Cancer Cell, Immunotherapy: Cancer Cell, ImmunotherapyIn a randomized, Phase II clinical trial, researchers at SWOG show certain patients with Stage III-IV melanoma had significantly better outcomes when given immunotherapy both before and after surgery as opposed to following surgery alone, which is the standard of care. Detailing their findings in the New England Journal of Medicine, the researchers reported that starting patients on pembrolizumab to activate immune cells prior to surgical resection of tumors significantly improved event-free survival (2023; doi: 10.1056/NEJMoa2211437). At 2 years, 72 percent of patients were free of recurrence if they received neoadjuvant pembrolizumab compared to 49 percent of patients who received adjuvant pembrolizumab only. “This study was designed to determine if adjuvant therapy is the right therapy, or if we should consider also giving neoadjuvant therapy to these patients,” said Bartosz Chmielowski, MD, PhD, Clinical Professor of Medicine in the Jonsson Comprehensive Cancer Center at the University of California Los Angeles, who was UCLA's primary investigator for the multicenter SWOG Cancer Research Network study known as S1801 (NCT03698019).Bartosz Chmielowski, MD, PhD: Bartosz Chmielowski, MD, PhDChmielowski is a member of the SWOG melanoma committee along with Antoni Ribas, MD, PhD, Director of the Tumor Immunology Program at UCLA and former chair of the SWOG melanoma committee, who is the senior author study. The research is led by Sapna Patel, MD, current chair of the SWOG melanoma committee and Associate Professor at The University of Texas MD Anderson Cancer Center. The researchers theorized that when the bulk of a tumor is removed so are tumor-fighting T cells, which prevent the proliferation of immune cells normally seen after PD-1 blockade. “It is interesting that pembrolizumab, a checkpoint inhibitor, does not bind to cancer cells; it binds to T cells and unleashes them to fight cancer,” Chmielowski said. “One must assume some of the cells that have specificity against the tumor are present inside of the tumor. And, when you do the surgery, you remove some of these tumor-specific cells. Immune therapy would have had a chance to activate them, but they are gone because they were removed with the bulk of the tumor. “Fortunately, we know that tumor-specific cells are not present only inside the tumor, otherwise, adjuvant immunotherapy would have no chance to work,” he continued. “We must also assume that the more cancer cells are present in the body the easier it is for them to elicit anti-cancer immune response.” The increase in event-free survival has “enormous implications,” Chmielowski told Oncology Times. “I actually would call the results of this trial revolutionary, generally, in oncology. Because it tells you right now that you cannot be comfortable just with selecting the correct drug, but that you have to choose the right timing of when to give it. No longer can physicians assume that they can just wait until after surgery to give patients immunotherapy, because later might be too late.” Trial Details The clinical trial included 313 patients with clinically detectable, or palpable, and measurable Stage IIIB-IVC melanoma indicating surgical resection. About one-half of the patients (154) were randomized to the neoadjuvant-adjuvant group and received three doses of pembrolizumab to begin activating immune cells in the tumor prior to surgical resection. They then received 15 more doses of the immune therapy post-surgery. In the adjuvant-only cohort following surgery, patients received pembrolizumab in 200 mg doses delivered intravenously every 3 weeks for a total of 18 doses over 1 year. At a median follow-up of 14.7 months, the neoadjuvant-adjuvant group had significantly longer event-free survival (P=0.0004 by the log-rank test). At the 24-month follow-up, which the researchers described as “a landmark analysis,” event-free survival was 72 percent (95% CI: 64-80) in the neoadjuvant-adjuvant group, compared to 49 percent (95% CI: 41-59) in the adjuvant-only group. Importantly, both arms of patients in the study at the end received the same treatment, Chmielowski noted. “One arm received three doses of pembrolizumab in the neoadjuvant setting followed by surgery and by additional pembrolizumab to complete 1 year of immunotherapy, while the other arm was randomized to immediate surgery and then completed 1 year of pembrolizumab,” he said. “And there was no difference in dosing or the kind of procedures; only the timing of the procedures was different.” The concept of neoadjuvant therapy is not new, Chmielowski noted. “But most of the time we are comparing chemotherapy A to chemotherapy B, or chemotherapy to no chemotherapy before surgery,” he said. “Here, we are actually using the same treatment but with different timing, and it still makes a difference.” It is also important to remember that neoadjuvant-adjuvant pembrolizumab is only for those patients with Stage III-IV disease who are planned for surgical resection with measurable disease on their scans, Chmielowski noted. “Adjuvant therapy would be a viable option for patients who do not have palpable lymph nodes and are only diagnosed with Stage III melanoma after surgical intervention,” he said. Surgical Precision The findings from the new study reinforce the need for medical oncologists and surgeons to communicate, Chmielowski said. “And we always do. But now, knowing the results of S1801, it is a little bit more of a responsibility. Very often these patients are first sent to a surgeon, and it is our responsibility to educate surgeons that immunotherapy should be considered before surgical procedures.” To be clear, immunotherapy does not replace the need for surgery. Resection of the involved lymph nodes is still needed; the procedure is just delayed, Chmielowski said. “Frequently, when neoadjuvant therapy is discussed, there is a worry that a possible curative surgical intervention is delayed by giving systemic therapy first. The S1801 study addressed this concern,” he emphasized. A number of patients in the neoadjuvant-adjuvant group in the SWOG clinical trial did not go to surgery because there was progression of the disease. “But in the adjuvant group, there was a similar number of patients who never started the immunotherapy because they had progression of the disease immediately after surgery,” Chmielowski said. “One can argue that neoadjuvant immunotherapy spared these patients from unnecessary surgery.” The Right Way to Go In terms of further research into the use of neoadjuvant pembrolizumab in patients with advanced melanoma, Chmielowski first noted that, in the new SWOG clinical trial, about 21 percent had a complete pathological response in the lymph node at the time of surgery. “So next, the question would be: ‘Do these patients require additional adjuvant therapy? Or can they start with the neoadjuvant therapy and, if there is a pathologic complete response in the removed lymph nodes, no additional therapy is given afterward?” he asked. Chmielowski pointed to the PRADO trial in which patients with high-risk Stage III melanoma were given personalized response-directed surgery and adjuvant therapy after just two doses of neoadjuvant ipilimumab and nivolumab. In this research, the drug combination produced high pathologic response rates (pRR) in patients with clinical Stage III nodal melanoma, and pathologic response was greatly associated with prolonged relapse-free survival. Ninety-nine patients participated in the PRADO study and received treatment with 6 weeks of neoadjuvant-ipilimumab 1 mg kg-1 and nivolumab 3 mg kg-1. The pRR was 72 percent, including 61 percent with major pathological response (MPR), while 22 percent of patients had Grade 3-4 toxicity in the first 12 weeks. What's more, 59 of the 60 patients with MPR did not have to undergo therapeutic lymph node dissection (Nat Med 2022; doi: 10.1038/s41591-022-01851-x). The low rates of relapse in patients enrolled in the study suggested that the two doses of the drug combination may be sufficient, but a longer follow-up is needed, Chmielowski said. “And so now we are asking, ‘Should we be using combination therapy in the neoadjuvant setting?’” he noted, adding, “If the combination therapy is better, then can we spare the patients from additional therapy after surgery?” Meanwhile, a number of other antibodies are being tested in the neoadjuvant and adjuvant settings, Chmielowski said. “Several questions remain, but right now we know that neoadjuvant therapy is the right way to go. Because after these results, nobody can be comfortable giving patients adjuvant therapy when they could be giving neoadjuvant therapy.” Chuck Holt is a contributing writer. Top 10 Best Hospitals for Cancer