Fewer nivolumab doses with ipilimumab appear effective in unresectable melanoma
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The first two doses of nivolumab with ipilimumab appeared to drive efficacy and toxicity of the combination among certain patients with melanoma, according to phase 2 study results presented during the ASCO20 Virtual Scientific Program.
The findings suggest early radiographic imaging 6 weeks after treatment initiation may identify patients who do not respond to this combination beyond two doses of nivolumab (Opdivo, Bristol-Myers Squibb).
“With medical treatment, studies to investigate lower doses of medication are essential, yet I don’t think they are as common as they perhaps should be,” Michael A. Postow, MD, medical oncologist at Memorial Sloan Kettering Cancer Center, told Healio. “The obvious benefit of these studies is to see whether we can decrease adverse events and financial toxicity.
“Yet, more importantly, these studies can also help establish important scientific principles like whether on-treatment assessments can help us consider de-escalating or escalating treatments,” he added. “These studies will be increasingly important as we continue to investigate multiple drug combinations.”
Standard combination immunotherapy for patients with unresectable stage III or stage IV melanoma consists of four doses of nivolumab, an anti-PD-1 antibody, and ipilimumab (Yervoy, Bristol-Myers Squibb), an anti-CTLA-4 antibody. However, retrospective studies have shown that patients who receive fewer than four doses because of toxicity still experience durable responses.
Postow and colleagues conducted a multicenter trial that included 60 patients with unresectable stage III or stage IV melanoma. Patients received two doses of nivolumab dosed at 1 mg/kg in combination with 3 mg/kg ipilimumab, followed by a CT scan at week 6.
Patients who achieved complete or partial responses or stable disease and exhibited no increase in total measurable tumor burden had protocol-defined early favorable antitumor effect and transitioned from the combination to maintenance nivolumab.
Patients who did not demonstrate favorable antitumor effect at week 6 received standard third and fourth doses of the combination, followed by maintenance nivolumab.
Response rate by RECIST version 1.1 at week 12 served as the primary endpoint. Additional efficacy assessments and safety served as secondary endpoints.
Results showed 41 patients (68%) achieved a favorable antitumor effect at week 6.
Best overall response rates — including partial and complete responses — were 48% (95% CI, 35.2-61.6) at week 12 and 53% (95% CI, 40-66.3) at any time after week 12.
Eighteen percent of patients received one dose of the combination, 58% received two doses, 12% received three doses and 10% received four doses.
All patients experienced any-grade treatment-related toxicities after median follow-up of 11 months, and 57% developed grade 3 or grade 4 treatment-related toxicities. Two patients died of myocarditis and one died of possible adrenal insufficiency related to treatment.
None of the 19 patients who did not achieve favorable antitumor effect at week 6 and were not selected to de-escalate the combination therapy responded with ongoing combination dosing.
Randomized studies are planned to evaluate whether efficacy is maintained after one dose of nivolumab plus ipilimumab while reducing toxicity.
“This study informs clinical management, as it provides reassuring information for physicians that they should not feel compelled to push for doses 3 and 4 of nivolumab in combination with ipilimumab in the presence of toxicity,” Postow told Healio. “[However, because] the study was still on the smaller side and not randomized against the existing standard of care, I don’t think we are ready to say that all patients should only be treated with two doses of nivolumab in combination with ipilimumab. Larger randomized studies are needed.”
Perspective
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Gino In, MD
This is a small study, but it provides a lot of intriguing information. We started using combination checkpoint blockade in 2015, when data first came out from CheckMate 067, which used this same dosing strategy. That regimen has produced some of the best data so far for metastatic or advanced melanoma.
Last year, 5-year OS data with this same combination showed a 52% survival rate for patients with metastatic disease, which is very impressive. Because of that, these drugs have been the best option for these patients. The issue, however, was high toxicity.
To date, combination checkpoint blockade using PD-1 and CTLA-4 inhibition has resulted in the best outcomes for any regimen to treat metastatic or advanced melanoma. In CheckMate 067, the combination of ipilimumab 3 mg/kg and nivolumab 1 mg/kg for four doses every 3 weeks, followed by maintenance nivolumab dosed at 3 mg/kg, achieved a response rate of approximately 60%, which is better than the roughly 35% to 40% we see with PD-1 inhibition alone. Five-year data with the combination, reported last year, led to a 52% survival rate for patients with metastatic disease. However, about 55% of patients experienced grade 3 or higher toxicity.
To address this, Postow and colleagues conducted a phase 2 study in which patients received the same dosing regimen as CheckMate 067 but, after the second dose of combination therapy, they included an early tumor assessment to identify patients who had already responded to treatment.
There are some intriguing takeaways from the results. The fact that response rates were not noticeably affected by eliminating two doses of combination therapy is quite promising. Correlative analyses suggest that the second dose of combination therapy did not result in any further immunologic changes beyond what had already occurred after the first dose, so perhaps dropping to even one dose of combination therapy would be enough for responding patients. On the other hand, fewer doses of combination checkpoint blockade did not result in lower toxicity.
Going forward, we need better strategies to capture the benefit of combination checkpoint blockade but with fewer side effects. We know that toxicity from CTLA-4 inhibition is dose-dependent. The phase 3 Checkmate-511 study showed that ipilimumab 1 mg/kg with nivolumab 3 mg/kg led to reduced toxicity — without loss of efficacy — compared with ipilimumab 3 mg/kg and nivolumab 1 mg/kg. There are other benefits, as well, to refining the dose and scheduling of checkpoint inhibitors. These include reducing financial toxicity and potentially decreasing the burden on the health care system through fewer infusion visits and fewer hospitalizations for adverse events, which may be particularly important during the COVID-19 pandemic.
We certainly have shown that checkpoint inhibitors are the right drugs to treat melanoma. Now we need to figure out the right dose.
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Postow MA, et al. Abstract 10003. Presented at: ASCO20 Virtual Scientific Program; May 29-31, 2020.
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