have a constituently activated androgen receptor. There's also AR mutations, and depending on the mutation that's, seen, there can be promiscuity of the different ligands binding to those muta, that receptors.

So whether it be, you know  progesterone or steroids or so forth, . And there's also potentially alternate ways of blocking testosterone. Here you can see that, we're all familiar with abiraterone, which is a C 17  liaise inhibitor, but you can actually block further upstream, in the pathway, and we'll talk about some of those strategies to be able to do that.

ARV-110

So, ARV-110 is a basically a prota, it's an androgen receptor degrader. It basically helps with targeting the androgen receptor ubiquitin it and basically degrading it in the proteasome. And there's been some very interesting data that's been presented about the activity of this agent, particularly in patients who have.

Antigen receptor, mutations and post-progression on drugs like abiraterone and enzalutamide. So there's  some excitement around this cuz this is  an unmet need in, in treating metastatic CRPC. You can see here this very elegant three phase preclinical study that was conducted where they treated patients with abiraterone with  the ARV-110 and then, they were just treated with abiraterone alone, and then the drug was reinstituted. And you can see in that Phase 3 section where there was real activity of, you know, efficacy, post-progression on these agents. . The other drug to highlight is ODM 208. This is a non-steroidal selective C 11 a inhibitor that actually blocks pretty high up with regards to  steroidal production, androgen production, and mineralocorticoid production within the adrenal gland.

And so when it's given, it's actually given mineralocorticoids and. Steroids as well, cuz you're replacing, loss from the inhibition. There was a phase two study that was conducted specifically in men with metastatic CRPC, having received a prior A R S I and a prior taxane. And you can see here,, there was a significant reduction in , You know, psa, that this is the PSA response waterfall pot.

It was like 53%, PSA 50 rates, which is pretty impressive. And all patients that actually had ar ligand binding domain mutations seem to have a response to therapy. The resistance response was 26%. You can also see the corresponding drops in cortisol, and Stein Dion. I think those are the. You know, this is basically inducing adrenal insufficiency, you know, in, in, the highest order, if you will.

Abemaciclib

So other drugs that are being tested in prostate cancer are abemaciclib. Abemaciclib is an oral CDK4/6 inhibitor that also has some activity at CDK nine. This agent is approved across the continu for patients with, ER positive  breast cancer. . And then there's actually three studies that have been ongoing of abemaciclib in  prostate cancer building on some very early preclinical work that you can see highlighted here from Karen Knudson's group and others, the Cyclone one study is looking at a very treatment refractory population of Abemaciclib as a monotherapy Cyclone 2 was, Basically, a phase two three study looking at abemaciclib with abiraterone in the frontline MCRPC study in patients that had never received a prior A R S I and Cyclone 3.

That study has completed accrual and hopefully we will be seeing results in the future. Cyclone 3 is a first line study being conducted in the metastatic hormone sensitive setting for patients with high risk disease where patients are randomized to Aira. Or placebo versus abiraterone and abemaciclib, and that study is currently ongoing.

Capivasertib

The next drug that I'll highlight is Capivasertib. This is a potent selective, a t p competitive inhibitor of all three AKT isoforms. There is a study that was published called the PROCAID Trial which looked at the combination of this agent with docetaxel and MCRPC and there did seem to be a signal of activity.

There's currently a large  phase three study that's ongoing. Frontline setting, looking at this agent in combination with abiraterone for patients with metastatic hormone sensitive disease. were familiar with the data regarding IPA AER in the metastatic CRPC setting. That study, you know, met its primary endpoint of PFS but was quite a toxic regimen and, and there was no signal of overall survival. And so, the EPA aib development has been halted in, prostate cancer research now. So we'll have to see sort of, how  Capivasertib AIB  pans out what happens with this study. And then DS seven 30. So this is a very exciting compound that I have a lot of excitement about.

I think, again,  building on the ADC model of Daichi Sanko. this is ADC, with a payload that targets B seven H three, and B seven. H three is highly expressed in prostate cancer and up other epithelial tors. it's in the same class of, receptors as actually pd. Suspected to function as a checkpoint, but we  don't know what it does. But nonetheless, it's a highly expressed agent in, in advanced prostate cancer. and even in hormone sensitive disease, I should say. but this is basically an ADC. , targeting, B seven H three, and there was some early preclinical or early data presented from the Phase 1 study last year at ASCO demonstrating p s a response and objective responses of this agent.

And so I think we're gonna have to see sort of what happens with it over time.

Prostate Specimen Membrane Antigen

All right. We can't have a prostate talk without talking about Prostate Specimen Membrane Antigen . I was gonna include some information about  Prostate Specimen Membrane Antigen  with kidney cancer, but I was not gonna have enough time. But Prostate Specimen Membrane Antigen , is a trans-membrane carboxypeptidase. It's highly expressed in prostate cancer. and particularly, Static lesions, you know, it's more so restricted, restricted , expression within normal tissue, it's an excellent target for pet imaging. . we've seen the data for, from the vision trial of, Lutetium  Prostate Specimen Membrane Antigen which is a beta emitting, you know, radioisotope that's linked to the small molecule inhibitor,  Prostate Specimen Membrane Antigen . There are other  Prostate Specimen Membrane Antigen  targeting compounds that are up there. This is the Lu-PNT2002  radiolabeled  Prostate Specimen Membrane Antigen  targeted small molecule inhibitor.

Splash Trial

This is the splash trial. It's a large Phase 3 that's currently ongoing and there's probably gonna be another me too  you know, agents  to , target PSMA. . And then, J N J oh eight one is a bispecific antibody that's binding  Prostate Specimen Membrane Antigen  and also CD three on T-cells. And there's a Phase 1 currently ongoing in dose escalation, and expansion with some early preclinical data, looking at, maxim PSA change and, it's interesting cuz this reg, this agent can be given subcutaneously or can be given intravenously and it almost seems to have a better, pharmacologic efficacy profile when given subq as opposed to given, intravenously. which is interesting. All right, so lastly, we'll talk about urothelial carcinoma, we're gonna talk about the Enfortumab vedotin + pembrolizumab data. We'll talk about Trastuzumab, Cabozantinib and . N-803. So Enfortumab vedotin is an antibody drug conjugate that targets nuttin four with a linker to an MMAAE payload. that's actually already FDA approved for the treatment of patients with, refractory urothelial carcinoma.

Enfortumab vedotin + pembrolizumab versus Enfortumab vedotin alone

We've seen some pretty exciting data about the combination of this agent when given with pembrolizumab. There was a large study large Phase 1 two studies. EV-103, which looked at this combination and in cohort K patients were randomized to  Enfortumab vedotin + pembrolizumab versus Enfortumab vedotin alone. not with an intent to compare between those two, allocations, but rather to understand, how Enfortab vedotin is performing in a cis ineligible frontline population and how the combination is performing.

