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Dual checkpoint blockade in metastatic melanoma: PFS makes a strong case, but overall survival impact still an unknown

By Greg Wolfe, Ph.D., Senior Consultant, Clinical & Scientific Assessment, Kantar Health and Stephanie Hawthorne, Ph.D., Senior Director, Clinical & Scientific Assessment, Kantar Health

The treatment armamentarium available for patients with advanced melanoma has become quite well stocked as recent progress in the development of novel therapeutic agents has been tremendous. Immune checkpoint inhibition and targeted inhibition of BRAF and MEK are two therapeutic approaches that have significantly improved survival for patients with advanced melanoma. Since 2011, the Food and Drug Administration(FDA) has approved three checkpoint inhibitors, starting with the cytotoxic T-lymphocyte-associated antigen 4 (CTLA4) inhibitor Yervoy® (ipilimumab, Bristol-Myers Squibb/Ono Pharmaceuticals), followed by subsequent approvals of programmed death-1 (PD-1) receptor inhibitors Keytruda® (pembrolizumab, Merck & Co.) and Opdivo® (nivolumab, Bristol-Myers Squibb/Ono Pharmaceuticals); for patients whose tumors harbor a BRAF mutation, the BRAF inhibitors Zelboraf® (vemurafenib, Roche/Plexxikon/Daiichi-Sankyo) and Tafinlar (dabrafenib, Novartis) and the MEK inhibitor Mekinist (trametinib, Novartis) round out the armamentarium.

Opdivo holds the title of the first PD-1 inhibitor to gain global regulatory approval when it was approved in Japan in July 2014 for metastatic melanoma. In September 2014, Keytruda became the first PD-1 inhibitor to gain approval in the U.S. when the FDA awarded it accelerated approval for treatment of patients with unresectable or metastatic melanoma and disease progression following Yervoy and, if BRAF V600 mutation positive, a BRAF inhibitor. However, the race to the U.S. market was tight as Opdivo received accelerated approval from the FDA in December 2014 for a similar indication.

With both Keytruda and Opdivo approved for refractory melanoma, the battle has shifted to treatment-naïve advanced melanoma, where Yervoy has ruled as the only approved checkpoint inhibitor in the U.S. since 2011. However, recent data from the Phase III KEYNOTE-006 trial demonstrated the superiority of Keytruda over Yervoy with regard to significant progression-free survival (PFS) and overall survival (OS).1 Thus, it is evident that the dominance of Yervoy monotherapy as front-line treatment for BRAF-wildtype patients will soon fade away.

The next logical step to consider is combinations of checkpoint inhibitors. Immune checkpoints play critical roles in balancing co-stimulatory and co-inhibitory signals that regulate human self-tolerance and control the amplitude and duration of T-cell responses. CTLA-4 and PD-1 are distinct yet complementary pathways that inhibit antitumor immunity. Published Phase I and II data already suggest that simultaneous blockade of both pathways with Yervoy and Opdivo may be more active than either monotherapy alone.2,3

Today, preliminary results from the phase III CheckMate-067 trial were reported in the Plenary Session of the annual meeting of the American Society for Clinical Oncology (ASCO).4,5 This trial is evaluating the impact of combining two immunotherapies, Opdivo and Yervoy, versus either single agent in treatment-naïve patients with Stage III (unresectable) or Stage IV melanoma. Patients were randomized (1:1:1) to receive Opdivo alone (3 mg/kg every two weeks, plus a Yervoy-matched placebo), versus Opdivo (1 mg/kg) in combination with Yervoy (3 mg/kg) administered every three weeks for four doses followed by Opdivo alone (3 mg/kg every two weeks) until disease progression, versus Yervoy alone (3 mg/kg every three weeks for a total of four doses, plus an Opdivo-matched placebo). OS and PFS are co-primary endpoints.

