ASCO 2022 Melanoma In-Depth Slides: MOASC Spotlight

ASCO 2022 Melanoma (American Society of Clinical Oncology) In-Depth Slides: MOASC Spotlight on Oncology

I’ll do a brief reminder of standard treatment options and then go over the DREAMseq trial and the RELATIVITY-047 and then if there’s time, if I was adequately caffeinated or something, we’ll also go onto the KEYNOTE-716 in the PRADO clinical trials in clinical oncology that may provide new evidence (additional information).

Is two better than one? Current Standard of Melanoma Treatment

Is two better than one? The current standard of care was based on the CheckMate 067 trial, where there were 3 arms. 945 patients were randomized to Nivolumab (NIVO) versus Nivolumab (NIVO) plus Ipilimumab (IPI) or Ipilimumab (IPI) alone and this defined the role of doublet combination therapy in advanced (melanoma) and metastatic melanoma. The progression-free survival for the combination doublet was 11.5 months and 6.9 months in the NIVO alone arm and was found to be superior when individually compared to Ipilimumab (IPI) alone importantly, this clinical trial didn’t compare NIVO versus NIVO plus IPI, or at least at a pre-specified statistical significance so these numbers are important to keep in mind, those PFS (progression-free survival) of 11.5 and 6.9 respectively for the doublet versus singlet NIVO for the abstracts today. However, as we all know, this melanoma treatment is probably very toxic.

Grade 3 to 4 events were seen in nearly 44% of the NIVO alone arm and 69%. Of the double combination with discontinuations and 5% and 29% of patients, respectively, due to the side effects. And now, we have a long-term follow-up at this trial. So this is the 6.5 year clinical follow-up. So, this is the bar we set for the first-line treatment of melanoma patients. The double combination led to 11.5 months of PFS (progression-free survival) and 72.1 months of overall survival median. At the same time, the NIVO was 6.9 months of PFS (progression-free survival) and just under 37 months of OS at the median level. So these numbers illustrate the impressive curative fraction for patients treated with a combination of NIVO and IPI.

CHECKMATE 511 Clinical Trial an ASCO (American Society of Clinical Oncology) 2022 Melanoma Update

But we know that melanoma treatment is very toxic. And so CHECKMATE 511 was designed where the lit NIVO IPI combination was compared in two dosing regimens. One dosing regimen was the standard dose. The other regimen was a quote flip dose, or renal dosing regimen, where the NIVO was three mg per kg and IPI was one mg per kg.

Will This Affect Clinical Practice?

In this trial, the median PFS (progression-free survival) and OS were not statistically different at first publication so far, but however, long-term overall survival follow-up is pending. But the main difference is that the treatment combination of the double led to significantly fewer grade 3 to 5 events, which only 34% of patients in the IPI one group versus 50% of patients in the IPI 3 group having grade 3 to 5 events, which was statistically significant treatment discontinuation was also less frequent in the IPI 1 group. With only 24% of discontinuations versus 33% discontent.  So these, are those that just set up in the discussion, our first abstract.

DREAMseq Trial from the Plenary ASCO (American Society of Clinical Oncology) 2022 Melanoma Focus

So the first melanoma abstract to discuss was from the plenary last year called the DREAMseq trial. This trial compared the sequencing of immunotherapy and targeted therapies for BRAF mutant melanoma. And so, in the top sequence, IPI and NIVO were given, followed by BRAF and MEK on disease progression versus BRAF and MEK inhibition on the first treatments and then NIVO and IPI on progression. There were melanoma patients who were stratified by ECOG and LDH. The demographics were similar. The objective response rates were similar for immunotherapy and target therapy in the first line. However, in the second line, the immunotherapy response rate was numerically lower than in the first line at only 30%. This also translated to a progression-free survival difference. Initially, you see that PFS (progression-free survival) benefits of targeted therapy over immunotherapy until about 9 months, at which time, the curves cross and support the improvement in PFS (progression-free survival) of 1 in 2 years for immunotherapy 19% for the targeted therapy first versus 42% progression-free at 24 months for the immunotherapy.