The top line data were presented. ESMO last year, and  we saw tremendous responses. you know, over 60% response rate that seemed to happen independent of lectin expression. Over 86% of bladder cancer tors have lectin expression. The 12 month PFS here was at 55.1. this regimen is, Not to say so active, but you know, it takes a lot to challenge cisplatin in the frontline setting in, in bladder cancer.

Cisplatin has  been sitting on the throne for a long time as a, as a, you know, very highly effective agent for advanced. bladder cancer, but there's actually a large Phase 3 trial currently ongoing called Enfortumab vedotin 302. That's randomizing patients who  to cisplatin carbo cis, or carbo plus gem versus  Enfortumab vedotin + pembrolizumab, so most of the studies that are done are frontline. Have historically actually been done in a cisplatin ineligible population because of just the strong activity of cisplatin. So we're gonna have to see what ends up happening with this, and this'll absolutely change, how we treat patients with, urothelial cancer.

What's unique about this study, however, I guess one of its pitfalls is, it was designed prior to, the approval. Zab in the maintenance setting post cis platin carboplatin. So this study doesn't allow for maintenance maintenance checkpoint inhibition in the control arm. And so I think there's always gonna be that outstanding question about what to do for those patients.

Trastuzumab Deruxtecan

But this is a very exciting combination regimen to look out for. All right, so then, Trastuzumab deruxtecan  is an antibody drug conjugate that's comprising an anti HER two antibody, a cleavable linker, and a a topoisomerase one inhibitor payload. And in a, Phase 1 trial of selected patients with urothelial cancer who are actually seeing.

Signal of activity, objective response rates of 37%. You can see the spider plots there demonstrating response. This is in a targeted population. So I think that her two targets in, bladder cancer is something to look out for. and, certainly  potential for more personalizing care for patients with urothelial cancer.

And then I'll highlight the data regarding Cabozantinib. I will invite Monty up here to  give this talk, but give this portion of the talk, cuz I think he presented the data at ASCO last year. ,, the cosmic O two one study looked at Cabozantinib in combination with the Tocilizab, demonstrating modest activity.

You can see sort of this, this  ineligible cohort there. Rate of around 20%. The CIS eligible response rate is around 30% of patients who'd received a prior checkpoint inhibitor response rate around 10%. There is a large cooperative group study called Main Cav being chaired by, Dr. Shepa Gupta, looking at adding Cabozantinib in the.

Setting, post a stable, progressive disease, or response to platinum-based chemotherapy. so that is an important trial that'll answer an important question. And lastly, I'll highlight N-803. And while this is an advanced, tor  discussion, I think this, this agent is  quite exciting. It's, immune activating I L 15 superagonist.

And the data were presented at ASCO last year and are now published as well. demonstrating significant response rates. complete response. This is for a local non-muscle invasive bladder cancer cohort. A looked at patients who had evidence of, carcinoma and CSU demonstrating a complete or partial response, rate of 71% median duration of response.

Almost two years. And so this agent, I think, is currently under expedited review, by the FDA for, approval. This is  an unmet need for people with persistent and recurrent cys, post, BCG or BCG unresponsive disease. It's a real unmet. . All right. So that was sort of our whirlwind tour, with technical challenges of novel therapies in genitive urinary malignancies, this is just  just a little color of the things that are out there. There's  a lot more  cool drugs and agents to be looking out for. So many novel agents are currently in development across all genitive urinary malignancies. There's a novel. There's novel modes of drug delivery in RCC novel TKs.

Eyes and Strategies to target the VEGF H pathway are under development, and additional checkpoints are also being explored for prostate cancer. Continued targeting of the anti angio receptor, remains important for this disease. In addition to targeting novel, targeted therapy pathways such as AKT and CDK 4/6 and in urothelial.

Combination strategies of targeted therapy and immunotherapy are being explored. And additional novel intravesical therapies I think are something to look out for in the future. So, you know, it's exciting to see the landscape continue to evolve, and I'll take any questions like, share and subscribe here on OncologyTube. For notifications when similar videos are available.

Gastrointestinal Malignancies Research Advancements: Insights from Farshid Dayyani, MD

By Farshid Dayyani, MD, PhD

Thank you so much for inviting me to this meeting. I was asked to give an overview of research in GI malignancies, and I made 200 slides. Then I realized we have 25 minutes. I practiced this morning.  I can't do it in 18 minutes, so it will be a very concise, here's my disclosures. What I will try to do is I think I'll show you very recent data, let's say the past year or so, where I think the practice might change based on the data or trials where I think will contribute in to change practice very soon when we read out on the on the data in GI cancers, it will be, boom boom. But I think it will be informative. Let's start with G Junction. The first thing we had GI ASCO (for gastrointestinal malignancies) was the confirmation of the CheckMate 649 trial, where the 3 year follow up of the addition of Nivolumab to chemo backbone, FOLFOX showed a sustained benefit in terms of overall survival. But in all comers, but also in patients specifically with a CPS score of 5 or more overall survival, as you can see here, and that was also maintained with a progression-free cell survival. About 1 in 6 patients remained progression-free at 2 years with the addition of Nivolumab. What's new? What's new is the competitor studies, so to speak, with the other PD-1 inhibitor Pembrolizumab. That was very recently presented as part of the ESMO virtual plenary, the check KEYNOTE-859 trial. The chemo backbone was a somewhat different, it was a global study and the IV backbone was infusion over 5 days with Cisplatin or CAPOX  challenging in patients in Orange County who are younger, from underserved communities who have a higher rate of cignet cell, poorly differentiated and have difficulty taking oral. When it comes to using the backbone chemo here is here's for you, one way to try to overcome the issues, you either have to give your patients 5 days of infusional, 5 if you with a Cisplatin, or if they can't take POS, then they can't go on a trial. So I think these are things to think about if you want to really do drug development. So either way this trial was presented primary endpoint overall survival chemo with or without Pembrolizumab and strikingly in, in my view, even if you're not supposed to do trial to trial comparison, strikingly similar result as we see confirming the benefit of addition of checkpoint inhibitor, anti-PD-1 inhibition in gastroesophageal adenocarcinomas in the first line setting in intent to treat OS and PFS very similar hazard ratios to CheckMate 649 duration of response, 8 months response rate also in increased this is not published to my knowledge in manuscript form and we don't have the PDL one CPS subsets yet. But still positive trial for OS. So you have now more options. So what about targets biologics in the first line setting. If you think, for example, patients with a CPS score of zero who might not be derived for significant benefit of addition of checkpoint inhibitors here we had at GI ASCO (for GI malignancies) the SPOTLIGHT trial. Patients with CLDN18.2 strongly positive tumors were randomized to FOLFOX with ORT without Azo uxb. So CLDN18.2 tight junction protein that can get exposed in solid tumors especially in gastroesophageal tumors and other GI cancers. Zolbetuximab is a monoclonal antibody against CLDN18.2 SPOTLIGHT trial. Straightforward randomization patients were pre-selected based on CLDN18.2 over expression 75% or higher of the tumor cells, strong expression they were randomized to now a much more modern mollified, FOLFOX6 regimen backbone with or without Zolbetuximab. Primary endpoint was primary primary progression-free survival, which was clearly met as you can see, clear early separation, 50% progression-free at 12 months. Key secondary endpoint was overall survival, and that was also met. This is one of the I think other significant improvements in gastrointestinal cancers (gastric cancer) for CLDN18.2. Obviously we need to wait for a companion diagnostic to become routine and the drug to get approved. What you, what I didn't include here because that was just presented yesterday, or two days ago, is the GLOW trial. GLOW trial is a companion to that with a CAPOX backbone rather than FOLFOX. We're very similar, that also showed the significant benefits. So no matter if you use a oral Fluorouracil Oxaliplatin, or FOLFOX backbone, I think that's one option, especially if you think about patients who are CPS 0.

