ASCO 2023: Key Melanoma Studies

CME

Key Studies in Skin Cancer: Independent Conference Coverage of the 2023 ASCO Annual Meeting

Physicians: Maximum of 1.00 AMA PRA Category 1 Credit

Released: August 21, 2023

Expiration: August 20, 2024

Jason Luke
Jason Luke, MD, FACP
Jeffrey S. Weber
Jeffrey S. Weber, MD, PhD

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KEYNOTE-716: Adjuvant Pembrolizumab vs Placebo in Stage IIB/IIC Melanoma

Jason Luke, MD, FACP:
Stage IIB/IIC melanoma is associated with a high risk of relapse and 5-year melanoma-specific survival similar to that of stage IIIB disease.1,2 KEYNOTE-716 is a randomized phase III trial that enrolled 976 patients aged 12 years or older with newly diagnosed, resected, and high-risk stage IIB/IIC melanoma.3,4 Patients had negative sentinel lymph node status, no previous adjuvant therapy, and an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0/1. Patients were stratified by T category (3b vs 4a vs 4b) and pediatric status and randomized 1:1 to receive pembrolizumab 200 mg every 3 weeks or placebo for up to 17 cycles. In part 2 of the clinical trial, patients with recurrence can crossover or be rechallenged with pembrolizumab, but those data are not mature and were not presented.

The primary endpoint for the trial is investigator-assessed RFS with key secondary endpoints of DMFS, overall survival (OS), and safety. The median follow-up at this analysis was 39.4 months.

The study met the primary endpoint of significant improvement in RFS with pembrolizumab vs placebo at the first interim analysis at 12 months and maintained that improvement at 24 months.3,5 DMFS was also significantly improved with pembrolizumab vs placebo at 24 months.5

The current report from KEYNOTE-716 presents the final analysis of DMFS and updated RFS.4

KEYNOTE-716: Patient Characteristics

Jason Luke, MD, FACP:
At baseline, patients were well matched for age, sex, ECOG PS, T category, and disease stage.4 Approximately two thirds of patients had stage IIB disease.

KEYNOTE-716: Final DMFS in ITT Population

Jason Luke, MD, FACP:
In the final DMFS analysis in the intention-to-treat population, after a median follow-up of 39.4 months, the 36-month DMFS rate was 84.4% with pembrolizumab vs 74.7% with placebo (HR: 0.59; 95% CI: 0.44-0.79).4 That is a 41% reduction in distant metastasis with the use of pembrolizumab in this population of patients.

Jeffrey S. Weber, MD, PhD:
These data are impressive. There is approximately a 10% absolute difference in DMFS with a break early at 6 months, which is when the first scans were done.

KEYNOTE-716: DMFS by Stage

Jason Luke, MD, FACP:
DMFS was analyzed by stage and the benefit of adjuvant pembrolizumab was consistent for stage IIB and IIC disease.4 For stage IIB disease, the 36-month DMFS rate was 86.7% with pembrolizumab vs 78.9% with placebo (HR: 0.62; 95% CI: 0.42-0.92). For stage IIC disease, the 36-month rates were 80.9% and 68.1%, respectively (HR: 0.57; 95% CI: 0.36-0.88).

KEYNOTE-716: DMFS Subgroup Analysis

Jason Luke, MD, FACP:
In the prespecified DMFS subgroup analysis, all the subgroups had a benefit with pembrolizumab compared with placebo.4

KEYNOTE-716: RFS in ITT Population

Jason Luke, MD, FACP:
The 36-month RFS was 76.2% with pembrolizumab vs 63.4% with placebo (HR: 0.62; 95% CI: 0.49-0.79), a 38% reduction in the risk of relapse.4 We have seen a similar advantage for RFS as for DMFS across melanoma clinical trials in the adjuvant setting with anti–PD-1 and BRAF inhibitors.

Jeffrey S. Weber, MD, PhD:
Looking at RFS—the primary endpoint of the study—the curves have really smoothed out and I think that there will continue to be a difference between these arms over time.

KEYNOTE-716: RFS by Stage

Jason Luke, MD, FACP:
The 36-month RFS rates for stage IIB and stage IIC were similar.4 For stage IIB disease, the 36-month RFS was 79.7% with pembrolizumab vs 66.5% with placebo. For stage IIC disease, RFS was 71.4% and 58.0%, respectively.

