Still Leading the Charge in Immunotherapy

Ahmad A. Tarhini, MD, PhD

Inside ASCO 2015: Melanoma

The plenary session was the most anticipated and most heavily attended session at the 2015 ASCO Annual Meeting. Two presentations given during the plenary session were of particular interest. The first of these was the lecture given by Science of Oncology Award recipient James Patrick Allison, PhD; his talk was entitled “Immune Checkpoint Blockade in Cancer Therapy: New Insights, Opportunities, and Prospects for a Cure.”[1] The second was the presentation by Jedd D. Wolchok, MD, of the results of the phase III CheckMate-067 trial.[2] The messages of these two presentations and the data presented underscore the promising future of systemic immunotherapy for melanoma-and perhaps the future of immunotherapy for many other malignancies.

CheckMate-067 was a randomized phase III trial in patients with previously untreated melanoma that tested therapy with nivolumab (anti–PD-1) alone or in combination with ipilimumab (anti–CTLA-4) vs ipilimumab alone.[2] Nivolumab alone more than doubled the median progression-free survival (PFS)-to 6.9 months, compared with 2.9 months for ipilimumab alone. The benefit was even greater with the combination, which resulted in a median PFS of 11.5 months. Tumor response rates were also significantly higher in patients who received the combination (57.6%) or nivolumab alone (43.7%), compared with rates in patients receiving ipilimumab alone (19%). Overall survival (OS) is not expected to be reported until further follow-up. This trial demonstrated the effectiveness of a combination of two nonredundant immune checkpoint-blocking antibodies that work differently and potentially synergistically. CTLA-4–blocking antibodies undo T-cell inhibition at the activation step of the antitumor immune response, while PD-1–blocking antibodies undo T-cell inhibition at the effector step of the antitumor immune response, activating or resurrecting exhausted T cells in the tumor microenvironment.

Immunologic checkpoints function in a complex system of self-regulation that, under physiologic conditions, may prevent autoimmune responses to the normal organ systems’ epithelial barriers and protein synthetic blocks. What we have learned from clinical trials testing immune checkpoint inhibitors is that the manipulation of the functions of these checkpoints, while resulting in therapeutic effects that can lead to the control or elimination of tumors, can also result in immune-mediated adverse events targeting self-tissues. These immune-related adverse events can be limiting, life-threatening, or, rarely, fatal. In CheckMate-067, grade 3/4 treatment-related adverse events were reported in 55% of the combination group, in 16.3% of patients who received nivolumab alone, and in 27.3% of those who received ipilimumab alone. No drug-related deaths were reported in the combination group, possibly reflecting a greater experience with the safety guidelines that were developed during earlier research involving both ipilimumab and nivolumab.[3]

These findings are extremely important and come on the heels of similar earlier results with the other anti–PD-1 antibody, pembrolizumab. In an update of the pooled analysis of the large KEYNOTE-001 phase I trial (N = 655), pembrolizumab was reported to yield sustained objective response rates in patients with advanced melanoma estimated at 33% overall (95% confidence interval [CI], 30%–37%), with a rate of 45.1% (95% CI, 36.5%–54%) in the first-line setting.[4] In the randomized phase III trial, KEYNOTE-006, presented at the 2014 American Association for Cancer Research Annual Meeting, pembrolizumab also demonstrated a clear superiority in terms of response rates and PFS, as well as OS, compared with ipilimumab.[5]

Data on PD-L1 expression in these trials suggest that the level of expression may emerge as a marker that can potentially guide regimen selection when a physician and his or her patient must choose between combination therapy and anti–PD-1 monotherapy. It may also define a group of patients (those with low PD-L1 expression) who need to be targeted separately in future anti–PD-1 combination trials. In CheckMate-067, in the group of patients with tumors that had more than 5% PD-L1 expression, the median PFS was 14 months with the combination and with nivolumab alone, while it was 3.9 months with ipilimumab alone. On the other hand, in patients whose tumors had PD-L1 expression of less than 5%, the median PFS was 11.2 months in the combination group, 5.3 months with nivolumab alone, and 2.8 months with ipilimumab alone.[3]

These unprecedented advances in melanoma immunotherapy are sure to pave the way for immunotherapy development in other tumors. We have already started to see important results in the treatment of lung cancer, bladder cancer, gastrointestinal malignancies, and other tumors.

Financial Disclosure:Dr. Tarhini serves as a consultant to Bristol-Myers Squibb and Merck (and is on Bristol-Myers Squibb’s advisory board); he receives research grant support from Amgen, Merck, and Novartis.

References:

1. Allison JP. Immune checkpoint blockade in cancer therapy: new insights, opportunities, and prospects for a cure. Presented at the American Society of Clinical Oncology Annual Meeting; May 29-June 2, 2015; Chicago.

2. 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 alone in treatment-naive patients (pts) with advanced melanoma (MEL) (CheckMate 067). Presented at the American Society of Clinical Oncology Annual Meeting; May 29-June 2, 2015; Chicago. Abstr LBA1.

3. Larkin J, Chiarion-Sileni V, Gonzalez R, et al. Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N Engl J Med. 2015 May 31. [Epub ahead of print]

4. Daud A, Ribas A, Robert C, et al. Long-term efficacy of pembrolizumab (pembro; MK-3475) in a pooled analysis of 655 patients (pts) with advanced melanoma (MEL) enrolled in KEYNOTE-001. Presented at the American Society of Clinical Oncology Annual Meeting; May 29-June 2, 2015; Chicago. Abstr 9005.

5. Robert C, Schachter J, Long GV, et al. Pembrolizumab versus ipilimumab in advanced melanoma. N Engl J Med. 2015 Apr 19. [Epub ahead of print]