So what's next for gastroesophageal cancers (gastric cancer)? I think I wanna highlight, two interesting targets that might change practice soon. One of them you might have heard about be Bevacizumab is a IgG1 monoclonal antibody against the FGFR2b receptor, right? If you're treating GI cancer as heil cancers (gastric cancer), you're used to a lot of TKIs for FGFR2 translocation and fusions, this is for protein overexpression for the FGFR2b protein it's an IHC assay. The phase 3 trial was based on this phase 2 randomized trial the FIGHT that was presented by Dr. Weinberg from UCLA in 2 20 21 we're about 80 patients were randomized, one to one to FOLFOX or without BEMA, and what we saw is PFS primary endpoint was met, was improved with the addition of BEMA and overalls valve was also improved. But what I want to show here we learned from that trial that target expression matters. The higher the targets expression, meaning FGFR2b expression, they higher the relative benefit from the addition of the monoclonal antibody. So that has led to the FoRtitude trials, there's 2 randomized phase 3 trials in first line setting based on FGFR2b overexpression. So you have to pre-screen your patients and only with high expressors will be eligible. There's two trials, one of them is with FOLFOX plus minus BEMA, and the other one is FOLFOX NIVO plus minus BEMA. At UCI, we decided to participate only in one, so we minimize competition. It's called UCI 21-193. So you have a new patient with metastatic gastroesophageal adenocarcinoma, consider this trial for them. The good thing is the trial allows for one cycle of FOLFOX, with or without NIVO. While the patient is in screening, so if they're symptomatic, and certainly try to cool them off while you're standing out the tissue and see whether they're eligible for FGFR2b overexpression.

The other trial that I'm excited about is a monoclonal antibody about against DKK1, Dickkopf-1 is a modulator of the wind signaling pathway, very important pathway in GI cancers. Colorectal cancers, but also gastroesophageal carcinomas. Here again, the preliminary data was the run-in trial. Of the DisTinGuished trial with DK N zero one, that's the monoclonal antibody that blocks DKK1 combined with an anti-PD-1 antibody Tislelizumab withCAPOX in advanced disease. So we participated in that one, and as you see on the waterfall plot a very encouraging everybody, almost everybody had some sort of tumor shrinkage independent of. PD-L1 expression level. So that's what with the green and blue bars here. So that has led to what we call UCI 20-63, the DisTinGuished trial where patients are with untreated metastatic gastroesophageal adenocarcinoma are eligible to go on this trial. The good thing about this one is, so we have both the FoRtitude and DisTinGuish open. And the way we triage the patient is again, in this trial you can also give a cycle of FOLFOX. And while you're waiting for biomarker, if their FGFR2b overexpressed, they go on FoRtitude. If they're negative, they can go on DisTinGuish. The good thing about DisTinGuish is it stratifies based on DKK1 expression, but doesn't select for it. So really you can maximize trial accrual by I think appropriate trial selection that you open for your patients. I want to highlight something that's homegrown, it's an investigative trial at UCI is the STOPGAP trial that our great Dr. Maggie Senthil, our chief of surgical oncology is spearheading with myself. It's a phase 2 trial of systemic chemotherapy followed by intraperitoneal chemotherapy and IPEC CRS in patients with gastric cancer, peritoneal carcinomatosis, again, when it comes to overcoming barriers to care, trying to bring in inequity. Here at UCI for example, we have 60% Asian and Latinx population patients in our gastric cancer population 80% of diffuse type gastric cancers are in these minorities. And they typically have a very characteristic distribution pattern with early peritoneal dissemination, poor prognosis. If you look at chemo only data 9 months or less. So the concept here was that, full systemic control of the disease for the first 3 to 4 months. And that goes beyond FOLFOX, maybe a checkpoint inhibitor. If the patient is symptomatic, it can give them flat and we cite to reduce them, and then we do a diagnostic laparoscopy. And if the PCI peritoneal carcinomatosis index is coming down, it's in the 10, 15 range, then we will place an IP port, and give them 3 months of IP chemo with the Nab-Paclitaxel and IV 5 if you, which I adopted based on the PHOENIX-GC trial, the Japanese trials, and afterwards, if there's a PCI score is reasonable, let's say 11 or less, they go to HYPIX CRS and we render these stage 4 patients disease free. We are about 10 patients in, and our first patient enrolled is now 13 months out in ET. So this is a, the good thing about this trial is I wrote it in a way where you can submit patients at any time. They can have up to 4 months of systemic treatment before they're screened for eligibility. So anytime the first two, 3 months, if you have a patient with peritoneal carcinomatosis consider enrollment. 

What about colorectal cancers (gastric cancer)? I think clearly a third line option, the SUNLIGHT trial presented at GI ASCO (for gastrointestinal malignancies) a few weeks ago where TAS-102 was combined with Bevacizumab based on very convincing phase 2 data published in Lancet Oncology a couple of years ago. And just very briefly see early separation of overall survival benefit with the addition of Bevacizumab to TAS-102, these are strictly third line patients, versus TAS-102 alone, and a I think a robust OS curve as well that you see with the addition. I think that might be a new standard of care. If you don't have a clinical trial, you have to look for neutropenia, nausea, cytopenias that we already knew from the phase 2 trial might be expected adverse events (vomiting blood, difficulty swallowing, helicobacter pylori). What we did at UCI, we were trying to see whether beyond VEGF inhibition, if you target some of the operative pathways meaning cMET and AXL through a TKI in this case, Cabozantinib, that's another investigating shared trial we present at GI ASCO (for GI malignancies) whether we get some activity and whether it's even possible to combine TAS-102 with Cabozantinib. So we enrolled in 6 months, 15 patients. We did not have any MTDs, and we could show that TAS-102 at the standard dose, 30 milligram per square days, 1 through 5 and eight through 12, combined with the standard CARBO dose of 40 for combinations is tolerable, no MTDs. These are much more heavily pretreated patients than the SUNLIGHT study. So that's another option that you might think even beyond progression on Bev, whether you might have still some additional activity with this combination. 

