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Nivolumab benefits patients with melanoma treated beyond progression
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Patients with melanoma continued to experience tumor response to nivolumab monotherapy when treated beyond progression, according to a pooled analysis of data from the CheckMate 066 and CheckMate 067 studies.
“The results of this analysis suggest that continued treatment with nivolumab [Opdivo, Bristol-Myers Squibb] may be an option to achieve further apparent clinical benefit in some patients with advanced melanoma,” Georgina V. Long, PhD, BSc, MBBS, FRACP, chair of melanoma medical oncology and translational research at Melanoma Institute Australia and Royal North Shore Hospital of The University of Sydney in Sydney, Australia, and colleagues wrote.
Nivolumab — a PD-1 inhibitor — monotherapy conferred better OS and PFS than dacarbazine among treatment-naive patients with BRAF wild-type melanoma in the CheckMate 066 study, and improved PFS and objective response rate among treatment-naive patients with BRAF-mutated melanoma over ipilimumab (Yervoy, Bristol-Myers Squibb) in the CheckMate 067 study.
Long and colleagues pooled data from these trials to assess the safety and potential benefit derived from continuing nivolumab after Response Evaluation Criteria in Solid Tumors (RECIST) v1.1–defined progression.
“Although disease progression is considered failure of treatment for nonimmunotherapeutic agents, resulting in treating discontinuation, the possibility of delayed, immune-related responses suggests that patients with disease progression could benefit from continued treatment with immune checkpoint inhibitors,” Long and colleagues wrote. “Therefore, across the nivolumab development program, patients were permitted to continued study treatment after initial investigator-assessed RECIST v1.1–defined progression, provided that they were considered to be deriving clinical benefit and tolerating the study drug.”
The analysis included 206 patients from CheckMate 066 and 313 from CheckMate 067 (39% women, median age, 62 years) who received 3 mg/kg IV nivolumab monotherapy biweekly until disease progression or unacceptable toxicity.
In total, 306 (58%) of patients experienced disease progression. Eight-five patients (CheckMate 066 = 30; CheckMate 067 = 55) treated beyond progression received their last dose of nivolumab more than 6 weeks after progression; 220 patients not treated after progression discontinued treatment before or at RECIST–defined progression.
Thirty-six patients (42%) treated beyond progression had a reduction in tumor burden after first progression, all of which occurred before week 24. In 24 patients (28%), the target lesion reduction exceeded 30% compared with baseline; researchers evaluated these patients as a separate subgroup. The median time from progression to greater than 30% reduction in tumor lesions was 1.4 months (range, 0.2-7).
The median time from randomization to death or last known date alive was 14.3 months (range, 5-27.9) among those treated beyond progression; 9.9 months (range, 0.3-27.6) among those not treated beyond progression; and 15 months (range, 10.4-24.7) in the target lesion reduction group.
At the time of analysis, 65 patients treated beyond progression and 21 in the target lesion group remained alive. Of these, 27 patients treated beyond progression and 11 in the target lesion group remained on treatment.
Patients received a median nine (range, 3-53) doses of nivolumab after progression; this increased to 16.5 (range, 5-41) in the target lesion group.
The median time from progression to the last dose of treatment was 4.7 months (range, 1.4-25.8) for all patients treated beyond progression and 7.6 months (range, 2.4-19.4) for patients in the target lesion group.
Patients treated beyond progression demonstrated longer median OS (not reached vs. 10.6 months) and higher rates of 24-month OS (59% vs. 25%) than patients not treated.
Treatment-related adverse events of any grade appeared similar between the groups, but occurred more frequently among those treated beyond progression. Grade 3 and grade 4 adverse events occurred in 4% of patients not treated beyond progression and 6% of those who continued treatment.
Because only 28% of patients in the beyond treatment group had a 30% reduction in tumor lesions, it suggests only a certain number of patients may benefit from this strategy, Gideon M. Blumenthal, MD, clinical team leader for lung and head and neck cancers, and scientific liaison for lung cancer, Office of Hematology Oncology Products at the U.S. FDA Center for Drug Evaluation and Research, and colleagues wrote in a related editorial.
“This suggests that this strategy only benefits a minority of patients, with potential harms: increased risk of toxic effects, increased cost to the patient and risk [for] forgoing or delaying switching to an alternative, more effective therapeutic option,” they wrote.
The editorial authors suggest “more systematic and uniform data collection” is needed to determine which patients benefit the most from treatment beyond progression. – by Melinda Stevens
Disclosure: Long reports personal fees from and consultant/advisory roles with Amgen, Bristol-Myers Squibb, GlaxoSmithKline, Merck and Roche; and honoraria from Bristol-Myers Squibb, GlaxoSmithKline, Merck and Roche. Please see the full study for a list of all other researchers’ relevant financial disclosures. Blumenthal and colleagues report no relevant financial disclosures.
Perspective
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Nivolumab (Opdivo, Bristol-Myers Squibb) and pembrolizumab (Keytruda, Merck) — the immune checkpoint inhibitors targeting PD-1 — have revolutionized the treatment of metastatic melanoma. This class of drugs has led to improvements in overall response rates, PFS and OS in patients with the disease. Rarely (< 10% of patients), pseudo progression in a patient can be seen. It has long been recognized that although important and valuable, objective tumor measurements via Response Evaluation Criteria for Solid Tumors, or RECIST, has its shortcomings. Therefore, despite the infrequency of pseudo progression, many immunotherapy protocols allow treatment beyond progression.
Long and colleagues retrospectively analyzed two large phase 3 studies, each of which contained a nivolumab monotherapy arm. In these studies, researchers allowed treatment beyond first evidence of progression. They found that some patients appeared to benefit from nivolumab when continuing beyond first progression.
It is important to note that the selection of patients who may benefit from checkpoint inhibition beyond progression is important. In this study, patients who had a performance status of at least 1, elevated lactate dehydrogenase, progression in nontarget lesions, or the finding of new lesions with an increase in target lesions appeared less likely to receive treatment beyond progression. Oncologists need to consider a number of factors before contemplating continuation beyond progression. However, as we have witnessed, and as indicated in this important analysis, a small number of patients may go on to have meaningful responses and can be considered for treatment beyond progression.
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