This clinical research also translates into a statistically significant overall survival benefit for the double immunotherapy followed by targeted BRAF MEK inhibition with nearly 20% difference between the two when compared at 2 years with 72% versus 52% survival rates; duration of response was also superior for the checkpoint inhibition with media.

Target therapy duration of only 12.7 months and the duration of meeting duration of response for the combination therapy, not yet reached at this time point of the present. And so, in summary, for this abstract, unless ineligible for checkpoint inhibition then an immune checkpoint inhibitor should be the first-line therapy of choice for all melanoma patients with BRAF mutant advanced (melanoma) or metastatic melanoma, and an impressive 20% survival difference compels us.

For this treatment option (in patients with BRAF mutant advanced melanoma or metastatic melanoma), when you look at the 2 years survival rates, however, there are still some melanoma patients in the first 10 months of therapy with checkpoint who experience relatively rapid progression, and the targeted therapy could have benefited their widely metastatic melanoma disease at that point.

RELATIVITY-047 Clinical Trial Data from the ASCO (American Society of Clinical Oncology) 2022 Melanoma Focused Plenary Session

Moving on to the next melanoma abstract. So the new kid on the block is the drug Relatlimab, which is the I three immune checkpoint inhibitor and Nivolumab (NIVO). And this is in the RELATIVITY-047. This is the updated clinical research from the March ASCO (American Society of Clinical Oncology) 2022 plenary of this year which is an update to the NEJM article by Dr. Tao.  So in this trial, patients were randomized to NIVO plus IPI versus NIVO alone.

Randomized one-to-one and stratified by LAG-3 PD-L1 BRAF status and stage version 8 on demographics, nothing concerning equally split. I’m looking at the LAG-3 expression. In the whole population, about 75% of patients had greater than 1% LAG-3 expression.  The primary endpoint was PFS (progression-free survival) for this trial.

The combination had improved PFS (progression-free survival) by 10.2 months versus only 4.6 months for the singlet arm hazard ratio of 0.78, and that was statistically significant for melanoma. I’m looking at the force plot for PFS (progression-free survival) across stratification factors. PD-L1 expression of less than 1% actually did lead to improved PFS (progression-free survival) compared to those with PD-L1 1% of greater than one favoring the combination arm LAG-3 expression was not at least statistically significant, although it looks like those trending that way.

The secondary overall secondary clinical endpoint was overall survival (OS). Overall survival data at this point, a follow-up shows a non statistically significant longer OS and meeting follow-up of 19.3 months for the combination with Relatlimab the fourth plot for overall survival, nothing was statistically significant, everything crosses one.

At least at this point,  looking at the objective response rate was 43% in the combination versus 32% of the NIVO arm. The complete response rate was ever so slightly higher. Maybe probably equal, sorry. For the double arm disease control rate was not drastically dissimilar as well.

Adverse events are one of the other things that are important. We know, as we just talked about, that the NIVO and IPI combination is very toxic. However, this combination was less toxic. If you think back to those numbers, the NIVO arm alone was only 11.1% of grade three to four events versus 21.1% for the NIVO and IPI.

There are no treatment-related deaths. The most common side effects were similar to what we’ve seen with other immunotherapies with rash, diarrhea, hyperthyroidism, hepatitis, adrenal insufficiency, and one I don’t think I put on this slide, but one of the things that’s interesting is they actually note how many patients had vitiligo in the paper, which I think is something that people are starting to recognize a little bit more.

Summary of RELATIVITY-047 Trial Data Released at ASCO (American Society of Clinical Oncology) 2022

 So, in summary, Relatlimab adds additional PFS (progression-free survival) benefits to NIVO without significant additive toxicity. OS is not yet shown to be superior to combination therapy. However, it is trending to improve OS. And so we’ll see if it seeks out a clinical superiority in survival. So maybe next month at ESMO or ASCO (American Society of Clinical Oncology) next annual meeting, we’ll see if there are any new updates or new evidence. notably, it was not compared to the standard of care regimen of neon IPI for those with good PFS (progression-free survival).