Switching gears quickly to hepatobiliary cancers, just as a reminder we have now a new second standard of care in first line unresectable HCC with child p a or preserved liver function with the addition of TM and anti-CDL-1 antibody, CTLA-4 antibody, to Durvalumab, anti-PDL-1 in unresectable disease based on the HIMALAYA trial, very brief, the design patients, this is very randomized to the STRIDE regiment Treme times single dose plus DURVA for up to 2 years or Serafenib the trial met the primary endpoint. I think one of the things that is intriguing is the 3 year survival rate of about 30% in the STRIDE regimen compared to Serafenib. So that was that led to the approval of that regimen in the first line setting. What about earlier lines of treatment? Now we've have, we've completed systemic trials, randomized systemic trials for intermediate disease neoadjuvant, but two important adjuvant trial completed. One of them reported per press release. That's the one I'm showing you here, the IMbrave 050 used the IMbrave 150 ATEZO BEV regimen, that has been our standard of care to date until recently ATEZO BEV for 1 year as adjuvant for HCC, that's high risk, and the high risk criteria are shown below. These patients were randomized, one to one to ATEZO BEV for a year, or active surveillance. And what we've heard is this press release the trial met its primary endpoint, which is recurrence-free survival. So we are looking very much forward to seeing the full set of data. Hopefully at the one of the upcoming meetings to look at the magnitude, benefit the toxicities and secondary endpoints to make an informed decision of whether to offer patients with high risk disease in the adjuvant setting systemic therapy. At UCI, we have another investing issue at trial that has been ongoing. We are Dr. Abi-Jaoudeh, our chief of Interventional Radiology, and I, we are investigators on that study. Where we took the concept of synergy between a checkpoint inhibitor and an anti-VEGF for multi tyrosine kinase inhibitor in HCC and tried to synergize with local regional treatment. I know there is a proliferation of this study, but this study is called UCI 19-49. That means the concept I discussed with XLs is as a supporter in thousand in year 2018. So what we will do is unresectable, non-metastatic liver confined HCC undergoes induction with one dose of Ipi-Nivo, CTLA and PD-1 blockade. And then we will tase the primary tumor to try to kill as much as possible. And then we maintain the patients up to 2 years of Nivolumab with Cabozantinib. That's a combo that I think has better data in RCC than HCC, but certainly it has activity in that disease as well. Just here as an example, that's one of our patients with cryptogenic HCC, she's a retired nurse who presented to us in September of 2021 with this huge tumor that you see on the right side. AFP curve shown below. So we induced her and you can already see by May, by about 6 months, significant necrosis, calcification. We took her to surgery, so this tumor that should have never gone to surgery, went to surgery, 80% necrosis, that's the path report and her most recent MRI from last month, NED. I also show you some MRD assays, tumor informed MRD assays;, she remained in remission and is traveling right now. 

For pancreatic cancers, for the first time, we have a randomized phase 3 trial in firstly metastatic pancreatic adenocarcinoma where the comparator was not Gemcitabine. So this was the NAPOLI 3 trials where the NLI Reflux regimen Oxsali-5 few, with Liposomal Irinotecan was compared to the standard regimen Gemcitabine Nab-Paclitaxel. That was also presented by Dr. Weinberg at GI ASCO (for gastrointestinal malignancies) this year. Patients were randomized one to one to NAF Vir Nab-Paclitaxel with overall survival as primary endpoint, study was positive. Primary endpoint was met 11.1 months versus 9.2 months. Again, hazard ratio 0.83, and you also see improvement in progression-free survival in the intended to treat population. The toxicities are somewhat different. You'll have more diarrhea, nausea, as you would expect with a triplet regimen with the Lyposomal Irinotecan, but more neuropathy and cytopenias with GEM/Nab-Paclitaxel. So that could be regarded as one of these first standard of care options in the first line setting. If you don't have a trial. 

Switching gears,  HCC t o Cholangiocarcinomas again, as a refresher, the TOPAZ-1 trial was presented where GemCis with or without Durvalumab were evaluated in unresectable patients. And this was presented at ESMO, I think last year for the first time and now published as well. The OS PFS improved with the addition of Durvalumab, independent of PD-L1 expression. Numerically higher response rate as well about 26-27%. So I think that's one standard option. And then the other trial that we all were eagerly participating and in the crude in a really a record time by my former colleague Dr. Shroff at the University of Arizona SWOG 1815 trial where treatment intensification by adding Nab-Paclitaxel to GEM/CIS was evaluated. I took these slides out because of time issues, the phase 2 trial in JAMA Oncology was a very convincing, 80% disease control rate, 40% plus response rate, and this was reaching 20 months in this poor risk population. So we were very eager to see, and that was presented at GI ASCO (for gastrointestinal malignancies) this year, unfortunately, negative study, no improvement in overall survival, no improvement in progression-free survival. There were some secondary analysis that were, I think, thought provoking if you have intraoperative cholangio or non-metastatic disease, there seemed to be a benefit to the triplet over the doublet therapy, gallbladder cancer seemed to have some. I think there's still a hypothesis generating to see how you can move the field forward in HCC in terms of target therapies, I took the slide out for Tivantinib  and other EFGR-1 through 4 highly seritive inhibitor was approved recently for a FGFR2 rearranged cholangiocarcinoma.

I'm gonna summarize here, I think for first line gastro esophageal adenocarcinomas, anti-PD-1 is now validated plus chemo backbone. Question based on CPS score. What we don't see is a detriment. So if you look at anti-EGFR therapy and RAs mutated colorectal carcinomas, and you give the biologic, you actually see a detriment in outcome. What we don't see is, what we don't appear to see is detrimental outcome. If you give the checkpoint inhibitors, the hazard ratio might be 0.9, 0.95. But that takes me to the second bullet point. If and when anti-Cldn1 monoclonal antibodies are approved Cetuximab based on the trial I showed you, that might be an option for patients with CPS 0 who are CLDN18.2 positive. In third line, purely third Lamin metastatic colorectal carcinoma. If you don't have a clinical trial, the addition of BEV to TAS-102 improves OS PFS. You have to look for cytopenia, maybe even use prophylactic growth factors, first line unresectable HCC Child-Pugh A, liver, because that was part of the eligibility criteria for all these trials. In addition to Atez Bev, now we have Treme+Durva, a anti-VEGF free regimen in first line setting that's approved advanced cholangiocarcinoma. Gem/Cis is possibly the new standard of care until something better comes along based on TOPAZ-1, GCN, or GAP as we used to call it. Treatment anticipation does not seem to improve outcomes, but will have some higher toxicities. Metastatic pancreatic adenocarcinoma Nalirifox improved OS/PFS over GEM/Nab-Paclitaxel. That's all we have in terms of randomized phase 3, there's other trials ongoing, including at UCI, with second generation immune therapies and obviously trials are ongoing to address further needs. Just to keep it brief here, I'm happy to answer any questions and if you want to look for trials, UCI oncology flowcharts. I'll stop here and thank you for your attention. 

What is exciting in the landscape for Gastrointestinal Malignancies in clinical trials?