KEYNOTE-716: RFS Subgroup Analysis

Jason Luke, MD, FACP:
The RFS benefit was approximately the same across most of the patient populations.4 Patients in the United States possibly had slightly less benefit, but there are very wide CIs, which make it difficult to interpret. There is no biological reason we know that would explain why patients in the United States would derive less benefit from adjuvant anti–PD-1 than people living outside of the United States. It seems likely that these findings could be because of the relatively small number of US patients included.

KEYNOTE-716: Safety

Jason Luke, MD, FACP:
Safety is an important consideration in an adjuvant clinical trial. As you would expect, the rates of adverse events (AEs) are higher for the pembrolizumab group.4 The rate of grade 3/4 treatment-related AEs was 17.2% with pembrolizumab vs 5.1% with placebo. Regarding grade 3/4 immune-related AEs (irAEs) and infusion reactions, 11.0% of patients receiving pembrolizumab were affected vs 1.2% of patients receiving placebo. This is approximately the same as we have seen with pembrolizumab across all indications in oncology, both in the metastatic setting and in the adjuvant setting.

KEYNOTE-716: Clinical Implications

Jason Luke, MD, FACP:
KEYNOTE-716 was the first modern clinical trial to examine the stage II disease setting.4 The study is important for 2 reasons: (1) The placebo arm describes the natural history of the disease at the current time and (2) pembrolizumab improves RFS and DMFS by approximately 35% to 40%, and that is similar to what we see in stage III disease.

The clinical implications are that it is now standard of care to offer pembrolizumab as an adjuvant therapy to patients with stage IIB and IIC melanoma, understanding that they would experience approximately the same benefit as patients who have stage III disease.

Of course, it is a risk calculation as well. Some patients will be concerned about the AEs. There are no new safety signals for pembrolizumab in this setting, but patients will sometimes rather defer treatment to avoid the AEs. That is at the crux of adjuvant therapy.

Jeffrey S. Weber, MD, PhD:
This update provided further confirmation that adjuvant pembrolizumab benefits patients with stage IIB and IIC melanoma. Patients with stage IIB and IIC melanoma fare more poorly without treatment than previously thought. Note this was a placebo-controlled trial because at the time, there was no standard of care for stage IIB or IIC resected melanoma. The DMFS benefit with pembrolizumab is impressive with an HR of 0.59, similar to that for RFS. Many healthcare professionals (HCPs) think that DMFS is a surrogate for overall outcome, and OS and the data from this trial were impressive. I think that the RFS at 5 years will be 70% or less. Personally, if there is a 30% risk of developing metastases at 5 years, I would prefer to have therapy vs no therapy. At this update, there is a 12.8% absolute difference in RFS between the arms, and I believe that this difference will continue over time.

Your 67-year-old patient with high-risk stage IIB melanoma is in your office to discuss adjuvant therapy after surgery. Based on results from the KEYNOTE-716 trial of adjuvant pembrolizumab vs placebo which of the following statements would you tell the patient regarding the efficacy of pembrolizumab?

Phase II KEYNOTE-942: Adjuvant mRNA-4157 (V940) Plus Pembrolizumab vs Pembrolizumab in Resected High-Risk Melanoma

Jeffrey S. Weber, MD, PhD:
The mRNA-4157 (V940) individualized neoantigen therapy targets a unique mutational signature in each patient’s tumor and encodes up to 34 neoantigens. A phase I study of mRNA-4157 was previously performed in combination with pembrolizumab that found clinical responses, and the safety profile was similar to pembrolizumab alone.6

The KEYNOTE-942 trial enrolled 157 patients with completely resected stage IIIB-IV melanoma.7 Patients had to complete surgery within 13 weeks of their first dose of pembrolizumab and be disease free, with an ECOG PS of 0/1. Of importance, tissue had to be available for next-generation sequencing to make the individualized neoantigen therapy product.

Patients were stratified by disease stage and randomized 2:1 to receive mRNA-4157 plus pembrolizumab vs pembrolizumab alone. Patients received mRNA-4157 1 mg IM every 3 weeks for up to 9 doses plus pembrolizumab 200 mg IV every 3 weeks for up to 18 cycles or pembrolizumab alone at the same dose.

