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The cancer treatment landscape dramatically changed since the first approval of an immune checkpoint inhibitor (ICI), ipilimumab, a CTLA-4 inhibitor, in 2011 for advanced melanoma. This landmark approval was soon followed by pembrolizumab, nivolumab, and a host of other PD-1/L1 antibodies that serve as ICIs.

Demonstrating efficacy across multiple tumor types, there is no question that ICIs have revolutionized our approach to treatment and are arguably the most utilized anti-cancer drugs available today. Many studies have indicated complete responses in patients with ICI use, irrespective of tumor type. The relatively milder toxicity profile compared with cytotoxic chemotherapy often makes these drugs a better option for patients deemed too frail for traditional chemo.

Despite their durable responses and survival advantages, however, ICIs can eventually stop working in the advanced malignancy setting. Tumors develop resistance mechanisms, as seen with use of other targeted therapies and cytotoxic chemotherapy. The recent article by Dr. Biagio Ricciuti, et al. published in the titled "Genomic and Immunophenotypic Landscape of Acquired Resistance to PD-(L)1 Blockade in Non-Small Cell Lung Cancer," explores these pathways of resistance.

While their data was limited to non-small cell lung cancer patients, the researchers created an intricate study, examining over 1,700 patients who had progressed on ICI therapy with or without chemo. The genomic landscape of initial tumor tissue was compared with that of post-ICI use. A control cohort of patients on non-ICI therapies were also included in this study. Resistance mutations were found in nearly 28% of immunotherapy-treated patients. These mutations which were not seen in the control group, include acquired loss-of function mutations in STK11, B2M, APC, MTOR, KEAP1, and JAK1/2. Furthermore, post-ICI samples showed a decrease in intratumoral lymphocytes.

The data presented in this study show that while ICIs often lead to robust responses, methods of resistance can and often will develop. Future approaches to mitigate resistance and provide a more durable response could include combination therapy with ICIs and targeted treatments against these mutations. The challenge is, however, predicting which resistance mutations will occur.

ICIs have revolutionized anti-cancer treatment, but with more robust responses, we must be prepared to tackle rapid resistance.

Rajasree Pia Chowdry, MD, is assistant professor of clinical medicine in the Section of Hematology/Oncology at LSU Health Sciences Center, Louisiana Cancer Research Center, in New Orleans.

Read the study here and an interview about it here.