There are several exciting developments in the landscape of clinical trials for gastrointestinal malignancies. Here are a few:

1. Targeted therapies: The development of targeted therapies that specifically attack cancer cells is a promising area of research. For example, clinical trials are exploring the use of drugs that target specific proteins or genetic mutations in cancer cells, such as HER2 inhibitors for gastric cancer and BRAF inhibitors for colorectal cancer.

2. Immunotherapy: Immunotherapy, which harnesses the power of the immune system to fight cancer, has shown exciting results in gastrointestinal malignancies. Clinical trials are exploring the use of checkpoint inhibitors, CAR-T cell therapy, and other immunotherapy approaches for various types of gastrointestinal cancers.

3. Combination therapies: Combination therapies that combine different treatment modalities, such as chemotherapy and radiation therapy or immunotherapy and targeted therapy, are being investigated in clinical trials. These approaches may offer improved outcomes compared to single therapies alone.

4. Liquid biopsies: Liquid biopsies, which involve the analysis of circulating tumor DNA (ctDNA) or other biomarkers in blood samples (Eg blood tests), are an emerging area of research in gastrointestinal malignancies. Clinical trials are exploring the use of liquid biopsies for early detection, monitoring treatment response, and predicting treatment resistance.

5. Precision medicine: The use of precision medicine, which involves tailoring treatment based on a patient's individual genetic and molecular characteristics, is an exciting area of research in gastrointestinal malignancies. Clinical trials are investigating the effectiveness of personalized treatment approaches for various types of gastrointestinal cancers.

Overall, there are many exciting developments in the landscape of clinical trials for gastrointestinal malignancies. These advances offer hope for improved outcomes and a brighter future for patients with these types of cancers.

10 Key Takeaways about Gastrointestinal Malignancies

1. Gastrointestinal malignancies are cancers that develop in the digestive system, including the esophagus, stomach, liver, pancreas, small intestine, colon, and rectum.

2. These cancers are often difficult to detect in their early stages, which can lead to a poorer prognosis (if not found in the digestive sysetem).

3. Risk factors for gastrointestinal malignancies include a family history of cancer, a diet high in processed and red meats, smoking, heavy alcohol consumption, and certain medical conditions such as inflammatory bowel disease.

4. Treatment for gastrointestinal malignancies typically involves a combination of surgery, chemotherapy, and radiation therapy.

5. Advances in diagnostic imaging and biomarker testing have improved the accuracy of diagnosis and allowed for more personalized treatment approaches.

6. Immunotherapy, which harnesses the power of the immune system to fight cancer, is a promising new treatment option for some types of gastrointestinal malignancies.

7. Multidisciplinary care teams, including gastroenterologists, oncologists, surgeons, and radiation oncologists, are crucial in providing comprehensive care for patients with gastrointestinal malignancies.

8. Screening and surveillance programs can help detect gastrointestinal malignancies early in high-risk populations, such as those with a family history of cancer or certain medical conditions.

9. Lifestyle modifications, such as maintaining a healthy weight, eating a balanced diet, and exercising regularly, can help reduce the risk of developing gastrointestinal malignancies.

10. Ongoing research is essential in developing new and improved treatments for gastrointestinal malignancies and improving outcomes for patients with these types of cancer.

Farshid Dayyani, MD, PhD - About The Author, Credentials, and Affiliations

Farshid Dayyani, MD, PhD, is a highly accomplished physician and researcher who holds both an MD and a PhD degree from the University of California, Irvine (UCI). Through cutting-edge research in gastric cancer and clinical practice, he has spent his whole career trying to improve medical knowledge and care for patients.

Dr. Dayyani's research is mostly about coming up with new ways to treat cancer, especially blood cancers like leukemia and lymphoma. He has written a lot of articles that have been published in top medical journals, and he has been asked to talk about his work at conferences all over the world.

Dr. Dayyani is a well-known researcher, but he is also an experienced doctor who has cared for thousands of patients with skill over the course of his career. He is known for his caring way of taking care of patients and his dedication to using the latest medical technologies and techniques to help his patients get better.

Dr. Dayyani's many accomplishments have earned him a reputation as a leading figure in the field of oncology, both nationally and internationally. He has won many awards and honors for his work in medical research and caring for patients, and he is still a driving force in the search for new and better ways to treat cancer.

Lung Cancer Trials: Insights into Latest Clinical Trials in Thoracic Oncology - Expert Analysis from Ravi Salgia, MD

By Ravi Salgia, MD, PhD

Thank you. After that introduction, I think my time is over, we can take questions now. If I can have my first slide. So for today, it's a whirlwind of a talk to talk about lung cancer and we've certainly come a long way, but I'll try to emphasize EGFR, KRAS, ALK and immunotherapy for non-small cell lung cancer. Lung cancer, as is a quite devastating illness. I've been in practice for over 33 years now and been practicing thoracic oncology and we know that it can metastasize to any organ. These are some of these representative examples and it is the leading cause of death. And unfortunately, about 2.2 million new cases will be diagnosed and 1.2, 1.8 million deaths worldwide, which is just quite devastating. And we need to make a difference in the context of lung cancer. And it's not just about smoking. We live in California, not too many smokers or a lot  former smokers potentially. But we are seeing non-smoking population with lung cancer, and that's really important for us to realize not only is it a worldwide issue, it's a United States issue, as well as, you can appreciate, it's the number one cause of death among cancers for men and women. So it is also a woman's disease as well. 

Over my career, we know that lung cancer has come a long way in terms of its classification. Initially it was just one disease. Then we had mis subtypes, histologically, be it non-small cell lung cancer and small cell lung cancer. Then adenocarcinoma, squamous cell carcinoma, large cell carcinoma, and small cell carcinoma. But then precision medicine really has defined further what lung cancer is and should be and how we should potentially treat. So we know that there's a lot of heterogeneity. I really don't consider lung cancer as lung cancer anymore. It's a cancer that arises within the lung with molecular abnormalities, with non-genetic abnormalities, with proteomics abnormality, and we have to be able to realize that this is a compilation of the data set from City of Hope, where we were able to look. The gender, race, smoking age ethnicity, as well as the various mutations that can occur. And in this tile plot, you can truly appreciate that we see a lot of EGFR patients here in Southern California, but we also see a lot of other patients with other molecular abnormalities such as KRAS or ALK. And these are some of the things that we'll talk about in a few minutes. I think if you can really understand this slide, this lecture is over. And truly what we wanna be able to say is there are so many different therapeutic strategies we utilize lung cancer, molecular evolution is incredibly important, the tumor heterogeneity is incredibly important, and these slides certainly are all available to you and I'm happy to share them as well. But you can appreciate in the non-squamous cell condition. Predominantly for adenocarcinoma, you can have EGFR mutation, but you can go down that pathway and to be able to say, are there EGFR mutations in Exon19, or Exon21 or Exon20? And there are also N-terminus Exxon deletions that can occur or abnormalities that can occur that we're identifying ALK fusions. There are over 15 ALK fusions known, and how do we challenge ourselves to the therapeutic decision making? ROS1, METex14, quite important in the context of how we decide therapeutics NTRK, BRAF, RET, and then we also have to look at the PD-L1 expression. How important is that in the context of non-therapeutic targets and then coming up with the immuno-oncology and immune-therapeutics themselves. And we'll talk about a few of these as well. 

