A question frequently asked...with no absolute answer is.... What if I take nivo after I've progressed....having already been on nivo....or if currently on nivo?????? These reports begin an answer:
Efficacy and safety of retreatment with nivolumab in metastatic melanoma patients previously treated with nivolumab. Nomura, Otasua, Konda, et al. Cancer Chemother Pharmacol. 2017 Oct 5.
Nivolumab is a monoclonal antibody directed against programmed death-1 that has been shown to improve survival in patients with metastatic melanoma. However, the efficacy of nivolumab and other agents in melanoma remains limited. The objective of this study was to evaluate the efficacy and safety of retreatment with nivolumab in metastatic melanoma patients who previously progressed on nivolumab.
A retrospective review was performed on eight consecutive metastatic melanoma patients retreated with nivolumab who progressed on previous nivolumab. These patients received nivolumab 2 mg/kg every 3 weeks. Best responses to each treatment were assessed using RECIST 1.1.
Of eight metastatic melanoma patients, three patients received chemotherapy before first nivolumab. The median first nivolumab treatment period was 4.1 months. During first nivolumab, 3 (37.5%) patients achieved a partial response and 3 (37.5%) patients achieved stable disease as their best response. First nivolumab was discontinued due to disease progression in seven patients and grade 3 colitis in 1 patient. Patients were subsequently treated with ipilimumab (n = 6), vemurafenib (n = 1), or no other medical treatment (n = 1). The median treatment period between first and second nivolumab was 3.0 months. Four patients received radiation therapy between first and second nivolumab. The median second nivolumab treatment period was 4.3 months. Among the eight patients who received second nivolumab, 2 (25%) patients achieved a partial response and 3 (37.5%) patients achieved stable disease as their best response. Second nivolumab was discontinued due to disease progression in seven patients. One patient continues to receive second nivolumab. Among the four patients treated with ipilimumab and radiotherapy between first and second nivolumab, the response rate was 50% and the disease control rate was 75%.
This study showed that retreatment with nivolumab is an option for select metastatic melanoma patients after previous nivolumab treatment.
Here, 8 patients were given nivo (3 of them had chemo beforehand). 37.5% had a partial response. 37.5% had stable disease. Nivo was stopped due to progression in 7 of the patients and colitis in 1. 6 were subsequently treated with ipi. 1 was given vemurafenib. 4 got radiation at that point. Then...these 8 folks were given a new round of nivo. 2 attained a partial response. 3 attained stable disease. Eventually, 7 of them had to stop nivo again due to progression. Interestingly, it sounds as though those that had radiation between therapies did better....at least for a while - though that is not entirely spelled out here.
So, it seems that round two of nivo can give patients a reprieve. Though for these 8 patients it doesn't sound as though it lasted long enough!
And....there's also this....
Nivolumab for Patients With Advanced Melanoma Treated Beyond Progression: Analysis of 2 Phase 3 Clinical Trials. Long, Weber, Larkin, ….Hodi, Wolchok. JAMA Oncol. 2017 Jun 29.
Immune checkpoint inhibitors have demonstrated atypical response patterns, which may not be fully captured by conventional response criteria. There is a need to better understand the potential benefit of continued immune checkpoint inhibition beyond progression.
To evaluate the safety and potential benefit of nivolumab (anti-programmed cell death receptor 1) monotherapy beyond Response Evaluation Criteria in Solid Tumors (RECIST) v1.1-defined progression.
Pooled, retrospective analysis of data from phase 3 trials of nivolumab in treatment-naive patients with advanced melanoma (CheckMate 066 or CheckMate 067) conducted at academic and clinical cancer centers. Participants were patients treated beyond first disease progression, defined as those who received their last dose of nivolumab more than 6 weeks after progression (TBP group); and patients not treated beyond progression, who discontinued nivolumab therapy before or at progression (non-TBP group). Data analyses were conducted from November 6, 2015, to January 11, 2017. Nivolumab (3 mg/kg every 2 weeks) administered until progression or unacceptable toxic effects. Patients could be treated beyond progression if deriving apparent clinical benefit and tolerating study drug, at the investigator's discretion. Tumor response and safety in TBP and non-TBP patients.
Among 526 randomized patients (39% [n = 203] female; median age, 62 years [range, 18-90 years]), 306 (58%) experienced disease progression, including 85 (28%) TBP patients and 221 (72%) non-TBP patients. Twenty-four (28%) of the TBP patients had a target lesion reduction of greater than 30% after progression compared with baseline (TBP greater than 30% group). At the time of this analysis, 65 (76%) TBP patients and 21 (87%) TBP greater than 30% patients were still alive; 27 (32%) and 11 (46%), respectively, continued to receive treatment. Median (range) time from progression to last dose of treatment was 4.7 (1.4-25.8) months for TBP patients and 7.6 (2.4-19.4) months for TBP greater than 30% patients. Median (range) time from progression to greater than 30% tumor reduction was 1.4 (0.2-7.0) months. Treatment-related select grade 3 to 4 adverse events were similar in the TBP and non-TBP groups (5 [6%] and 9 [4%], respectively).
A substantial proportion of selected patients treated with frontline nivolumab who were clinically stable and judged to be eligible for treatment beyond RECIST v1.1-defined progression by the treating investigators derived apparent clinical benefit without compromising safety. Further analysis will help define the potential benefit of continued nivolumab treatment beyond progression.
Here they looked at the outcomes of 3 trials in which nivo was used....in 526 patients. 306 had progression. But 85 of those who progressed were given nivo more than 6 weeks AFTER their known progression, while 221 were not. Of those 85 patients "treated beyond progression", 24 "had a target lesion reduction of greater than 30% after progression compared to baseline." And at follow-up further down the line, many of those were still alive.
There is much we still don't understand about immunotherapy. But, I think the statement Agarwala and Weber made to, "Be patient with the patient!" still holds. Hang tough, ratties! And, thanks! - c
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