Suzanne L.Topalian, MD
The neoadjuvant use of checkpoint blockade immunotherapy is showing promise in early clinical findings, opening up a potential new frontier for the game-changing modality to make an impact in earlier treatment settings in multiple solid tumor types.
Patients who received PD-1 or PD-L1 inhibitors before surgery or chemotherapy demonstrated positive outcomes in phase II studies in Merkel cell carcinoma (MCC), non–small-cell lung cancer (NSCLC), muscle-invasive bladder cancer (MIBC), and triple-negative breast cancer (TNBC), according to results reported at the 2018 American Society of Clinical Oncology (ASCO) Annual Meeting.
The rationale for earlier use of these agents stems from analyses of T-cell activity after the administration of the immune checkpoint blocking agents. Whereas conventional neoadjuvant chemotherapy is intended to shrink the tumor before surgery, immunotherapy serves as a primer for systemic antitumor responses, activating tumor-specific T cells that seek out distant micrometastases.1
Suzanne L. Topalian, MD, a pioneer in the development of anti–PD-1/PD-L1 immunotherapy, discussed the potential for the checkpoint blocking drugs in the neoadjuvant setting recently during the Noreen O’Neill Melanoma Research Symposium at the Wistar Institute in Philadelphia, Pennsylvania.
Melanoma and other skin cancers are serving as a proving ground for immunotherapy concepts, noted Topalian, who is associate director, Johns Hopkins Bloomberg–Kimmel Institute for Cancer Immunotherapy in Baltimore, Maryland. In MCC, a rare and aggressive skin cancer, investigators showed that neoadjuvant nivolumab (Opdivo) administered as 2 doses over approximately 4 weeks before surgery generated a pathologic complete response (pCR) or a major pathological response (MPR), defined as ≤10% residual viable tumor cells in the surgical specimen, in 65% of 17 patients whose samples were centrally reviewed.2
The strategy is being explored in other types of skin cancers, including melanoma. “The future development of anti–PD-1 in skin cancers is going to focus on earlier disease settings such as neoadjuvant therapy, adjuvant therapy, and on difficult-to-treat patient populations such as immunosuppressed patients,” Topalian said.
Topalian believes that neoadjuvant studies in melanoma will help pave the way for advancements in other tumor types, the pattern that has emerged over the past decade with checkpoint blocking agents. Melanoma “has always been the first tumor that people have looked at to develop immunotherapies for cancer. We realized a long time ago that melanoma was particularly responsive to immune therapies,” she said in an interview with OncologyLive®
After decades of research, investigators believe that “melanomas are very immune-responsive because they contain a lot of mutations, and they contain a lot of mutations because many of them are caused by a carcinogen, which is ultraviolet light,” Topalian said. “Those mutations create new proteins that have never been seen by the immune system before. Because they are not normal, the immune system can recognize these mutant proteins very vigorously. This is one of the working theories for why melanoma is so immune-responsive, similar to lung cancer and bladder cancer. These are all carcinogeninduced cancers that have many mutations.”
Among the hundreds of ongoing clinical trials exploring anticancer immunotherapy regimens, many early studies are focusing on the neoadjuvant setting in a range of tumor types. These include several phase II and phase III studies (Table
). Meanwhile, early-stage findings are being reported, including research presented at ASCO 2018.
More data from larger populations will be needed to draw firm conclusions about the efficacy of neoadjuvant checkpoint blocking immunotherapy, experts say. Future developments in new settings and with new combinations, Topalian noted, will increasingly focus on biomarkers. The FDA has approved the use of tumor PD-L1 expression level and microsatellite instability (DNA mismatch repair deficiency) as biomarkers to recommend patients for anti-PD-1/PD-L1 therapy in several settings and is considering tumor mutation burden as another marker.
“There’s been a lot of research activity around biomarkers and also around combination therapies,” she said. “Those 2 things are really linked, because the biomarker work can identify molecules associated with treatment resistance that we might want to direct drugs against in combination with anti–PD1 or anti–PD-L1 therapy.”
Table. Selected Neoadjuvant Immunotherapy Trials
The CheckMate-358 study represents the first trial of anti–PD-1 therapy in a neoadjuvant (presurgical) setting for patients with unresectable MCC, Topalian said in presenting the data at ASCO 2018. In 2017, avelumab (Bavencio), which targets PD-L1, gained the FDA’s approval for patients with unresectable metastatic MCC.