So let's talk about EGFR first. EGFR is a receptor tyrosine kinase located on chromosome seven. It's very important as a tyrosine kinase, as the engine of the cell, and it interacts with many other receptors itself, such as the ErbB family, but it also interacts with MET and other receptor tyrosine kinase. But the systems' biology, as you can see in the circle, is you can have a Ras/Raf pathway, B activated, PI3K activated, STAT pathway activated, but ultimately genetic alterations that can occur that leads to increased proliferation, decrease apoptosis, increase invasion, increase metastasis, and that's why EGFR therapeutics was quite important for us, as we discovered in the context of non-small cell lung cancer. First generations were Gefitinib and Erlotinib. Many of you have experience with that. Then it was Afatinib and Dacomitinib. And thereafter, Osimertinib, Lazertinib has not been approved here in the United States, but certainly in South Korea. And now we have these fourth generations, such as the blue drugs themselves.

Here's a timeline of FDA approvals. I won't read this whole slide, but to be able to say EGFR was identified as a receptor kinase in the 1970s. And at the same time, the tyrosine kinase domain mutations were identified, which led to therapeutic targeting, and we're quite excited that we have all of these options available, such as Erlotinib, Gefitinib, Afatinib, as well as Osimertinib and others that are coming to fruition. So what are some of these options for some of our patients? We know that osimertinib is a first line option for common EGFR mutations, and the most common EGFR mutations one has to consider is L858R, and Exon21, as well as Exon19 deletions. And you can see this in the survival curve, as you can see on the ordinance, is the overall survival on the emphasize, months to randomization and the curves do separate with a hazard ratio of 0.8. It's also important to realize in a lot of artificial intelligence is going into that, that p53 alteration can inhibit sometimes the Osimertinib responses as well. p53 alteration with RB alteration can lead to small cell or neuroendocrine phenotype after certain months of Osimertinib. So you have to be considerate and cognizant of that for your patients, and then even in Exon19, not all Exon19s are created equal. You can have the 746 versus the 747, you can have the L-P abnormalities in Exon19. And all of those, we really take into account in our clinical decision making, sometimes we not only give Osimertinib as a first line, but we tend to combine it with chemotherapy as well, depending on the p53 and which domain of p53 is abnormal. Again, more and more new data is emerging that we have to be cognizant of that. We also know that Osimertinib has been approved for adjuvant non-small cell lung cancer. You can see the curve separating on the left. In terms of the d f s on the ordinance on the left, as well as with stage IB to 3A on the right end, panel B, it's quite significant and we utilize that in our clinical practice as well. But we talked about L858R as Exon21. We talked about Exon19, but there are different Exons that can be abnormal. Most recently, the code is being broken for Exon20. So Exon20, not all Exon20s are created equal, but certainly. Agents such as Mobocertinib, as you can see here, has been FDA approved, as well as, Amivantamab that has been FDA approved as well. However, there are issues in terms of they don't have as much of response in terms of duration of response as compared to agents such as osimertinib. And we have to be cognizant of that. We also know that we might have to combine it with chemotherapy in first line setting, and those lung cancer trials are actually ongoing. But I think the most important message, if I can send out today, is there are genetic and non-genetic alterations as mechanisms of resistance. We have to be aware of, we've all been taught, or we've all been ingrained to be able to say that there are genetic alterations. So as an example, With Osimertinib, you can have a C797S abnormality, you can have RAF fusions. You can also have MET amplification about a third of the time with Osimertinib. But those are all genetic changes. But what we didn't appreciate except starting from the past few years, we're starting to appreciate their non-genetic mechanisms of alterations. So MET expression itself, so protein expression can be abnormal. There are, you can see in this cartoon diagram, oncogenic EGFR mutation, genetic I just talked about, but the non-genetic, you can have cell phenotype changes. So going from non-small cell lung cancer, yeah, to small cell lung cancer or sarcomatoid or spindle cell cancer or squamous cell carcinoma, and those are important. You can have MET expression IGFR expression. You can also have this phenotypic switching. That's really important in the plasticity, so keep that in mind as we go forward. I think some of you might have seen CNN a few days ago, and then there's a lot of hype in terms of having colorectal cancer in young patients, but they're really not genetic abnormalities, but it really points to these non-genetic abnormalities we have to pay attention to as well. So what can we do? Dr. Budde is absolutely correct in the sense of we should be able to enroll patients on lung cancer trials. Many of you have those here in Southern California and across the nation and across the world. Again, this is a laundry list. I don't expect everyone to read this, and there's no quiz at the end, so don't worry.

But at the same time, we know that we need to go forward and we need to be able to still cure non-small cell lung cancer in the metastatic setting. And in a TKI setting, you have lots of resistance where you don't really see cure, but control. But then at the end of the day, how do you define cure? If a patient has no evidence of disease after 7 years or 10 years of getting Osimertinib, is that a cure or is that a control? And I think we need to redefine some of the definitions we have. So going beyond EGFR is a receptor tyrosine kinase. We know KRAS, the code has been broken, especially for G12C. We know that there are a lot of KRAS abnormalities that can occur and we clearly know G12C is important, but so is G12D and G12V, Q13 is important, Q61 is important, Q146 is important for KRAS. These are all important in terms of your decision making for precision medicine and personalized medicine. And here's just a summary of some of this data that occurs. Within the various tumors as well as within lung cancer itself. We know that there are a number of therapeutic approaches one can use, such as the neoantigen vaccine that has been used by the NCI. Direct KRAS inhibitors will talk about that in a minute, but we also know downstream signaling is important.

So phosphatase such as Shp2 (phosphatase 2), that's a 68 kilodalton protein, that's important as a downstream for KRAS, but we also know that you can have other downstream signaling molecules that you can target, such as Paxillin, which is a focal adhesion kinase downstream target. At the same time, ICIs work pretty well for KRAS unless you have other abnormalities such as MDM2 amplification or STK11 abnormalities or other abnormalities that we, or KEAP1 abnormalities as an example. So here are some of these lung cancer trials that are ongoing, and you can find them certainly in Southern California as well as throughout the country. . But at the same time, we know that these KRAS inhibitors work and they work well, but only up to a time.

