SPOTLIGHT Motivated by the success of ipilimumab and the need to provide new treatment options for patients who did not achieve longterm response to ipilimumab, researchers focused on targeting a second checkpoint protein, PD-1, as well as one of the proteins that attaches to it, PD-L1. The first FDA approval of an ICI targeting PD-1 or PD-L1 occurred in September 2014, when pembrolizumab (Keytruda), which targets PD-1, was approved for treating certain patients with metastatic melanoma. Notably, since the approval of pembrolizumab, three additional ICIs have been approved by FDA for the treatment of patients with metastatic melanoma, to be used alone or in combination with another ICI or molecularly targeted therapeutics. Thanks to these clinical breakthroughs, mortality from melanoma has declined significantly, for the first time in four decades, during the period between 2013 and 2017, and continues to trend downward (425). The third immune checkpoint protein targeted by an ICI is LAG-3. The first and, so far, only LAG-3 targeted ICI, relatlimab-rmbw, was approved by FDA in March 2022 in combination with nivolumab (Opdualag) for treatment of certain patients with melanoma. Two researchers whose pioneering work established the field of ICIs, James P. Allison, PhD, p. 104, and Tasuku Honjo, MD, PhD, were recognized with the 2018 Nobel Prize in Physiology or Medicine for “their discovery of cancer therapy by inhibition of negative immune regulation.” The use of ICIs in the treatment of cancer has rapidly expanded over the last decade and these therapeutics are considered one of the most exciting approaches to cancer treatment. This is in part because some patients with metastatic disease who have been treated with these therapeutics have had remarkable and durable responses. As one example, long-term results from a clinical trial testing the ICI pembrolizumab for patients with advanced NSCLC showed that 23 percent lived 5 or more years, which stands in stark contrast to the historical 5-year relative survival rate for patients with advanced NSCLC of about 5 percent (426). Recent analysis suggests that the use of ICIs is also favorably associated with patients’ quality of life (427). As of July 31, 2023, FDA has approved eleven ICIs, targeting one of three different T-cell brakes, CTLA-4, PD-1/PD-L1, or LAG-3. Notably, these groundbreaking treatments are FDA approved for an increasingly broad array of cancer types (see Figure 19, p. 106). As of July 31, 2023, there was at least one checkpoint inhibitor approved for treating 20 cancer types and for treating any type of solid tumor characterized by the presence of either of three specific molecular characteristics (see Figure 19, p. 106). A watershed moment in cancer medicine was the May 2017 FDA approval of the ICI pembrolizumab for treatment of patients with solid tumors not of a specific organ/tissue type but rather characterized by the presence of either of two specific molecular characteristics, or biomarkers, called microsatellite instability– high and DNA mismatch–repair deficiency. These biomarkers are found in a small proportion of cancers arising at numerous sites in the body, including the colon, endometrium, stomach, and rectum. This was the first ever approval of a therapeutic to treat cancer based solely on its molecular alterations rather than the site of origin. It was also an example of precision immunotherapy, whereby a patient’s immunotherapy is tailored to the molecular characteristics of his or her tumor. Remarkable progress in our understanding of cancer biology and in the conduct of clinical research led to this approval. Since 2017, pembrolizumab has been approved for the treatment of patients with tumors characterized by another biomarker known as high tumor mutational burden (TMB); additionally, a second ICI, dostarlimab-gxly, and several molecularly targeted therapeutics have received site-agnostic FDA approvals based on biomarkers and are providing new treatment options and new hope to patients with a wide range of cancer types. Changing the landscape of FDA-approved immune checkpoint inhibitors • In 2022, 1,236 new clinical studies were initiated, globally, testing PD-1/ PD-L1 targeted immune checkpoint inhibitors in cancer, a 54 percent increase from 2017 (332). • There are >3,000 ongoing clinical studies, worldwide, testing PD-1/PD-L1 inhibitors; >80 percent of these trials are evaluating these agents in combination. The combination agents target >300 different pathways (332). IMMUNE CHECKPOINT PROTEIN TARGETED 2013 2023 (as of July 31) CTLA-4 PD1/PD-L1 LAG-3 ipilimumab tremelimumab ipilimumab pembrolizumab nivolumab atezolizumab avelumab durvalumab cemiplimab-rwlc dostarlimab-gxly retifanlimab-dlwr relatlimab-rmbw continued on page 106 Immunotherapy: Pushing the Frontier of Cancer Medicine AACR Cancer Progress Report 2023 103
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