Encouraging results from two new studies presented during the last ESMO congress: the effectiveness of neoadjuvant immunotherapy in patients with mismatch repair-deficient (dMMR) colon cancer was shown for the first time in the exploratory NICHE trial, and a neoadjuvant therapy with anti-PD-1 demonstrated better results than adjuvant therapy in resectable Stage IIIB-IV melanoma patients in the SWOG S1801 trial.
In the NICHE-2 trial, 112 patients with non-metastatic dMMR colon cancer received one dose of ipilimumab and two doses of nivolumab ≤6 weeks prior to surgery (with a median 5.4 weeks from first dose to surgery). The primary endpoint of safety was met and a pathological response was observed in 99% of patients, with major pathological response and pathological complete response achieved in 95% and 67% of patients, respectively. No patients had disease recurrence after a median follow-up of 13.1 months.
In the SWOG S1801 trial, 313 patients with resectable Stage IIIB-IV melanoma were randomized to adjuvant therapy (surgery followed by 18 doses of pembrolizumab) or neoadjuvant therapy (3 doses of preoperative pembrolizumab, surgery and 15 doses of adjuvant pembrolizumab). With a median follow-up of 14.7 months, event-free survival was significantly higher on neoadjuvant therapy compared to adjuvant therapy, with similar adverse events and 21% of the patients in the neoadjuvant arm with a complete pathological response.
Both studies show an advantage in neoadjuvant therapy: it offers the opportunity to reduce the risk of disease relapse using short courses of treatment that are beneficial in terms of efficacy, patient quality of life and healthcare resource use. The counterintuitive strategy of retaining the tumor during treatment is based on sound rationale: neoadjuvant use of checkpoint inhibitors activates both the priming phase of immunity within tumor tissue and the effector phase within the tumor microenvironment. This dual attack is elicited to a lesser extent if the macroscopic tumor has already been removed, as is the case for adjuvant therapy, and data show that neoadjuvant immunotherapy expands more T-cell clones than adjuvant treatment. The data from these trials have the potential to be paradigm changing, however there’s the need to a deeper understanding of the relative benefits of neoadjuvant and adjuvant therapy by a proper design of clinical trials: many trials comparing the two approaches are actually comparing neoadjuvant plus adjuvant therapy versus adjuvant therapy, making it difficult to unpick which element of treatment is giving the benefit. In order to determine the relative benefits of neoadjuvant and adjuvant approaches, the most important challenge now is to conduct well-designed, controlled trials that distinguish between the two components of treatment.