Treatment with the combination of Opdivo plus Yervoy or with Opdivo monotherapy yielded superior clinical activity compared to treatment with Yervoy alone. Median PFS were 11.5 months (Opdivo + Yervoy; HR 0.42 and p<0.00001 vs. Yervoy), 6.9 months (Opdivo; HR 0.57 and p<0.00001 vs. Yervoy) and 2.9 months (Yervoy). Objective response rates were 57.6% (Opdivo + Yervoy; p<0.00001 vs. Yervoy), 43.7% (Opdivo; p<0.00001 vs. Yervoy) and 19.0% (Yervoy). Quite disappointingly, OS data are immature and were not presented. PFS was also analyzed in prespecified subgroups of patients according to PD-L1 expression. Among patients with PD-L1-positive tumors (defined as ≥1% PD-L1-positive tumor cells) the median PFS was 12.4 months for both the Opdivo + Yervoy arm and the Opdivo-alone arm, which was strongly improved compared to the 3.9–month median PFS for patients treated with Yervoy alone. Patients with PD-L1-negative tumors (<1% PD-L1-positive tumor cells) had median PFS of 11.2 months (Opdivo + Yervoy), versus 2.8 months (Opdivo alone) versus 2.8 months (Yervoy alone). Improved clinical efficacy of the combination comes at a cost, however. Drug-related Grade 3/4 adverse events were reported in 55% of patients in the combination arm versus 16.3% in the Opdivo-alone arm and 27.3% in the Yervoy-alone arm. Approximately 36% of patients in the combination arm discontinued treatment due to toxicity, compared to only 8% of patients treated with Opdivo monotherapy and 15% of patients treated with Yervoy monotherapy. Interestingly, a majority of patients who required a treatment discontinuation actually developed an objective tumor response after drug discontinuation.

Results from this trial are practice changing, and now either Opdivo + Yervoy or a PD-1 checkpoint inhibitor alone (Keytruda or Opdivo) should be considered standard of care for front-line BRAF wildtype melanoma. Although the efficacy of dual checkpoint pathway blockade is impressive, management of toxicity and patient selection remain challenges. Greater effort is needed to develop biomarkers/assays that will identify those patients who are likely to respond and those who are not. PD-L1 expression is a weak biomarker, and current assays are technically difficult and imperfect, especially for patients with low PD-L1 expression. The need for a better biomarker assay is particularly important when considering that Yervoy + Opdivo is associated with Grade 3/4 toxicity in 55% of patients. In patients where tolerance of toxicity is a key consideration, a PD-1 checkpoint inhibitor monotherapy may be the appropriate choice. Furthermore, appropriate patient selection is critical with regard to cost of therapy. Opdivo + Yervoy has an annual price tag in excess of $180,000, further necessitating the development of an assay to differentiate between potential responders and non-responders to contain costs (although Dr. Jedd D. Wolchok made a point at the end of his presentation to advertise a BMS-sponsored expanded access program now available for this combination, which may alleviate the financial burden in the short term ahead of FDA approval). Other alternatives may also help ease the disadvantages of this regimen. Could a lower dose of Yervoy (such as two doses rather than four) be equally efficacious but help reduce both toxicity and the cost of dual checkpoint inhibitor therapy?  We also don’t yet know if the observed PFS benefit will also translate into an OS benefit. While hope is high that dual checkpoint blockade will raise the survival curve plateau (how high can it go?), would we achieve the same OS outcomes if both drugs are combined in first-line compared with their use in sequential lines of therapy? Unfortunately, this remains a blackbox since not even a hint of OS outcomes were reported at today’s Plenary Session.

While development of checkpoint inhibitors has revolutionized melanoma treatment and dual checkpoint therapy appears very promising, balancing safety, efficacy and cost requires further consideration, and there is a long way to go toward identification of patients who are best suited to this combination therapy.


  1. Robert C, Schachter J, Long GV, et al. Pembrolizumab versus ipilimumb in advanced melanoma. New Engl J Med. 2015; DOI: 10.1056/NEJMoa1503093.
  2. Wolchok JD, Kluger H, Callahan MK, et al. Nivolumab plus ipilimumab in advanced Melanoma. N Engl J Med. 2013;369:122-133.
  3. Postow MA, Chesney J, Pavlick AC, et al.; “Nivolumab and ipilimumab versus ipilimumab in untreated melanoma.” N Eng J Med, 2015; 372 (21): 2006-2017.
  4. Larkin J, Chiarion-Sileni V, Gonzalez R, et al.; “Combined Nivolumab and Ipilimumab or Monotherapy in Untreated Melanoma.” N Eng J Med, 2015; DOI: 10.1056/NEJMoa1504030.
  5. Wolchok JD, Chiarion-Sileni V, Gonzalez R, et al., “Efficacy and safety results from a phase III trial of nivolumab (NIVO) alone or combined with ipilimumab (IPI) versus IPI alnoe in treatment-naïve patients (pts) with advanced melanoma.” J Clin Oncol, 33, 2015 (suppl; abstr LBA1).

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