And then I come back to that mechanisms of resistance with KRAS inhibition that we have to pay attention to as well. So here's the first study that was presented. Phase 1 was done and then thereafter phase 2 was reflected in, Sotorasib. But you can appreciate the median progression-free survival is only 6.8 months. This is second line type of study and we have to be really be aware of this because even though this was breaking the code, but it's not good enough for us and we have to continue to do go forward in this context. Similarly, at Adagrasib at very similar results, you can see that the median progression-free survival on the right is 6.5 months. And the overall survival is 12.6 months. Again, our patients deserve this drug, no question, along with Sotorasib and other drugs that are being developed. But in my mind having practiced for so long, not good enough, and we need to make it better for our KRAS patient. So here's the dilemma we all have, many patients, if not all, may develop resistance. So how do you define these resistant mechanisms? You have to think about genetic resistant mechanisms and genetic resistant mechanisms in KRAS for non-small cell lung cancer. If you read the papers that have come out in Nature as well as namely Journal of Medicine, especially for Mark Awad and other colleagues over at the Farber. You see That in non-small cell lung cancer, you don't really have these genetic abnormalities except for other KRAS mutations that can occur or MET amplification That can occur, but that only happens in about 10 to 20% of the time. So that leaves us to non-genetic mechanisms of resistance, and we need to pay a lot of attention to that and be able to overcome that. Again, on the right is a cartoon diagram that shows this primary resistance versus acquired resistance, but the genetic non durable response in a tolerance state and then acquiring resistance is quite important. I emphasize this continuously because people ask us is, what is the future for non-small cell lung cancer? It's really understanding the mechanisms of resistance and overcoming it. De novo or Ipso facto after therapy itself. We also know that there are large number of lung cancer trials that are ongoing and there are PAN KRAS inhibitors that are G12C inhibitors. A number of inhibitors will come for G12D as well as G12V, but then we have to worry about the other codons as well, like I said, like codon 13 and 61. So all of these studies are ongoing and we're very much looking forward to the various trials themselves. 

So we did EGFR, we did KRAS, I think this is a whirlwind tour. We're going across the country and across the world, and we've just really talked about a lot of discoveries that have been made, but ALK has been one of the greatest discoveries as well. ALK fusion such as EML4, ALK occurs on chromosome 2p that was initially described, in a Japanese patient by Dr. Noda and colleagues in their Nature paper, where they showed in a young Japanese male with a cignet ring cell phenotype that had an EML4 ALK, a fusion and responded ultimately to a TKI, and Crizotinib was the first TKI that was discovered. Crizotinib, as you remember, is, was used to be known as PFO2341066, and I remember that because 1066 is the battle of Hasting. So any history fans can really appreciate true chemistry that gets developed and how things get named as well. So when ALK rearrangements can be detected by fish, by NextGen sequencing, by meniscus chemistry, but you can see these ALK fusion partners. It's not just EML4 on the right, but it's KIF5B, TFG, and others. And do they respond to the therapeutics versus non therapeutics is a very big question as well. Here's the timeline for alk inhibitors. Timeline for ALK inhibitors was incredibly fast. So as a timeline for met, which I don't talk about, we initially discovered the MET Exon 14 in really 2001, but therapeutic fruitions really came over the past decade or so. That was a long-term discovery. Whereas ALK discovery was initially, like I said, was described by Nota and colleagues in 1994, and then EML4 ALK was rearranged, I'm sorry, the 1994 was anaplastic large cell, but nothing happened for non-small cell until 2007. And then certainly we were quite involved and I was one of the first ones to help write the protocol for Crizotinib, and we got that approved through the FDA after only a phase 1 clinical trial. Crizotinib was a great drug except it didn't cross the blood-brain barrier as well as we should have. You see these millary pattern of brain metastases that can occur in out positive tumors. We also see that the potential for metastasis in a tumors is completely different as compared to other tumors that we see. So they can actually go onto the  ANXA so you can have it metastasized to the uterus, to the ovaries that we've seen. It can metastasize to the stomach, it can metastasize to the peritoneum, and you can't really reproduce that in the mouse model. It's only the human model that you see that as well. And then certainly a lot of other drugs have come to fruition. We'll talk about right now is to be able to say that you have Crizotinib then Ceritinib, Alectinib, Brigatinib, Lorlatinib, and at the same time, Lorlatinib has been really powerful in terms of its overall response rate as well as overall survival and PFS. And certainly that's one of the drugs that one can use. And here's one of the rationale for utilizing Lorlatinib in the first line setting, but it can be used in second line, third line setting as well. There are many mutations that occur. I tend to, when we have fellows as well as students in the room with us, with patients without positive tumors or EGFR. We always say you have to really know these mechanisms and the therapeutic responsiveness. And at the same time, you have to be able to have a cheat sheet with you in the clinic room to be able to say it's an ALK fusion, but it's not an EML4 ALK. And how should we choose our drugs? And these are some of the ways that we can do that by preclinical data selections as well. Again, mechanism of resistance, genetic versus non-genetic. Genetic. You can have gatekeeper mutations that are important, and it's very important to do your liquid biopsies, your biopsies, do next gen (NGS) sequencing after disease progression for patients so that you can really select out these drugs. Again, this is a little bit more complex in terms of signal transduction, but the theme is there. The theme is that you can have genetic alterations and you have to be cognizant of that, and then you can give therapeutic re therapeutics based on that. The non-genetic is tougher because we don't understand it at this point, but certainly if you have MET overexpression, you can think about other drugs that are being developed for MET as well.

