Thank you so much. For the opportunity today, I'm Misako Nagasaka, I'm from UC Irvine, in thoracic (clinical) oncology. Today, I will be talking about updates from ASCO 2022 (lung cancer), but in the interest of time and because of my interest, I will be focusing my talk on lung cancer for targeted therapies for (advanced) non-small cell lung cancer. Here are my disclosures.
So here is a table that Dr. Ho has kindly shared with me. And I have to update it a little more because the last one, HER2 mutation Fam-Trastuzumab Deruxtecan got FDA approval on August 11, just 2 weeks ago. So the title of this slide, I should have taken off, and potential in the parenthesis, but I think this is a perfect slide that gives us an overview of all the targeted mutations or alterations we can detect in lung cancer.
And we have treatments for today. I will be mainly talking about KRAS EGFR Exon 20 insertion mutations c-MET and HER2, which are all relatively new Biomark. So here is my agenda. Kreon 20 insertions c-Met, and HER2 for KRAS. I will be talking about the 4 abstracts that were presented at ASCO (2022 lung cancer).
One on sotorasib resistance, one on Adagrasib (medicine) overall efficacy and safety. Another one on Adagrasib and CNS data. And then VS-6766. This is a very interesting agent that I'll be talking about for EGFR exon 20. I will be discussing CLN-081, which I think is a very interesting drug in the sense that the tolerability appears to be improved compared to other agents in this.
In the setting for cMET, I'll be talking about new data coming from Amivantamab and Teliso-V (medicine). I hope I'm pronouncing that right. And for HER2, this wasn't updated in ASCO (2022 lung cancer), but I thought going over the new indication for Trastuzumab Deruxtecan and for lung cancer would be important. For KRAS, I will start with discussing Sortorasib.
But first, KRAS G12C mutation is found in approximately 13% of lung cancer, 3% of colorectal cancers and appendix cancers, and one to 1 of other solid tumors, as we know. So is a small molecule that specifically and irreversibly inhibits KRAS G12C by permanently locking it in an inactive GDP-bound state.
Here is the (new) data that led to the accelerated FDA approval of Sortorasib (medicine). The objective (pathologic complete) response rate was 37.1% disease control rate was 80.6%, and the median progression-free survival was 6.8 months in ASCO (Annual Meeting, 2022 American Society of Clinical Oncology) this year. The largest evaluation of acquired resistance to Sortorasib in KRAS G12C mutated (advanced) non-small cell lung cancer, and colorectal cancer was presented.
The subjects in this study had submitted their plasma prior to study entry. And at the time of their progression, here are the key results, 31 acquired alterations were detected in 19 28% of patients (participants) with non-small cell lung cancer. And as you can see from the pie chart on the right, the most common was receptor tyrosine kinase, gene alteration, or RTK alteration.
The second most common was PI3K/Akt/mTOR pathway alteration. And the third was secondary RAS, alteration, and other changes. in patients (participants) with KRAS G12C mutated non-small cell lung cancer, RTK mutations were found to be the most common mechanism of CARD resistance. And I agree with the authors of this abstract that further research is warranted on the combination of Sortorasib plus tyrosine kinase inhibitor.
The next 2 abstracts are going to be on Adagrasib (medicine). The first one is for Adagrasib's overall (progress of) safety and efficacy (benefit outcomes). The second one is on CNS data. KRYSTAL-1 was a study similar to the CODEBREAK study for Sortorasib that evaluated the safety and efficacy (benefit) of adding Adagrasib patients with metastatic advanced non-small cell lung cancer with G12C mutation.
The primary endpoint was the objective response rate, and the secondary endpoint was, and endpoints included duration of (pathologic complete) response, PFS (progression-free survival), and OS. And here are the key results. The objective response rate was 43% in 112 patients who traded without aggression. The median overall survival was 12.6 months, 6 months.
Overall (progress) survival was 71%, and median progression-free survival was 6.5 months.
Here are the key results on safety. Like Sortorasib, GI toxicity, such as diarrhea, nausea, and vomiting, was most common in patients with metastatic non-small cell lung cancer, and KRAS G12C mutation Adagrasib showed anti-tumor activity and a manageable safety profile.
The second ASCO 2022 lung cancer abstract on Adagrasib was on its CNS activity, which I believe is a very important endpoint in those with lung cancer. As shown here, the intracranial response by BICR (mRANO-BM) and active untreated CNS METwere 32%, and the disease control rate was 84%. Some significant size decreases were shown on the waterfall plot on the right.
Although some had non-target lesion progression and thus were not categorized as PR or CR.
They also reported CNS-specific treatment-related adverse events, including dizziness in grades 1 to 2, aphasia, and insomnia. In conclusion, in patients with non-small cell lung cancer, harboring KRAS G12C mutation at an aggress demonstrated, encouraging, and durable CNS. Specific activity, including untreated and untreated CNS metastasis, while the numbers reported from this abstract were still small.
