Mario Sznol, MD

The major treatment advances for melanoma can be attributed to anti–-cytotoxic T-lymphocyte–associated protein 4 (anti–CTLA-4; ipilimumab) and anti–programmed cell death protein 1 (anti–PD-1; nivolumab, pembrolizumab) immune checkpoint inhibitors and the combination of BRAF and MEK inhibitors (vemurafenib/cobimetinib, dabrafenib/trametinib, encorafenib/binimetinib). Data are now available from 5-year follow-up of several trials in metastatic melanoma and clearly demonstrate the dramatic and lasting impact of these treatments on overall survival.

In the not-too-distant past, overall 5-year survival for patients with metastatic melanoma was in the range of 5% to 10%. Interleukin-2 was the best therapy available and was associated with durable complete remissions in at most 5% to 10% of a select subset who could tolerate its severe adverse events. Today, because of the immune checkpoint inhibitors and the BRAF/MEK inhibitors, the expected 5-year survival rate for patients such as those enrolled on clinical trials approaches 50%. Although comprehensive data on the status of 5-year survivors are not available, our institutional experience suggests that a substantial proportion of those survivors who were treated with anti–PD-1 or the combination of anti–PD-1 and anti–CTLA-4 therapies are not currently receiving treatment, have no active disease, and have returned to a normal life.

Improved Survival Rates, but Many Questions Remain

As reviewed in this issue of The ASCO Post, Robert et al reported a 4-year progression-free survival rate of 26.9% and 4- and 5-year survival rates of 45.7% and 43.2%, respectively, in the KEYNOTE-006 trial of first-line treatment of metastatic melanoma with pembrolizumab.¹ In the recently published 5-year follow-up of CA209-067, a randomized trial of ipilimumab/nivolumab or nivolumab vs ipilimumab in the first-line treatment of metastatic melanoma, the 5-year progression-free survival for nivolumab alone was 29% and for the ipilimumab/nivolumab combination, it was 36%.² The 5-year survival rates for nivolumab and ipilimumab/nivolumab were 44% (almost identical to those in the KEYNOTE-006 trial) and 52%, respectively. In these trials, the progression-free and overall survival curves are nearly flat beyond 3 years.

Publication of the long-term follow-up of the melanoma trials provides assurance of the long-term benefit of treatment, but the major questions surrounding the treatment of metastatic melanoma remain the same:

• When immune checkpoint inhibitors are selected for treatment, is it possible to identify those who would benefit from adding ipilimumab to anti–PD-1 or, alternatively, those who could achieve long-term durable remissions with anti–PD-1 alone?
• Are there alternate dose-schedule regimens of ipilimumab/nivolumab with equal efficacy but less toxicity?
• Will sequential administration of ipilimumab or ipilimumab/nivolumab after disease progression on anti–PD-1 treatment alone provide equal outcome to upfront concurrent ipilimumab/nivolumab?
• What other combinations with anti–PD-1 treatment could improve outcomes with less toxicity than ipilimumab/nivolumab?
• In patients with BRAF-mutant tumors, which first-line treatment offers the best long-term outcome: BRAF plus MEK inhibitors vs either anti–PD-1 treatment alone or nivolumab/ipilimumab?
• Which subgroups of patients are most likely to survive 5 years with therapy?
• What accounts for the discrepancy between overall and progression-free survival over time and now at 5 years?
• What is the optimal duration of treatment, or, alternatively, when can therapy be discontinued without compromising efficacy?
• What is the optimal management of patients presenting with brain metastases?
• How will the use of anti–PD-1 treatment in the adjuvant setting affect treatment of patients who subsequently develop metastatic disease?
• What are the major mechanisms of resistance to the different treatments, and can they be prospectively identified by biomarkers?
• What approaches are effective or promising in patients whose disease becomes unresponsive to current therapies or in subsets of melanoma that are much less responsive to current therapies such as ocular melanoma?
• How can new active agents be identified efficiently, and, in the setting of substantial activity for current agents in a relatively uncommon disease, what are the best and most efficient endpoints and trial designs for evaluating new agents in the first-line
  treatment setting?

