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ASCO GI 2021 | Long-term results from CheckMate 040: nivolumab + ipilimumab in advanced HCC

Anthony B. El-Khoueiry, MD, Keck School of Medicine of USC, Los Angeles, CA, provides an update of the long-term results from CheckMate 040 (NCT01658878), a Phase III study evaluating nivolumab plus ipilimumab combination therapy in patients with advanced hepatocellular carcinoma (HCC). In this update, Dr El-Khoueiry discusses how at a minimum of 44-month follow-up, second-line nivolumab and ipilimumab continued to demonstrate clinically meaningful responses and long-term survival benefit in advanced HCC, with a manageable safety profile and no new safety signals. This interview was recorded via an online conference call with The Video Journal of Oncology (VJOncology).

Transcript (edited for clarity)

We presented the updated results from the CheckMate 040 nivolumab plus ipilimumab cohort. Again, to refresh your memory, CheckMate 040 is a Phase I/II study of nivolumab in HCC, with some of the cohorts evaluating different combinations. Here we focus on the nivo ipi combination. For this combination, there were three different arms that were evaluated in parallel with different doses and schedules of ipilimumab...

We presented the updated results from the CheckMate 040 nivolumab plus ipilimumab cohort. Again, to refresh your memory, CheckMate 040 is a Phase I/II study of nivolumab in HCC, with some of the cohorts evaluating different combinations. Here we focus on the nivo ipi combination. For this combination, there were three different arms that were evaluated in parallel with different doses and schedules of ipilimumab. So arm A was nivo 1 mg/kg, ipi 3 mg/kg every three weeks, followed by nivo maintenance. B was nivo 3 mg/kg, ipi 1 mg/kg every three weeks, followed by nivo maintenance. And arm C was nivo 3 mg/kg every two weeks with ipi 1 mg/kg every six weeks continuously until progression or unacceptable toxicity.

At the time of the primary analysis, we had reported a response rate of 31 to 32% across all of these three arms of nivo and ipi. And with arm A having the most intriguing median OS of 22 months, which resulted in the accelerated approval of the nivo one, ipi three, combination regimen for patients with HCC who’ve had prior sorafenib in the United States. In this presentation, we have longer follow-ups. So at the primary analysis, the median follow-up was 30.7 months. For the purposes of this presentation, this is a long-term follow-up with a median of 46.5 months. And in summary, the response rate has continued to be at 31 to 32% across arms, there are known new safety signals with longer follow-up. And the median overall survival continues to be at 22 months for arm A.

What is most intriguing is the long-term OS follow-ups. So for arm A, the 36 months overall survival rate stood at 42%, which is quite intriguing for this patient population that had had prior sorafenib. Another important factor that I’d like to draw your attention to, is that all patients had had prior sorafenib and the majority had disease progression on sorafenib, but a subset of patients, actual 40% percent of patients in arm A, had two or more prior lines of therapy. So that’s an important fact to keep in mind.

So in summary, with longer follow-up, the safety still stands. Manageable safety profile and arm A continues to have a median OS of 22 months and an intriguing 36 months overall survival rate of 42%. This is meaningful for HCC patients, especially those who have had prior therapy with sorafenib, since it offers a treatment option that could be quite effective. Of course it has to be for the right patients. As a reminder, the eligibility was limited to patients with Child-Pugh A disease and preserved performance status.

Of course, one should also remember that there is a significant rate of immune-mediated events with this combination, especially in arm A with ipi 3 mg/kg, and that around 50% of patients required some steroid therapy for immune-mediated events. All of these were reversible, a large proportion of patients were rechallenged and with no recurrence of the immune-mediated events. Again, it was manageable, but one has to be aware of the incidents of immune-mediated events with this combination.

Lastly, of course, this combination was studied prior to the current approval or recent approval of the combination of atezolizumab and bevacizumab for first-line HCC. So it’s exact place in the treatment paradigm will continue to evolve as it had not been evaluated post PD-1 progression, of course it was only post sorafenib. Lastly, it’s important to remember, one limitation is that this is a single arm study, with no control arm, that is currently in ongoing Phase III study evaluating the combination of nivo and ipi versus sorafenib or lenvatinib in first-line HCC.

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