I believe that seeing early CNS activity with Adagrasib is promising. The last study that I wanted to mention for KRAS was the study on VS-6766, which is a RAF/MEK clamp agent, and was used in combination with Everolimus to treat non-small cell lung cancer with different care as variants. The primary endpoint was safety, and the secondary endpoint was anti-tumor activity.
The total number of patients valuable for the response was 11, a little small. However, as you can see from the spotter plant, there appears to be potential activity in G12V and G12A, which is very exciting.
The drugs appear to be well tolerated. And in this heavily pretreated patient with KRAS mutant non-small cell lung cancer, VS-6766 plus Everolimus demonstrated activity and was generally well tolerated. This is a potentially interesting combination moving on to our second target. I'd like to switch gears and talk about EGFR exon 20 insertions.
As EGFR exon 20 insertion mutations are the third most common EGFR alteration. Following EGFR exon 19 deletion and L858R mutation. It occurs in about 12% of EGFR mutated patients. Here is a figure showing the sites of mutations. Currently, the standard of care for EGFR, Exon 19 deletion, and L858R mutation is (adjuvant) Osimertinib, but Osimertinib does not bind to Exon 20 insertions well. There is a significant overlap in confirmation between EGFR for Exon 20 mutations and wild-type EGFR in the ATP binding pocket, which is why osimertinib lacks selectivity against EGFR for exon 20 insertion mutations.
And also the reason why EGFR for Exon 20 in insertion inhibitors tends to cause easier wall-type related adverse events, such as ration. Here are three things to know about EGFR for Exon 20 insertions. Again, it is the third most frequent EGFR for mutation after the common mutations, L58R an Exon 19 deletion. It is insensitive to EGFR TKIs, a traditional one due to steric hindrance at the TKI bonding site, and Amivantamab and Mobocertinib are approved post platinum.
First, let me just go over Amivantamab is an anti-EGFR MET by specific antibody, and monotherapy activity in patients has been seen in diverse EGFR mutant diseases, including EGFR for exon 20 insertions. This was reported in World Lung in 2020; the (progress of) overall response rate was 40%, and the median duration of response was 11.1 months.
Here is a slide on the adverse events. As you can see safety profile was consistent with inhibition of EGFR MET pathways. So for EGFR-related reactions, there were rash, paronychia, dermatitis, and pruritus; hypoalbuminemia and peripheral edema were commonly reported for MET-related adverse events. The other important adverse event to be aware of this (new) drug is the infusion-related reactions that occur most commonly.
The first time the patients are given the infusion. However, with supportive medications like Benadryl, Demerol, Dermatol, and all that stuff usually, the patients are able to continue subsequent therapy, and usually, the next time or the third time they receive the agent, we do not see these infusion-related reactions anymore.
So with that, Amivantamab was given accelerated approval. And the other agent that has been given accelerated approval in the setting is Mobocertinib. Mobocertinib is a first-in-class potent oral TKI targeting EGFR exon 20 in the frame, insertion mutations. Mobo was structurally designed to gain selectivity by targeting proteins in the vicinity of the αC Helix, a binding site not exploited by Osimertinib.
Here is the result from the EXCLAIM study in the patient cohort, post platinum therapy objective response rate was 28%, and the median duration of 7 was 17.5 months. And with this data, FDA granted accelerated approval to Mobocertinib in September of last year. The most common adverse reactions were diarrhea, rash, nausea, dermatitis, vomiting, decreased appetite, paronychia fatigue, dry skin, and musculoskeletal pain.
But I want to emphasize here that, most importantly, it's diarrhea. So if you look at the figure, 90% of the patients had some grade of diarrhea. And if you look at the little table beneath it, 21% of patients had grade 3 or higher diarrhea as an adverse event of this (new) drug. So, in contrast, I wanted to talk about this one abstract presented at ASCO (Annual Meeting, 2022 American Society of Clinical Oncology).
You are evaluating the agent CLN-081, another EGFR exon 20 inhibitor. As you can see here, the overall efficacy (benefit) results, the response rate was 38.4%. And the median duration of response was 10 months, roughly in the range of what Amivantamab and Mobocertinib showed. But what caught my attention was the lack of high-grade toxicities. So there were no grade 3 or higher rash or diarrhea.
When the doses were under 150 milligrams, and even with the higher dose of 150 milligrams, the rates of ration diarrhea were very common adverse events. When we started to inhibit EGFR Exon 20 insertions were lower than was previously reported from other compounds, so the authors concluded that at the hundred milligrams BID dose, the observed response rate was 41%, median duration of response was longer than 21 months, and the median PFS (progression-free survival) was 12 months, and the study is ongoing. And also, they're planning to enroll patients with CNS metastasis to evaluate for CNS response.
