Nivolumab Plus Ipilimumab in Advanced Melanoma

Jedd D. Wolchok, MD, PhD

Concurrent nivolumab and ipilimumab produced “rapid and deep” responses, with ≥80% tumor reduction at 12 weeks in 30% of patients with advanced melanoma who took part in the first phase I trial to evaluate the PD-1-blocking antibody nivolumab, along with the CTLA-4-blocking antibody ipilimumab.¹Strongly positive efficacy data along with manageable adverse events (AEs) provoked a member of the audience attending the presentation at the 2013 American Society of Clinical Oncology (ASCO) Annual Meeting to ask whether a phase III study was needed.

“Whether a phase III study is necessary, I don’t know,” said investigator Jedd D. Wolchok, MD, PhD, from Memorial Sloan-Kettering Cancer Center in New York City, who presented these data at the Chicago meeting. “We need more sites and larger numbers,” he said, referring to planned phase II and III studies as well as sites joining the final cohort of the phase I trial.

This study was undertaken against a background of evidence that pointed to promising results. Enhanced antitumor activity was seen with the combination in mouse models. Ipilimumab treatment was associated with improved overall survival (OS) in two phase III trials in metastatic melanoma, and nivolumab produced an objective response rate (ORR) of >30% in a phase I trial.

Dr. Sosman on Checkpoint Inhibitors in Cancer Care

Sosman is the director of the melanoma and tumor immunotherapy program at Vanderbilt-Ingram Cancer Center.

Still, a need remains to increase the number of patients who respond to these agents, Wolchok said, and to identify a way to increase the proportion of patients who achieve complete or near-complete responses, “given the rarity of these events in the monotherapy experience.”

The design of this phase I clinical trial involved concurrent and sequential cohorts. In the concurrent cohorts, various dosages of nivolumab and ipilimumab were investigated in a dose-escalation design in patients who were not previously treated with ipilimumab.

The concurrent treatment resulted in a 53% grade 3 or 4 treatment-related AE rate, with the most common being asymptomatic elevation of lipase and AST and ALT. However, only 21% of patients discontinued treatment. The sequenced treatment resulted in an 18% treatment-related grade 3/4 AE rate. The only grade 3/4 AEs occurring in >10% of patients were asymptomatic laboratory abnormalities, which usually resolved spontaneously and had neither symptoms nor radiological correlates associated with them.

Eleven patients discontinued concurrent treatment due to AEs. Three patients in the sequenced cohort discontinued treatment due to treatment-related AEs. The treatment-related AEs were managed and reversible using a standard protocol algorithm. No treatment-related deaths occurred in this study.

After the cohort with a dosage level of nivolumab 3 mg/kg plus ipilimumab 3 mg/kg exceeded the maximum tolerated dose, (3 of 6 patients experienced dose-limiting toxicities of asymptomatic grade 3/4 lipase elevation that did not resolve within 3 weeks), the investigators elected to move forward with nivolumab 1 mg/kg plus ipilimumab 3 mg/kg dosage.

Clinical Activity: Sequenced Regimen

The change in tumor burden in the sequenced cohorts, (representing patients who had progressive disease after prior ipilimumab treatment) was convincing evidence that patients could still respond to nivolumab even after progressing on ipilimumab. Approximately 20% of patients had objective responses using modified WHO criteria, with several patients showing a >80% reduction in tumor burden by week 8, a response that was “…perhaps due to the [effects] of remaining presence of ipilimumab, since the last dose was 12 weeks before enrollment,” Wolchok said. “If one broadens this [report on responses] to those who had delayed responses or stable disease, then 43% had evidence of clinical activity with the sequenced regimen.”

This suggests, said Wolchok, that CTLA-4 and PD-1 blockade are not necessarily coupled in the context of clinical efficacy.

Clinical Activity: Concurrent Regimen

When all of the concurrent cohorts are considered together, 40% of patients experienced objective responses. If patients with immune-related or delayed responses, or stable disease, are considered, 65% of patients had evidence of clinical activity with the concurrent combination across all cohorts.

“What was unique in our experience was that most of these responding patients had rapid and deep regressions, with many showing a >80% reduction in tumor burden by the time the first scans were performed,” said Wolchok.

The largest group within the concurrent cohorts used the nivolumab 1 mg/ kg and ipilimumab 3 mg/kg regimen. This cohort had an ORR of 53%. All responding patients in this cohort had a >80% reduction in the baseline tumor-burden at the time of the first radiographic assessment, at week 12.

The overall efficacy of the combination was “impressive” across the concurrent cohorts, Wolchok said. The majority of patients had a reduction in their baseline tumor burden, and 90% of responses were durable as of the last data analysis in February 2013.

The quality and rapidity of responses with the combination also appeared to be materially distinct from what has been seen with immunotherapies in the past. “The response kinetics and magnitude for the 1 mg/kg nivolumab plus 3 mg/kg ipilimumab is reminiscent of responses to targeted pathway inhibitors. Yet, the durability of these responses maintains consistency with the long-lasting nature of immunotherapy in prior studies,” Wolchok explained in reference to a waterfall plot showing these results.

Overall Survival?

Given the high level of clinical activity with the concurrent regimen, the investigators went on to assess OS for these cohorts. At a median follow-up of 13 months, by Kaplan-Meier analysis, the median survival had not been reached in the combined concurrent cohorts or in the concurrent cohort using nivolumab 1 mg/kg plus ipilimumab 3 mg/kg. The estimated 1-year survival across all of the concurrent cohorts is 82% in 53 patients, Wolchok said.

Based on these results, a phase III trial is now open to accrual, investigating the efficacy of concurrent nivolumab and ipilimumab versus nivolumab or ipilimumab alone in patients with advanced melanoma.²The concurrent combination is also being investigated in non-small cell lung cancer and renal cell carcinoma.

References

1. Wolchok JD, Kluger HM, Callahan MK, et al. Safety and clinical activity of nivolumab (anti- PD-1, BMS-936558, ONO-4538) in combination with ipilimumab in patients (pts) with advanced melanoma (MEL).J Clin Oncol. 2013;31(suppl; abstr 9012).
2. ClinicalTrials.gov. Phase 3 study of nivolumab or nivolumab plus ipilimumab versus ipilimumab alone in previously untreated advanced melanoma (CheckMate-067). NCT01844505. Available at: http://clinicaltrials.gov/ct2/ show/NCT01844505?term=nivolumab+and+i pilimumab+and+melanoma&rank=4. Accessed October 16, 2013.
3. Wolchok JD, Kluger H, Callahan MK, et al. Nivolumab plus ipilimumab in advanced melanoma.N Engl J Med. 2013;369(2):122-133.