Discrepancies in Long-Term Data

The recently published long-term data only partially address the various questions. The true complete response rate induced by the immune checkpoint inhibitors has been underestimated in the trials if compared with the higher 5-year progression-free survival rate, which would seem to be a better indicator that all disease has been eliminated. The discrepancy between the complete response rate and progression-free survival rate is likely explained by residual lesions that no longer contain tumor.

Focusing clinical research on poor-prognosis groups in the front-line setting and in resistant or refractory disease will likely expedite the discovery of active and impactful agents.

— Mario Sznol, MD

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A second striking discrepancy is the difference between overall survival at 5 years and the progression-free survival rate. The discrepancy exists even in BRAF wild-type melanoma, where second-line effective therapies are not available, particularly in patients treated with concurrent ipilimumab/nivolumab. In our institutional experience with immune checkpoint inhibitors, surgery (or radiation) to treat progressing single or limited metastatic new lesions or recurrent disease, even in the setting of other nonprogressive persistent disease, may be associated with long survival, and a subset of patients achieve subsequent long-term progression-free survival.³ The Robert et al report on KEYNOTE-006¹ also demonstrates relatively high response rates to re-induction treatment with pembrolizumab in a small number of prior responders who experienced disease progression after discontinuing treatment.

Major Challenges Moving Forward

The major challenge currently is to identify single agents or combinations to raise the 5-year survival rate beyond 50%. At least for immunotherapies and combination therapies, survival at 5 years may correlate either with cure or subsequent prolonged melanoma-specific survival. Multiple mechanisms for resistance to BRAF/MEK inhibitors and for nonresponse to immune checkpoint inhibitors have been identified, suggesting that multiple new therapies may be required, each perhaps incrementally improving outcomes. Given the complexity of the tumor biology and immune microenvironment, developing predictive biomarkers and selecting optimal treatments for defined subgroups will be challenging.

Nevertheless, as a community we should continue to develop and study new therapies in the clinic. We should also strive to obtain pre- and post-treatment tumor and other tissue samples to improve our understanding of tumor biology/immunobiology and the mechanisms of drug response and resistance. Focusing clinical research on poor-prognosis groups in the front-line setting and in resistant or refractory disease will likely expedite the discovery of active and impactful agents. ■

Dr. Sznol is Professor of Medicine (Medical Oncology); Co-Director, Cancer Immunology Program, Yale Cancer Center; and Co-Director, Yale SPORE in Skin Cancer, New Haven, Connecticut.

DISCLOSURE: Dr. Sznol has stock and other ownership interests in Adaptive Biotechnologies, Amphivena, Intensity Therapeutics, Torque, and NextCure; has served as a consultant or advisor to Adaptimmune, AstraZeneca/MedImmune, Baxalta/Shire, Biodesix, Bristol-Myers Squibb, Genentech/Roche, Inovio Pharmaceuticals, Kyowa Hakko Kirin, Lilly, Merck Sharp & Dohme, Modulate, Molecular Partners, NewLink Genetics, Novartis, Omniox, Pfizer, Pierre Fabre, Seattle Genetics, Theravance, AcademicCME, Dava Oncology, Haymarket Media, Physician Education Resource, Research to Practice, Symphogen, NextCure, Verastem, Innate, Incyte, Iovance, Genmab, Celldex, AbbVie, Immunocore, Almac, Hinge, Anaeropharma, Array, BioNTech, Pieris, Actym, Gritstone, and Torque.

REFERENCES

1. Robert C, Ribas A, Schachter J, et al: Pembrolizumab versus ipilimumab in advanced melanoma (KEYNOTE-006): Post-hoc 5-year results from an open-label, multicentre, randomised, controlled, phase 3 study. Lancet Oncol 20:1239-1251, 2019.

2. Larkin, J, Chiarion-Sileni V, Gonzales R, et al: Five-year survival with combined nivolumab and ipilimumab in advanced melanoma. N Engl J Med. September 28, 2019 (early release online).

3. Klemen ND, Wang M, Feingold PL, et al: Patterns of failure after immunotherapy with checkpoint inhibitors predict durable progression-free survival after local therapy for metastatic melanoma. J Immunother Cancer 7:196, 2019.