All the patients in this trial had good PFS (progression-free survival). So it’s one thing to keep in mind that they did not compare it to the NIVO and IPI, which is the standard of care. This is a chart I really like how Dr. Dowd presented in his discussion that it gives DOTS for each of the clinical trials DOT 8 comparing side effects and PFS (progression-free survival).

And so if you look at Checkmate-067, the top rate red Is the best at PFS (progression-free survival), but also the worst at side effects, whereas Relatlimab and then the flip dose NIVO IPI seem to show a little bit better balance of side effects and progression-free survival. But again, this is just a progression-free survival chart.

We really need that overall survival chart. So hopefully, we’ll be able to update this graph with overall survival.  Okay. I guess I did talk quickly enough.  So the other interesting abstract that I think is important to know about is the adjuvant checkpoint inhibition for stage 2B, or 2C melanomas.

KEYNOTE-716 Trial Data Updated from ASCO 2022

This is phase three of KEYNOTE-716. This clinical research was initially presented by Dr. Luke at ASCO 2022 or, sorry, ESMO in Paris last year. But then it was again updated by Dr. Long here at ASCO 2022 this year at the annual meeting. And so, this study design was taking patients were stage 2 resected disease negative lymph nodes.

2B and 2C mean the T stage of 3B, 4A, and 4B. They were randomized to Keytruda (pembrolizumab) versus placebo. And they were followed up for recurrence, and obviously, they were unblinded, and they were allowed Pembrolizumab. If they progressed, the primary endpoint was recurrence-free survival, secondary disease, distant metastatic-free survival, and overall survival based on characteristics pretty equal.

You can see, though, that this is different than this is an adjuvant study. So the ECOG is almost all zero. It’s one thing just to point out cause these patients are very healthy coming into the trial. Recurrence-free survival. So this is the at-interval analysis three then there’s been 95 events in the Pembrolizumab arm versus 140 in the placebo arm for 24 months.

The survival rate of 81 versus 73 median months overall response rate was 37 versus not yet reached.  Distant metastasis free survival, 24 months, only about a 6% difference. And 4% difference at 12 months. It is statistically significant, though. They calculate, probably largely, due to these larger numbers they were able to recruit.

Adverse events treatment-related were 83 events, 83%, sorry, 17% had grade 3 in the treatment arm 16 discontinued. Importantly, zero patients had a death from this adjuvant melanoma treatment, and then looking at these grade 3 side effects, diarrhea again, something we’re used to seeing the rash.

So, in summary, this treatment is now FDA-approved for adjuvant therapy in stage 2B and 2C melanomas. If and when an overall survival benefit is confirmed, then treatment should have a high recommendation in this population of patients to confirm treatment improves survival, however, given the side effects of immunotherapy can persist lifelong, it’s still an individual decision, and you have to counsel patients in your clinical practice, the benefits may be outweighed by the risks. Then I think I’ll leave this one out.

PRADO Trial Clinical Data Presented at ASCO 2022

So this is one of the most exciting abstracts concerning melanoma, I think. So this is from Dr. Blank from the Netherlands Cancer Institute (in clinical oncology) presented at ASCO 2022 this year. So this was this phase 2 study of neoadjuvant IPI and NIVO in clinical oncology stage III melanomas. So the thought is that, in an adjuvant setting,  there’s little tumor bulk for the antigen-presenting cells to be able to activate, be activated from the immunotherapy, or, sorry, the T cells will be activated from the immunotherapy and so, giving it in a new adjuvant setting where there’s lots of tumor bulk might be a benefit and generating those T-cell clones that are going to respond to the melanoma. And this is the OpACIN-neo trial with the updated clinical results. And so what they saw was that in the Anti-PD-1, only arm pathologic non-response was seen in 66% of patients with melanoma.

Whereas in the combination. NIVO and IPI arm, only 25% had a pathologic non-response, and this is how they defined this. So after they gave the NIVO and IPI, they looked at the path. The pathology and path CR was 0% viable tumor path near CR was up to 10% viable tumor path pressure response was 10 to 50% viable tumor and path non responses still greater than 50% viable tumor.