So last thing I wanna talk about is immunotherapy. Again, not enough time to talk about everything, but we all talked about earlier today, PD-1 as well as anti PDL-1, quite important. And here's the timeline for various approval. Lung cancer, it's great. When I started my career, it was Carboplatinum, Paclitaxel, and Hospice (or palliative care). You didn't know who was gonna respond, who, and you even had phenomenal colleagues who were able to do biopsies such as radiology or surgery or pulmonary. But they would tell the patients, oh, don't go to the MI oncologist, just go to hospice if you have stage four disease. Been there, done that. And so fast forward 30 years now, and we have so many incredible approvals for various drugs for non-small cell lung cancer. That it represents the paradigm for precision medicine and clearly the overall survival and the PFS for chemotherapy IO versus IO alone is reflected here. But I wanna show you what has happened with all these clinical trials for immunotherapy itself. So as an example for Keynote-189, that was chemotherapy or immunotherapy, chemotherapy, and you can even see 5 year survival. Who would've thought in our career that we can say, talk about 5 year survival and cure for metastatic non-small cell lung cancer? I think small cell is still a holy grail for us. We need to put a lot of time and effort into it, but at least a large subset of non-small cell lung cancer can be targetable or they can get immunotherapy and you can have nice responses as well. And that's a huge thing for our patients. But not only is Pembrolizumab approved, but Daratumumab, Ipilimumab in combination has been approved either by itself or in combination with chemotherapy. As you can see from these graphics themselves, Cemiplimab is the new kit on the block as well, and that has been approved for first line setting as well. And this is the EMPOWER-Lung 3 data set, which is reflecting this 12 month overall survival versus the PFS, and clearly you can see the separation of the curves themselves. Most recently you also had Daratumumab and Tremelimumab that got approved, and that also brings to a point that you can have negative predictor for immunotherapeutic responses to STK11 or KEAP1. Sometimes MDM2 amplification and there can be hyperprogression with your patients who get this immunotherapy. That's very clear and it's not like melanoma where one can say there's pseudoprogression in non-small cell lung cancer. I really don't see pseudoprogression. We really see hyperprogression, so you have to keep that in mind, but can that hyperprogression be overcome by combinations of anti CTLA-4 as well as anti PD-1 or anti PDL-1? We tend to believe so, but a lot of this can be retrospective data analysis and we need to do a lot of prospective analysis. Here's a, again, a summary diagram that we adopted from the Reck article, but then added on, you can have monotherapy such as Pembrolizumab, Atezoluzumab, Cemiplimab, or combination therapies, and more and more are coming to fruition as you go into FDA approval. And then we updated this in November, 2022, previously with the Cemiplimab chemotherapy as well, Durvalumab and Tremelimumab and chemotherapy, and again, more and more is coming. And how do you make a decision? You really have to make that personalized decision. You not only have to take into account the gender, the performance status and others, but you have to take the molecular abnormalities into account as well. So here's a, again, a simplistic first line treatment algorithm. Take it with a grain of salt because I may follow it and I may not follow it. And it really depends on your decision making in that clinic. It's nice to have all these clinical trials, but we don't really incorporate the geriatric populations into clinical trials, that's important. We don't incorporate the poor performance status patients into our decision making. We don't incorporate somebody who has thrombocytopenia or let's say nephrotic syndrome and how we should deal with that. How do we deal with perineal plastic syndrome? Those are all realities in our clinical decision making. So at least what one can think about is non-small cell lung cancer treatment algorithm. Are they PD-L1 less than 50% or PD-L1 over 50%. We can have large argument, is it the 22C3  versus the 28A versus the SP of 142 versus the SP263. These are all immunohistochemistry antibodies and which one is the right one to utilize? At least this gives you a little bit of a sense if you were to follow some guidelines that these are some of the things to be able to say immunotherapy by itself versus immunotherapy in combination versus in combination with anti CTLA-4. Again, the field is gonna get even more complex and that is to be able to look at the current and potential therapeutics in non-small cell lung cancer. And you can see all of these drugs that are being developed, all of these pathways that are being considered. And you have to think about it in an early stage two, do you combine that with radiation therapy? Do you combine that ipso facto surgery? Do you do pre therapy before surgery? So like neoadjuvant, which I didn't talk about, and that's here to stay as well. And so as you think about non-small cell lung cancer itself, It's a very heterogeneous disease. Dr. Budde presented very nicely lymphomas and there are so many different types of lymphomas. Same thing with sarcomas, same thing with non-small cell lung cancer. And there are a number of actionable targets giving better PFS and OS, and the mechanisms of resistance are very important to understand and we need to be able to sentence all of our to sequence all of our patients themselves. I say all of this data in a very quick fashion. I'm actually on time itself, but I also feel like I'm a reporter. I'm reporting on the activities for City of Hope for all of my colleagues. I want to thank all of our colleagues. Many of my colleagues are here from City of Hope and obviously from other places as well. So nice to see everybody and we should take a group picture if I can suggest something. And at the same time, our laboratory is very important as well for the structure function, mechanisms of resistance. So I do want to thank the organizers for inviting me, and thanks to the board as well. And thank you all for coming as well, and I'm happy to take questions.

What is EGFR, KRAS, ALK and immunotherapy for non-small cell lung cancer (NSCLC)?

Non-small cell lung cancer (NSCLC) is a common type of lung cancer, and several molecular targets have been identified that can be exploited for therapeutic purposes. Among these targets, EGFR, KRAS, and ALK mutations are the most common, and recent clinical trials have explored the efficacy of targeted therapies against these mutations. Additionally, immunotherapy has emerged as a promising approach for treating NSCLC.

EGFR mutations are present in approximately 10-15% of NSCLC cases and can be targeted with EGFR tyrosine kinase inhibitors (TKIs) such as erlotinib, gefitinib, and osimertinib. These agents have demonstrated improved progression-free survival and overall survival in patients with EGFR-mutant NSCLC. However, resistance to EGFR TKIs can develop, and new strategies to overcome this resistance are under investigation.

KRAS mutations are present in approximately 20-25% of NSCLC cases, but effective targeted therapies for KRAS-mutant NSCLC have been elusive. Recently, efforts to develop KRAS inhibitors have shown promise, and early clinical trials of KRASG12C inhibitors have demonstrated clinical activity in a subset of patients with KRAS-mutant NSCLC.

ALK rearrangements are present in approximately 5% of NSCLC cases and can be targeted with ALK inhibitors such as crizotinib, ceritinib, and alectinib. These agents have shown efficacy in both treatment-naive and previously treated patients with ALK-positive NSCLC.

Immunotherapy has also emerged as a promising approach for treating NSCLC. Checkpoint inhibitors such as pembrolizumab, nivolumab, and atezolizumab have demonstrated improved overall survival in patients with advanced NSCLC, particularly those with high levels of PD-L1 expression.

In summary, targeted therapies against EGFR, KRAS, and ALK mutations have demonstrated efficacy in NSCLC, and efforts to develop new strategies for overcoming resistance to these therapies are ongoing. Additionally, immunotherapy has emerged as a promising approach for treating NSCLC, and further research is needed to identify predictive biomarkers and optimize treatment strategies and be aware of possible side effects.

Ravi Salgia, MD, PhD - About The Author, Credentials, and Affiliations

He then did a fellowship in hematology and oncology at the University of California, Los Angeles (UCLA). During this time, he became very interested in thoracic oncology. He then did a fellowship in hematology and oncology at the University of California, Los Angeles (UCLA). During this time, he became very interested in thoracic oncology.

Through his groundbreaking research and clinical work, Dr. Salgia has worked hard to move the field of thoracic oncology forward over the course of his career. He has written many papers that have been published in the New England Journal of Medicine, the Journal of Clinical Oncology, and Cancer Research, among others. He has also been asked to talk about his research at many national and international conferences.

Dr. Salgia's clinical expertise is highly sought after, and he has been recognized as one of the top oncologists in the United States by Castle Connolly and U.S. News & World Report. He is also a member of many professional groups, such as the American Society of Clinical Oncology, the International Association for the Study of Lung Cancer, and the American Association for Cancer Research.

At the City of Hope, Dr. Salgia serves as the Chair of the Department of Medical Oncology & Therapeutics Research as well as the Associate Director for Clinical Sciences in the Comprehensive Cancer Center. In these roles, he is in charge of overseeing clinical trials, coming up with new treatments for cancer patients, and giving his colleagues expert advice.

Overall, Dr. Ravi Salgia is a highly accomplished and respected physician-scientist whose work has had a significant impact on the field of thoracic oncology. His hard work to improve cancer treatment and patient outcomes has won him the respect of his colleagues and the thanks of many patients and their families.