Immunotherapy, once considered a niche treatment for a few specific cancers, has rapidly emerged as an additional pillar of cancer therapeutics. With the proliferation of promising results, clinical trials, and new drug approvals, one cannot help but be amazed that only 3 years have elapsed since Dr. Topalian and colleagues’ seminal study of nivolumab’s (Opdivo) activity1 and only 2 years have passed since the first description of pembrolizumab (Keytruda; previously known as lambrolizumab).2 Over that short period, agents targeting programmed cell death protein 1 receptor (PD-1) and its ligand (PD-L1) have demonstrated clinical activity in cancers originating from at least nine different organ systems, and several promising combination regimens have also emerged.3,4
KEYNOTE-002 Trial
Among the highest response rates for anti–PD-1 have been observed in advanced melanoma. This issue of The ASCO Post summarizes another example of anti–PD-1’s efficacy in this disease: a phase II study of pembrolizumab vs investigator’s choice chemotherapy in treatment-refractory melanoma.5
In this study, Dr. Ribas and colleagues reported the results for 540 patients who had previously received ipilimumab (Yervoy) and, in patients with a BRAF V600 mutation, BRAF inhibitors with or without MEK inhibitors. Two doses of pembrolizumab (2 mg/kg every 3 weeks—the now U.S. Food and Drug Administration–approved dose—and 10 mg/kg every 3 weeks) were compared with investigator’s choice of several different chemotherapeutic agents, including dacarbazine, temozolomide, carboplatin, paclitaxel, or the latter two in combination.
This study found that both doses of pembrolizumab produced superior progression-free survival, objective response rate, and toxicities compared with chemotherapy. Median progression-free survival by investigator review (3.7 and 5.4 months vs 2.6 months), progression-free survival at 6 months (34% and 38% vs 16%), and overall response rate (21% and 26% vs 4%) were all improved in the pembrolizumab arms. In addition, grade 3 to 4 toxicities were less frequent with both doses of pembrolizumab (11% and 14% vs 26%). This study established pembrolizumab as a new standard of care in ipilimumab-refractory melanoma and led to the drug’s regulatory approval in 2014.
Results in Context
Although the superiority of pembrolizumab compared with cytotoxic chemotherapy in this setting is a welcome confirmation, it is not surprising in view of several previously published studies. In a phase I study of 173 patients, pembrolizumab previously demonstrated an overall response rate of 26% in ipilimumab-refractory melanoma, dramatically better than historical response rates to chemotherapy.6 A phase II study compared nivolumab with investigator’s choice chemotherapy and noted an improved overall response rate with nivolumab (31.7% vs 10.6% in ipilimumab-refractory melanoma).7
A phase III study compared nivolumab with dacarbazine in patients with untreated BRAF wild-type melanoma. This study reported improved overall survival at 1 year (72.9% vs 42.1%), median progression-free survival (5.1 vs 2.2 months), and overall response rate (40% vs 13.9%).8 Finally, two separate studies have demonstrated the superiority of both pembrolizumab and nivolumab compared with ipilimumab, the previous standard-of-care immunotherapy.4,9
Even though similar results have been reported with in-class agents, this study provides several additional insights to the existing literature. First, this is the first study to report progression-free survival data for patients treated with anti–PD-1 in the ipilimumab-refractory setting. Although the median progression-free survival for pembrolizumab is not extremely impressive, the 24% to 36% of patients who are progression-free at 9 months (depending on whether progression is investigator or centrally assessed) is dramatically better than the 8% to 10% of patients who receive chemotherapy.
Second, this study includes patient-reported outcomes and quality-of-life metrics (EORTC QLQ-C30 global health status and quality-of-life scores). As would be hoped for an agent with less toxicity and more responses, quality-of-life score decrements were fewer in the pembrolizumab arms compared with chemotherapy.
Future Directions
With the advent of durable responses induced by pembrolizumab and other anti–PD-1 agents, assessing patient-reported quality-of-life outcomes and delayed toxicities in the long-term follow-up settings will also become increasingly important. This is particularly true as these agents are used in a variety of cancers and as they are tested in the adjuvant setting.
Our group evaluated a small cohort of patients with long-term (> 2 year) survival after being treated with ipilimumab.10 Although quality of life and overall functional status were generally excellent, several patients developed presumed delayed radiation toxicities, and several others had persistent endocrine deficits. Characterizing these endpoints in patients who receive anti–PD-1 alone or in combination will be a critical next step.
Conclusion
Pembrolizumab was superior to cytotoxic chemotherapy among patients with advanced melanoma who previously failed to respond to ipilimumab and (if applicable) a BRAF inhibitor. A number of critical questions remain surrounding front-line therapy for patients with advanced melanoma, including the use of single-agent anti–PD-1 vs nivolumab and ipilimumab in combination, the preference of targeted vs immune therapy in patients with BRAF V600-mutated melanoma, and the development of predictive biomarkers to discriminate between potential treatment options. In this treatment-refractory setting, however, the data are clear and unequivocal: pembrolizumab (and nivolumab) should be strongly preferred over cytotoxic chemotherapy. ■
Disclosure: Dr. Johnson serves on advisory boards for Bristol-Myers Squibb and Genoptix.
References
1. Topalian SL, Hodi FS, Brahmer JR, et al: Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med 366:2443-2454, 2012.
2. Hamid O, Robert C, Daud A, et al: Safety and tumor responses with lambrolizumab (anti-PD-1) in melanoma. N Engl J Med 369:134-144, 2013.
3. Wolchok JD: PD-1 blockers. Cell 162:937, 2015.
4. Larkin J, Chiarion-Sileni V, Gonzalez R, et al: Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N Engl J Med 373:23-34, 2015.
5. Ribas A, Puzanov I, Dummer R, et al: Pembrolizumab versus investigator-choice chemotherapy for ipilimumab-refractory melanoma (KEYNOTE-002): A randomised, controlled, phase 2 trial. Lancet Oncol 16:908-918, 2015.
6. Robert C, Ribas A, Wolchok JD, et al: Anti-programmed-death-receptor-1 treatment with pembrolizumab in ipilimumab-refractory advanced melanoma: A randomised dose-comparison cohort of a phase 1 trial. Lancet 384:1109-1117, 2014.
7. Weber JS, D’Angelo SP, Minor D, et al: Nivolumab versus chemotherapy in patients with advanced melanoma who progressed after anti-CTLA-4 treatment (CheckMate 037): A randomised, controlled, open-label, phase 3 trial. Lancet Oncol 16:375-384, 2015.
8. Robert C, Long GV, Brady B, et al: Nivolumab in previously untreated melanoma without BRAF mutation. N Engl J Med 372:320-330, 2015.
9. Robert C, Schachter J, Long GV, et al: Pembrolizumab versus ipilimumab in advanced melanoma. N Engl J Med 372:2521-2532, 2015.
10. Johnson DB, Friedman DL, Berry E, et al: Survivorship in immune therapy: Assessing chronic immune toxicities, health outcomes, and functional status among long-term ipilimumab survivors at a single referral center. Cancer Immunol Res 3:464-469, 2015.
Dr. Johnson is Assistant Professor of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee.