The primary endpoint is RFS and secondary endpoints include DMFS, safety, and tolerability. The current update at ASCO 2023 reports the first DMFS results from KEYNOTE-942.

Phase II KEYNOTE-942: Baseline Characteristics

Jason Luke, MD, FACP:
The baseline characteristics of each arm are well matched.7 Positive PD-L1 status is slightly more common in the combination arm, at 64.5% vs 54.0%. Tumor mutation burden (TMB) ≥10 mutations/Mb is also slightly more common with the combination vs pembrolizumab alone, at 73.8% vs 60.0%. We previously presented an analysis suggesting that PD-L1 and TMB did not make a big difference in outcomes.8

Phase II KEYNOTE-942: Recurrence-Free Survival

Jeffrey S. Weber, MD, PhD:
Earlier this year at the American Association for Cancer Research (AACR), I reported an HR of 0.561 for RFS with the combination vs pembrolizumab.8 There was a late break in the curve at approximately 9 months, and the 18-month RFS is 78.6% vs 62.2% This is not a trivial difference in RFS, as the HR reflects a 44% reduction in the risk of recurrence.

Jason Luke, MD, FACP:
This is quite a tremendous increase in benefit for adjuvant therapy vs pembrolizumab alone. I cannot emphasize enough that previous clinical trials of adjuvant therapy in melanoma randomized patients to placebo vs an active comparator, whereas this trial compares the combination against an active therapy, and we still see this very large benefit.

Phase II KEYNOTE-942: Distant Metastasis-Free Survival

Jeffrey S. Weber, MD, PhD:
As I noted earlier, DMFS is felt by many to be a surrogate endpoint for OS. Here you see a very late break just beyond 12 months in the DMFS curve, which further separates at 18 months for a 15% absolute difference.7 The HR is very impressive at 0.347 (95% CI: 0.145-0.828; P = .0063).

Jason Luke, MD, FACP:
This is an astounding HR for DMFS, suggesting the combination was almost 70% better than pembrolizumab monotherapy. The caveats are that this is a phase II trial, not a phase III, and it was not powered to analyze this point. The magnitude of the HR will probably not be this high in a phase III trial. Regardless, this is a very impressive number for a clinical trial like this.

Another thing to note is that it is only after approximately 1 year of exposure to the mRNA that these curves split. I think that will be very interesting to watch in the phase III clinical trial. If mRNA-4157 becomes available outside of clinical trials, we will have to consider this potential lag time when setting expectations about what we are likely to see in terms of treatment responses.

Phase II KEYNOTE-942: Recurrence Type and Site of Distant Recurrences

Jason Luke, MD, FACP:
The absolute number of recurrences in this trial is not very large.7 The incidence of local/regional and distant recurrences are similar between the arms, suggesting that there are no major differences in relapse pattern with the addition of the individualized neoantigen therapy.

Phase II KEYNOTE-942: DMFS by Baseline ctDNA Status

Jason Luke, MD, FACP:
There was an analysis presented for DMFS as dictated by baseline circulating-tumor DNA (ctDNA) status. This showed that ctDNA positivity at baseline is a major marker of risk.7

None of the patients who were ctDNA negative at baseline and received the combination regimen had a recurrence, and only a small number who received pembrolizumab monotherapy had a recurrence. But the addition of individualized neoantigen therapy made a difference for the patients who were ctDNA negative. This will be very interesting to watch.

Phase II KEYNOTE-942: Safety

Jason Luke, MD, FACP:
Safety in an adjuvant trial is quite important. There was a slight increase in the rates of AEs and serious AEs with the combination compared with pembrolizumab monotherapy.7 The rate of serious grade 3/4 AEs was 12.5% vs 8.0% for monotherapy, so not a major difference, but a suggestion that adding the individualized neoantigen therapy adds some toxicity. The toxicities added by the mRNA-4157 are injection site pain and early immune activation types of AEs. This is not surprising since it is an intramuscular injection.

Jeffrey S. Weber, MD, PhD:
The AEs associated with the vaccine, such as injection site reaction, muscle aches, fevers, and chills, that are not common with pembrolizumab alone are slightly more severe than what you would expect from a COVID-19 vaccine or a flu shot, but very few patients stopped therapy because of vaccine-related AEs.

