Pathological response to neoadjuvant therapy correlates to RFS, OS in stage III melanoma
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Pathological response should be an early surrogate endpoint for clinical trials of neoadjuvant therapy for melanoma, according to results of a pooled analysis published in Nature Medicine.
Pathological complete response (pCR) also should be a new benchmark for drug development and approval, study authors concluded.
“Neoadjuvant systemic therapy has the potential to reduce tumor burden to facilitate and likely reduce the extent of surgical resection for stage III melanoma, as well as provide prognostic information to allow personalized follow-up and alternative adjuvant therapy in poor-prognosis patients,” Alexander Menzies, BSc(Med), MBBS(Hons), FRACP, PhD, medical oncologist and associate professor of melanoma medical oncology at Melanoma Institute Australia, told Healio. “This study confirms that pCR correlates with RFS and OS with neoadjuvant therapy in stage III melanoma, and that immunotherapy — particularly combination immunotherapy — appears more active than targeted therapy. In contrast to targeted therapy, where attainment of a pCR appears critical, any degree of pathological response with immunotherapy is sufficient to confer excellent survival.”
Multiple immunotherapy and targeted therapy regimens have been approved in the past decade for patients with distant or unresectable metastatic melanoma, as well as for adjuvant treatment of patients with stage III disease.
Although these regimens are superior to prior standard treatments, many patients with stage III disease continue to experience poor outcomes.
Clinical trial results showed relapse rates of 40% at 2 years with adjuvant immunotherapy and at 3 years with adjuvant targeted therapy. This may not account for an additional 15% to 20% of trial participants who experienced early recurrence prior to initiation of adjuvant therapy, the true recurrence rate in adjuvant trials is underestimated, according to study background.
Researchers have hypothesized that neoadjuvant therapy may benefit patients with resectable stage III melanoma in several ways, including by improving outcomes of surgery for macrometastatic disease and allowing for personalization of adjuvant therapy based on neoadjuvant response.
Several recent trials assessed PD-1-based immunotherapy or BRAF/MEK-targeted therapy as neoadjuvant treatment for melanoma.
“These trials demonstrated that neoadjuvant therapies achieve high pCR rates and impressive RFS,” Menzies said. “In several other cancers, the pCR rate to neoadjuvant therapy correlates with survival and, thus, has been used as an endpoint for registration studies for novel drug therapies.
“The relationship between pathological response and RFS and OS in stage III melanoma was unknown, largely due to the small number of patients enrolled in the individual trials conducted to date,” Menzies added. “The demonstration of a significant association could have a very significant impact in this disease, due to the large number of combinatorial strategies being considered and lower frequency of stage III/stage IV melanoma compared with other common malignancies.”
Menzies and colleagues with the International Neoadjuvant Melanoma Consortium conducted a pooled analysis of six trials to assess the relationship between pathological response and clinical outcomes with neoadjuvant anti-PD-1 immunotherapy or BRAF/MEK targeted therapy for patients with stage III melanoma.
The analysis included 192 patients (median age, 57.2 years; 58.9% men). The majority (73.4%; n = 141) received anti-PD-1 immunotherapy. This consisted of either nivolumab (Opdivo, Bristol Myers Squibb; n = 104) in combination with the anti-CTLA-4 antibody ipilimumab (Yervoy, Bristol Myers Squibb) or anti-PD-1 monotherapy (n = 37). The remaining patients (26.5%; n = 51) received targeted therapy.
Forty percent of patients achieved pCR. Researchers reported a higher pCR rate among patients who received targeted therapy (47%) than immunotherapy (33% overall; 43% with combination therapy; 20% with monotherapy).
Results showed patients who achieved pCR were more likely to achieve 2-year RFS (89% vs. 50%; P < .001) and 2-year OS (95% vs. 83%; P = .027).
Among immunotherapy-treated patients, 96% of those who achieved pCR, near pCR or partial pathological response remained relapse free at 2 years. No patient in this group had died of melanoma at data cutoff.
Among patients who received targeted therapy, pCR was associated with a 2-year RFS rate of 79% and a 2-year OS rate of 91%.
“Animal models have suggested that immunotherapy given before rather than after surgery results in a more robust immune response, with superior response and survival,” Menzies told Healio. “[Although] this pooled analysis — and comprising individual trials — of neoadjuvant therapy was not conducted head-to-head against adjuvant therapy to enable a definitive assessment, the landmark survivals appear higher, fitting with the preclinical data. As such, the magnitude of benefit of neoadjuvant therapy was as expected. Furthermore, the associations between response and survival were striking — particularly for those receiving immunotherapy, where responders seldom recur.”
Results of this trial should apply not just to melanoma, but rather to all cancers in which immunotherapy is active, Menzies said.
This could lead “to improved use of current treatments in the neoadjuvant setting, and more rapid and efficient drug development in the neoadjuvant space,” he said.
However, it is important to remember that — for now — neoadjuvant therapy for melanoma is experimental, Menzies said. It will remain so until upcoming phase 3 trials designed to compare neoadjuvant vs. adjuvant immunotherapy are completed.
“It is expected that these trials will show that the neoadjuvant approach is more effective than the currently approved adjuvant regimens,” Menzies said. “This will enable a shift in drug development to the neoadjuvant setting, whereby regimens with meaningful pathological response rates — for example, pCR rates [of 50% or higher] or response rates in populations predicted to be resistant to current therapies based on translational data — should then be prioritized for further development. This will be a more rapid and efficient way [to] develop drugs than the current heterogeneous, congested and expensive metastatic setting.”
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