Some patients being treated with nivolumab (Opdivo) for advanced renal cell carcinoma may still derive benefit if continued on the immunotherapy after disease progression, according to an analysis of phase III study data.
Some patients being treated with nivolumab (Opdivo) for advanced renal cell carcinoma (RCC) may still derive benefit if continued on the immunotherapy agent after disease progression, according to a subgroup analysis of data from the phase III CheckMate 025 study.
The findings, which were published online in European Urology (April 12, 2017), showed that among 153 patients treated with nivolumab for a median duration of 3.4 months beyond disease progression, 74 (48%) had evidence of some tumor burden reduction, and 20 patients (13%) had ≥30% tumor burden reduction. Median overall survival in patients treated beyond progression with nivolumab was 28.1 months versus 15.3 months in patients not treated beyond RECIST progression.
Continued nivolumab therapy had an acceptable safety profile. The incidence of treatment-related adverse events was 59% compared with 71% while the same patients were being treated before progression.
“This analysis from a large, international, phase III study is consistent with results from the phase II study [JAMA Oncol 2016; 2:1179–86], demonstrating that patients [treated beyond RECIST progression] with nivolumab resulted in additional clinical benefit as evidenced by 13% of patients experiencing a subsequent 30% decrease in tumor burden,” wrote the authors, led by led by Bernard Escudier, MD, of the Institut Gustave Roussy, Villejuif, France.
Based on the findings, the authors concluded that clinical judgment remains essential when switching therapy for patients. They also noted the data support overall survival as a primary endpoint for future trials, considering that some patients treated with nivolumab benefit despite progression.
The basis for maintaining patients on immunotherapy beyond RECIST progression derives from the potential for tumor flare to occur before onset of any clinical treatment benefit. Tumor flare may represent infiltration of immune cells into the tumor as a response to the immunotherapy or actual growth of the tumor before the immune system has been primed to produce an antitumor response.
As noted in the paper, there have been previous reports of patients with a variety of cancers benefiting from ongoing treatment after RECIST progression. In fact, in the phase II study of nivolumab for advanced RCC, 25 of 36 patients (69%) treated beyond RECIST progression demonstrated tumor reduction or stabilization in their target lesion when continued on the immune checkpoint inhibitor.
To further explore this potential for benefit, data from the larger, phase III CheckMate 025 study were analyzed. CheckMate 025 included 406 patients randomized to treatment with intravenous nivolumab, 3 mg/kg every 2 weeks, of whom 316 (78%) progressed by RECIST criteria. The latter patients were eligible to remain on treatment if they were tolerating nivolumab and had investigator-assessed clinical benefit.
Of the 153 patients treated beyond progression, 29 had a complete/partial response as their best response before being treated beyond progression, 47 had stable disease, and 66 had progressive disease. Rates of ≥30% reduction in tumor burden with nivolumab treatment beyond progression achieved in these three subgroups were 28%, 6%, and 14%, respectively.
Comparing patients who achieved a ≥30% reduction in tumor burden when treated with nivolumab beyond progression with their counterparts not treated beyond progression showed the former group had a better median quality of life and included a higher proportion of patients with a favorable Memorial Sloan Kettering Cancer Center risk score and with lung metastases.
Comparisons of characteristics of patients treated with nivolumab beyond progression and those who were not found no difference between the two groups in the frequency of treatment-related adverse events from randomization to first progression. However, the patients treated beyond progression had better Karnofsky performance status, less deterioration in Karnofsky performance status, shorter time to response, lower incidence of new bone lesions, and better quality of life.
It was noted that data on the investigators’ rationale for treating patients beyond progression were not available. The more favorable characteristics of the patients treated beyond progression may have influenced the investigators’ decision to continue nivolumab treatment but also impacted their survival.
With the aim of avoiding excessive duration of therapy, the authors stated that further investigations are warranted to better determine which patients may benefit from treatment beyond progression.
The study was sponsored by Bristol-Myers Squibb and Ono Pharmaceutical Co., Ltd. Dr. Escudier has received honoraria from Bayer, Bristol-Myers Squibb, Exelixis, Novartis, and Pfizer. Several of his co-authors have a financial and/or other relationship with pharmaceutical companies.
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