Phase II KEYNOTE-942: Immune-Related AEs

Jeffrey S. Weber, MD, PhD:
It is important to note that the grade ≥3 irAEs were similar between the arms at 10.6% with the vaccine combination vs 14.0% with pembrolizumab.7 The addition of the vaccine did not increase the number of irAEs (35.6% vs 36.0% for the combination vs pembrolizumab, respectively). Most of the AEs were grade 1/2, so in my view, the combination is well tolerated.

Phase II KEYNOTE-942: Clinical Implications

Jeffrey S. Weber, MD, PhD:
This is the first randomized trial of a neoantigen vaccine approach in cancer and suggests that there is benefit to the combination of a neoantigen mRNA vaccine with standard-of-care PD-1 blockade in resected high‑risk melanoma compared with PD-1 blockade alone. The combination of the neoantigen vaccine with pembrolizumab showed superior RFS and DMFS compared with the standard of care of pembrolizumab alone.

A phase III clinical trial combining mRNA-4157 with pembrolizumab vs pembrolizumab monotherapy for high-risk stage IIB-IV melanoma has begun enrolling patients (NCT05933577).

Jason Luke, MD, FACP:
I think there is little doubt that KEYNOTE-942 is a landmark study. The immediate clinical implications are that this could become a standard-of-care therapy in melanoma once the phase III data are available. Neoantigens have been a very important biological mediator of immunotherapy response but have not previously broken through as a therapeutic modality in oncology. There is no reason to think that this is a melanoma-specific phenomenon because we are looking for the mutational differences in the cancer vs the normal tissue, so this concept should apply more broadly to other cancers. I think this is the tip of the iceberg for individualized neoantigen therapy, and clinical trials will try to leverage it across many solid tumors. I think that is very exciting as it presents a new therapeutic modality in cancer treatment beyond chemotherapy, radiation, surgery, and immunotherapy.

Which of the following represents the key findings reported from the phase II KEYNOTE-942 trial of an individualized neoantigen mRNA vaccine plus pembrolizumab vs pembrolizumab alone for patients with completely resected, high-risk (stage IIIB-D/IV) melanoma?

CheckMate 76K: Adjuvant Nivolumab vs Placebo in High-Risk Stage IIB/C Melanoma

Jason Luke, MD, FACP:
CheckMate 76K is a blinded, randomized phase III trial that enrolled 790 patients with resected stage IIB and IIC melanoma who underwent standard surgery and had a negative sentinel lymph node biopsy.9 Stratification was by T category and patients were randomized 2:1 to receive adjuvant nivolumab 480 mg IV every 4 weeks for 12 months or a matched placebo. This study also has an optional on-protocol open-label crossover/retreatment, although these data are not mature and were not presented.

The primary endpoint is RFS with key secondary endpoints of OS, DMFS, second progression-free survival (PFS2), and safety. The biomarker analysis was exploratory and based on the primary tumor biopsy and serum.

It was previously reported that this study met its primary endpoint with a significant improvement in RFS vs placebo (HR: 0.42; 95% CI: 0.30-0.59; P <.0001).10 The current report is an exploratory biomarker analysis that assessed recurrence rates by subgroup and the potential benefit of adjuvant nivolumab in biomarker defined subgroups.

CheckMate 76K: Biomarker-Evaluable Population

Jason Luke, MD, FACP:
In the study, the biomarker-evaluable population included only those patients in whom these biomarkers could be identified.9 C-reactive protein (CRP) levels, tumor mitotic rates, CD8 T-cell infiltration, TMB, BRAFV600 mutation status, interferon gamma signature, and PD-L1 expression on tumor cells were the biomarkers assessed in these patients.

CheckMate 76K: RFS Outcomes Based on Higher vs Lower Biomarker Levels

Jason Luke, MD, FACP:
RFS outcomes were analyzed in the biomarker subgroups based on whether patients had higher vs lower biomarker levels. Patients with a higher interferon gamma signature, TMB, and CD8 T-cell infiltration had better RFS outcomes with nivolumab.9 However, lower levels of CRP were associated with improved RFS in the nivolumab arm. It has been known for a long time that high interferon gamma improves outcomes and CRP worsens immunotherapy outcomes, so these results were not surprising.