So given that the efficacy (benefit results are comparable at this time, it appears to be better tolerated. I believe this drug has a shot at making it and has been granted FDA breakthrough therapy designation. So we'll see what happens. Moving along. I have two abstracts that I wanted to share regarding cMET. One is on Amivantamab, which we just talked about. And the other one is Teliso-V, which is an antibody-drug conjugate. so just to provide a baseline, here are the main efficacy results of Capmatinib and Tepotinib.
The overall response rate appeared to be better with Capmatinib in the treatment-naive patients, but the numbers were small. So hard to tell, and I think it is otherwise comparable Capmatinib was approved in May of 2020, and Tepotinib was approved in February of 2021 in the CHRYSALIS study, there was a cohort looking at MET Exon 14 skipping mutation, and in ASCO (Annual Meeting, American Society of Clinical Oncology), the results of that cohort was also presented.
The primary endpoint was efficacy, and the secondary endpoint was safety, as shown on the waterfall plot in treatment-naive patients. The objective response rate was 57% in all patients. The objective response rate was 33%.
The majority of adverse events in the MET Exon 14 skipping subset were grade 1 to 2, including infusion-related reactions that we have already talked about. Dermatitis, acne form 40% and paronychia 38%. So, in conclusion, in patients with non-small cell lung cancer MET Exon 14, skipping mutations, Amivantamab demonstrated promising anti-tumor activity, and no new safety signals were reported.
This is the second abstract in the cMET category that I wanted to introduce Teliso-V is an ADC composed of ac-MET antibody, ABT-700, and a microtubule inhibitor of MMAE. The LUMINOSITY study evaluated previously pretreated non-small cell lung cancer patients with c-MET overexpression. The primary endpoint was the objective response rate, and the secondary endpoints included the duration of response and safety.
Here are the results. Although the numbers are small, overall response rates higher than 50% in the cMET high cohort is promising, especially in this heavily pretreated population. The drug appeared to be well tolerated. So, in conclusion, previously treated patients with CMA overexpressing advanced non-small cell lung cancer to Teliso-V showed potential anti-tumor activity and was generally well tolerated.
This is the last target I wanted to talk about, which is HER2 mutation. is an activating mutation that occurs in about 2% of lung cancers. And these are transforming in lung cancer models and result in kinase activation, Trastuzumab Deruxtecan, and is a novel ADC designed to deliver an optimal anti-tumor effect. And it has 3 components, a humanized anti-HER2 IGG1 MAP with the same amino acid sequence as Trastuzumab Deruxtecan.
A topoisomerase 1 inhibitor, payload Exatecan derivative, and Tetra peptide-based cleavable linker. The drug had already been FDA approved for breast cancer and for gastric GE junctional tumors. And it was recently approved for HER2 muted lung cancer on August 11th, 2020. The data is not from ASCO (american society of clinical).
The data was presented at ESMO last year (giving insights). And as you can see, the confirmed overall response rate by ICR was 54.9%. CR 1.1% PR 53.8% disease control rate was 92.3%. The median duration of response was 9.3 months. Median PFS (progression-free survival) was 8.2 months. And median OS was 17.8 months. We do have to be careful, though.
Any treatment-related adverse events were seen in 96.7% of patients and adjudicated drug-related ILD in 26% of patients, although grade 3 and higher ILD was 6.6%. This was the first, although patients must be closely monitored for ILD, and the study needs to further identify risk factors for ILD.
This was the first drug approved for HER2 mutant lung cancer and the first ADC approved in lung cancer.
So this is my last slide. New targeted therapies are coming out. So we need to know the targets in order to treat NCCN Guidelines panel strongly advises broad molecular testing with the goal of identifying rare driver mutations for which effective drugs may be available or to counsel patients regarding trials.
Thank you. I'd like to take in questions.
Dr. Misako Nagasaka - ASCO 2022 Lung Cancer Cancer Question & Answer
Misako Nagasaka, MD, Ph.D. - About The Author, Credentials, and Affiliations
At the University of California in Irvine, Dr. Nagasaka is a board-certified thoracic (oncology) oncologist who specializes in the detection and treatment of lung and thyroid cancer. She also treats patients with other types of thoracic cancer. In addition to that, early-phase clinical studies, medical ethics, and survivorship care for patients are some of her clinical (practice) interests. She attended the St. Marianna University School of Medicine in Kawasaki, Japan, where she was awarded both a doctoral degree and a medical degree. After completing her residency in internal medicine at Mount Sinai Beth Israel Hospital in New York City, she went on to finish a fellowship in hematology and (clinical) oncology at the Karmanos Cancer Institute, which is part of the Wayne State University School of Medicine.