And so this is what sets a stage. These are earlier phase two trials and so the PRADO design was stage (III) 3B 3C. They were given one Mg per Kg of IPI 3 Mg per Kg of NIVO for 2 cycles, 3 weeks apart. After an indexed node was, a marker was placed, and then they underwent resection at week 6. Suppose they had a past CR or near past CR. They did not undergo therapeutic lymph node dissection. If they had a partial response, they did still go under a path of therapeutic lymph node dissection, but they didn’t have any more adjuvant therapy. If they had nonresponse, they were able to go, or they had to go onto therapeutic lymph node dissection and were allowed to get more adjuvant therapy with either BRAF or immune checkpoint inhibitors.

And so, the primary objective was to confirm the pathologic response and see how many patients had a major pathologic response based on characteristics. So the relatively young population, predominantly male ECOG zero, almost everybody, and these are all European institutions. I think they’re all in the Netherlands Cancer Institute (focusing on clinical oncology trials), it is predominant.

And most of the patients only had 1 node, and very few had greater than 3 nodes to be enrolled in this trial. 30% had a grade 3 to 4 event with the treatment relapse-free survival for the overall population was 85% versus This metastasis was 89% for the major pathologic response. These are excellent numbers and we await additional information.

It’s making melanoma look like breast cancer, maybe. And so the relapse-free survival was 93% at 2 years. And 98% distant metastasis-free survival at 24 for those 60 patients that had a major pathologic response, then editing in the non-responders pathologic non-response, in the red. They didn’t do as well. They had 81% at 12 months and 71% at 24 months. And then the near response actually did the worst at 73% at one year and 64% at 2 years. So this is the cart that gives those numbers. So the complete responders did the best partial responders actually did worse than the no response.

And they estimate that this is likely due to the addition of further adjuvant therapy for the non-responders and so that’s the end of these abstracts. So hopefully, these 4 abstracts were good in clinical oncology if anybody wants another melanoma abstract. The other one I didn’t present is desmoplastic melanoma, neoadjuvant Keytruda (pembrolizumab), which is a SWOG study. That’s another good one to look at. If you need another metastatic melanoma abstract.

 

Justin Moyers, MD – MOASC 2022 Exit Interview –

https://oncologytube.com/v/41283

Justin Moyers, MD – MOASC Question and Answer Session –

https://oncologytube.com/v/41313

Zachary Hanson, DO – Anemia and Zinc Deficiency [2022]: MOASC Spotlight
https://oncologytube.com/video/41301

 

Justin Moyer, MD- About The Author, Credentials, and Affiliations

Medical oncologist and assistant clinical professor of medicine at the University of California, Irvine School of Medicine Justin T. Moyers is board certified in medical oncology and works at the University of California, Irvine Medical Center.

 

His clinical practice interests include skin cancers. Melanoma is another one of his clinical (oncology) specialties. His research interests include both the creation of therapies and the first phase, as well as the application of biomarkers and genomic data to the process of patient selection. He is now serving as the ASCO (American Society of Clinical Oncology) ( Editorial Fellow for JCO Precision Oncology, and he has presented research in the areas of melanoma database research, immunotherapy predictive biomarker research, and phase 1 combinatorial trial design at ASCO, SITC, ASCO-SITC, AACR, and ESMO.

 

Dr. Moyers attended the University of Kansas, where he was awarded a Bachelor of Science degree in Chemistry. He then went on to earn his medical degree from the University of Kansas School of Medicine. After completing his internship in internal medicine at Providence St. Vincent Medical Center in Portland, Oregon, he went on to do a fellowship in hematology and clinical oncology at Loma Linda University Medical Center in Loma Linda, California. Last but not least, he finished a fellowship at the University of Texas MD Anderson Cancer Center in Houston, Texas. The fellowship was in the Department of Investigational Cancer Therapeutics (in clinical oncology).