One interesting thing is that the mitotic rate, which we normally consider a marker of poor prognosis, did not seem to make much difference in RFS outcomes in the clinical trial.

CheckMate 76K: RFS Outcomes With Nivolumab vs Placebo Within Higher/Lower Biomarker Level Cohorts

Jason Luke, MD, FACP:
The authors did a further analysis comparing nivolumab vs placebo in patients with a higher or lower level of any of these biomarkers.9 Nivolumab was effective across these different scenarios, but patients had somewhat better outcomes with nivolumab vs placebo if they had higher levels of interferon gamma signature, TMB, CD8 T-cell infiltration, and tumor PD-L1 expression. As noted before, high CRP reduces the utility of nivolumab, but outcomes were still better with nivolumab compared with placebo.

Functionally speaking, these biomarkers that we have been aware of for a long time in the metastatic setting also affect the adjuvant setting. How we go forward and use them is an important question for our field.

CheckMate 76K: RFS Outcomes Based on Biomarker Median Cutoff or BRAF Mutation Status

Jason Luke, MD, FACP:
The authors also examined RFS outcomes based on biomarker median cutoffs and BRAF mutation status.9 Patients with BRAF-mutated tumors had better outcomes with nivolumab vs placebo, with a HR of 0.33 compared with an HR of 0.56 for wild-type tumors. This is similar to what has been seen in previous clinical trials.

Low CRP value was a strong prognostic marker for patients benefiting from immunotherapy, with an HR of 0.30 vs 0.56 for high signature. Again, these results are consistent with what we have seen previously.

CheckMate 76K: Clinical Implications

Jason Luke, MD, FACP:
These data from the CheckMate 76K trial suggest that patients with certain biomarker signatures benefit more from adjuvant immunotherapy than do others, similar to what has been observed in the metastatic setting.9

This is important because overtreatment of patients is a major issue. Most patients with stage IIB or IIC melanoma are cured after surgery, and an HCP recommending adjuvant therapy is hoping to reduce recurrence rates. If we can identify patients who we think are at higher risk for recurrence based on their biomarkers, that would reduce the number of people exposed to adjuvant therapy and reduce the number of AEs that patients experience.

I think these are important early data for multidimensional modeling. In the future, we may not use American Joint Committee on Cancer (AJCC) stage alone to determine whether a patient needs adjuvant therapy but also use biomarkers to determine tumor risk. Then we should use all of that information when considering to whom we offer adjuvant therapy.

OpACIN-neo and PRADO: Neoadjuvant Immune Checkpoint Inhibitor Blockade in Stage III Melanoma

Jason Luke, MD, FACP:
Neoadjuvant immunotherapy induces pathologic responses associated with favorable RFS in patients with high-risk stage III melanoma.11 Response-directed therapy is emerging as a critical topic in oncology, and the trials we discuss here are trying to address that topic.

OpACIN-neo is a randomized, open-label phase II trial that enrolled 86 patients with stage IIIB/C de novo or recurrent melanoma with measurable disease.12,13 The trial randomized patients 1:1:1 to receive standard nivolumab (1 mg/kg) plus ipilimumab (3 mg/kg), the flipped dose of ipilimumab (1 mg/kg) and nivolumab (3 mg/kg), or a sequence of ipilimumab (3 mg/kg) and nivolumab (3 mg/kg). Then patients received total lymph node dissection surgery and follow-up. The primary endpoints of OpACIN-neo are grade 3/4 irAEs within the first 12 weeks, the response rate at Week 6, and pathologic response rate at Week 6.

By contrast, the PRADO study enrolled the same population of patients, but all 99 patients received ipilimumab 1 mg/kg and nivolumab 3 mg/kg.12,14 A marker was placed on the index lymph node, and after treatment, that lymph node was evaluated for the status of pathologic response. Patients who had a major pathologic response (≤10% viable tumor) did not have total lymph node dissection, whereas patients who had less than a major pathologic response had lymph node dissection. Patients who achieved a pathologic partial response (>10% to ≤50% viable tumor) did not receive further treatment, and patients with a pathologic nonresponse (>50% viable tumor) went on to receive adjuvant therapy with nivolumab or dabrafenib plus trametinib. The primary endpoint of PRADO is pathologic response rate in marked index lymph node and RFS at 24 months.

