This issue of Clinical Cancer Research includes a CCR Focus on immunotherapy, appearing 10 years after Drs. Zang and Allison in a Focus article introduced our readers to the idea that blocking the PD-L1/PD-1 interaction could enhance antitumor immunity and reverse the poor prognosis conferred by expression of PD-L1 on tumor cells (1). In the decade that followed, we have seen the introduction of blocking antibodies to the clinic and FDA approval in rapid succession, based on overall response rate (ORR), progression-free survival (PFS), and overall survival (OS) endpoints, as shown in an abbreviated list:
Pembrolizumab
Mismatch repair deficient tumors – 39.6% ORR
Urothelial cancer (first-line) – 29% ORR
NSCLC (first-line with pemetrexed/cisplatin) – 55% vs. 29% ORR
Hodgkin lymphoma – 69% ORR
NSCLC (first line) – 10.3 months versus 6.0 months PFS
Squamous cell carcinoma head and neck – 16% ORR
Melanoma (first line) – at 33 months, 50% versus 39% OS
NSCLC – 41% ORR
Melanoma – 24% ORR
Nivolumab
Urothelial cancer – 19.6% ORR
Squamous cell carcinoma head and neck – 7.5 months versus 5.1 months OS
Hodgkin lymphoma – 65% ORR
Melanoma – nivolumab with ipilimumab, 11.5 months versus 6.9 months PFS
Renal cell carcinoma – 25 months versus 19.6 months OS
NSCLC –12.2 months versus 9.4 months OS
Melanoma – 32% ORR
Atezolizumab
Bladder cancer – 23.5% ORR
NSCLC – 13.8 months versus 9.6 months OS
Urothelial cancer – 14.8% ORR
Durvalumab
Bladder cancer – ORR 17%
The over 20 FDA approvals have brought numerous additional questions, and Guest Editors Lillian Siu, Percy Ivy, and Gary Rosner have assembled a thoughtful group of experts to examine prevailing to current challenges in the development of checkpoint inhibitors. No one can doubt that the activity of immune therapies in diverse tumor types represents a paradigm shift long awaited by those working diligently in the field. But as the series plays out, it is clear that the “rapid approval track” we have been so thrilled to observe (2) has had its limitations. The experts here discuss the design of clinical trials; the fact that traditional endpoints may fall short; the need for biomarkers to predict and report responses; the need to understand pseudoprogression and the possibility of hyperprogression (3, 4); the need to understand what patient populations should/should not be treated; and next steps toward successful combinations. Some of these things might have been worked out in a more traditional development scheme, but most represent the second wave that comes after a therapy has been shown to be successful. The question about patient populations is critical. For example, are checkpoint inhibitors safe in those with comorbidities such as heart, lung, or liver disease; are they safe with underlying viral illnesses; or in the elderly or the very young? The FDA has approved checkpoint inhibitors without biomarker selection, thereby approving agents that in the absence of PD-L1 expression could have response rates in the single digits, not worthy of approval.
The issue of pseudoprogression, unique to immunotherapies, needs to be definitively studied. A recent data analysis showed an ORR of 8.3% in patients treated past progression (3). We must query whether this response rate warrants the practice of treating past progression. But resolving these questions will not solve the overarching problem – that the majority of patients do not benefit from these therapies. We have noted before how difficult it is for patients to reconcile the disconnect between the headlines and their own bottom line.
As with every CCR Focus, this one is meant to interest and inform those not expert on a topic, and inspire those working in the field. For me personally, this issue brings to a close my stewardship of CCR Focus. It has been a great privilege for me to bring the work of so many talented and dedicated researchers to the readers of Clinical Cancer Research. I am grateful for their insights and expert opinions, and most of all to the readers who have encouraged and cited its content. The past 12 years of CCR Focus represent a remarkable chronicle of cancer research at the cutting edge. As a community working to improve outcomes for cancer patients looking back on this period, we are thankful for our successes and disappointed by our failures. We still have a long way to go, but as the CCR Focus archive demonstrates, our community is creative, resilient, optimistic, and determined to work for better and less toxic therapies.
Susan E. Bates
Deputy Editor, CCR Focus
Columbia University Medical Center
See all articles in this CCR Focus section, “Clinical Trial Design Considerations in the Immuno-oncology Era.”
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