The current analysis of OpACIN-neo and PRADO reports the impact of total lymph node dissection on long-term survival in patients with stage III melanoma achieving a major pathologic response after neoadjuvant immunotherapy.12 It also reports the impact of adjuvant therapy on survival in patients with pathologic nonresponse.

OpACIN-neo and PRADO: Baseline Characteristics

Jason Luke, MD, FACP:
Baseline characteristics were similar across all groups of patients.12 The incidence of BRAF mutations ranged from 36% to 41%. The incidence of PD-L1 status <1% is approximately that same range.

OpACIN-neo and PRADO: Pathologic Response Rates

Jason Luke, MD, FACP:
The incidence of major pathologic response is fairly similar from OpACIN-neo to PRADO at approximately 60%.12 The partial pathologic response rate was 14% in OpACIN-neo and 11% in PRADO and approximately 20% had a pathologic nonresponse.

OpACIN-neo and PRADO: Survival Outcomes in Patients Who Achieved MPR With or Without TLND

Jason Luke, MD, FACP:
Among the patients who had a major pathologic response, only a few patients relapsed or had distant metastasis.12 That is pretty amazing when you think about how aggressive melanoma can be.

Jeffrey S. Weber, MD, PhD:
At 2.5 years of follow-up, RFS and DMFS were impressive regardless of whether patients underwent total lymph node dissection. Total lymph node dissection does not seem to be needed, which is potentially practice changing.

OpACIN-neo and PRADO: Survival Outcomes in Patients With pNR With or Without Adjuvant Systemic Therapy

Jason Luke, MD, FACP:
For patients with a pathologic nonresponse to neoadjuvant therapy, not surprisingly, the addition of adjuvant therapy improved RFS and DMFS.12 These results are important because I think we will eventually tailor neoadjuvant interventions for individual patients.

OpACIN-neo and PRADO: Survival Outcomes in Patients With pNR by Adjuvant PD-1 Inhibitor or BRAF/MEK Inhibitor Therapy

Jason Luke, MD, FACP:
Comparing adjuvant PD-1 inhibitor vs BRAF/MEK inhibitor therapy for patients who had a pathologic nonresponse to neoadjuvant therapy, there may be some slight benefit for PD-1 inhibition vs BRAF/MEK inhibition, but these are very small numbers.12

OpACIN-neo and PRADO: Survival Outcomes in Patients With pNR With or Without Adjuvant Systemic Therapy and RT

Jason Luke, MD, FACP:
Some patients received radiotherapy.12 I think stacking therapies in patients nonresponsive to neoadjuvant therapy can improve outcomes over an extended period of time.

Jeffrey S. Weber, MD, PhD:
I think the take‑home lesson here is that radiation added little to efficacy. What was important is that patients with a poor neoadjuvant response absolutely need adjuvant therapy.

OpACIN-neo and PRADO: Clinical Implications

Jeffrey S. Weber, MD, PhD:
In OpACIN-neo and PRADO, the achievement of a major pathologic response was associated with excellent RFS and DMFS regardless of lymph node dissection.12 However, nonresponding patients benefit from subsequent adjuvant systemic therapy, whether that be an anti–PD-1 antibody or dabrafenib plus trametinib in patients with BRAF-mutated disease. The addition of radiation therapy to adjuvant therapy did not clearly benefit patients with a pathologic nonresponse.

Jason Luke, MD, FACP:
The SWOG S1801 trial previously showed a large advantage for neoadjuvant plus adjuvant pembrolizumab vs adjuvant pembrolizumab alone.15 I think we will see more therapies moving from the setting of metastatic disease to adjuvant and then neoadjuvant settings.

The data from this study underpin the ongoing phase III NADINA trial in Europe, the United States, and Australia.16 NADINA plans to randomize 420 patients with macroscopic stage III melanoma to receive neoadjuvant ipilimumab plus nivolumab or standard adjuvant nivolumab depending on pathologic response (NCT04949113).

I think that in 3-5 years from now, we may tell patients that if their immunotherapy response before surgery is adequate, they may not need to receive adjuvant therapy. Having personalized therapies for our patients with melanoma is a very exciting possibility.