In this podcast, the authors provide an overview of the primary safety and efficacy data from CheckMate 9DW study (NCT04039607) and share their opinions on how it impacts the treatment landscape for first-line unresectable hepatocellular carcinoma.

This is the first episode in a four-part podcast series published in Future Oncology, listen to all of the episodes here.

1. Transcript

Part 1 – Overview of the CheckMate 9DW study – primary efficacy, safety, and additional findings [Citation1–6] BRUNO SANGRO: Hello everyone, and welcome to this podcast. I’m Bruno Sangro. I’m a hepatologist working in the University of Navarra in Spain. Thank you for listening as we discuss the CheckMate 9DW study and how it impacts the treatment landscape for first-line nonresectable hepatocellular carcinoma or HCC. It’s a great pleasure to be joined by my colleague and friend from Germany, Dr. Peter Galle. Peter, would you like to introduce yourself? PETER GALLE: With much pleasure, Bruno. As always, a pleasure to present with you together. My name is Peter Galle. I’m a hepatologist and gastroenterologist from Mainz University Hospital in Germany. I’m actually quite excited to take a deep dive into the discussion of the CheckMate 9DW trial, just another exciting option in the systemic treatment armamentarium. We will first start with the first part of this four-part broadcast, and we will walk you through the key clinical results and consider their relevance for the first-line treatment decision making. BRUNO SANGRO: And to begin, CheckMate 9DW was carried out to really address the unmet needs seen in the advanced hepatocellular carcinoma setting [Citation1]. Liver cancer in general is the sixth most common cancer in the world and the third leading cause of cancer-related death. Interestingly, it counts in fact for up to 85% of liver cancers, and the five-year survival rate for advanced disease remains very low at 5% only. And despite advances in the first-line treatment options for unresectable HCC over the last past five years or so, the prognosis remained poor and this unmet need is what led to the design and execution of CheckMate 9DW [Citation1]. So, Peter, could you share a little bit about the CheckMate 9DW Phase III study? PETER GALLE: Sure, Bruno. So CheckMate 9DW is an open label, randomized, Phase III study assessing nivolumab [nivo] plus ipilimumab [ipi], so pure IO-based therapy versus a control arm of lenvatinib or sorafenib for unresectable HCC in the first-line setting [Citation1]. In the end, this investigator’s choice of the TKI resulted in 85% use of lenvatinib. Patients include adults with histologically confirmed advanced hepatocellular carcinoma, and they were enrolled at 163 hospitals or cancer centers across 25 countries, so truly representing a broad geographic representation that supports the global relevance of the findings which we are going to discuss [Citation1–5]. Importantly, patients are all systemic therapy-naïve, so it’s a pure first-line inclusion, ensuring that the trial accurately reflected the initial treatment decision point commonly encountered in real-world HCC care. So patients were randomly assigned 1:1 to receive nivo plus ipi followed by nivo monotherapy, versus investigator’s choice of lenvatinib or sorafenib in the control arm and, as mentioned, that was for the most part lenvatinib [Citation1]. The dosing was nivo 1 mg/kg and ipi 3 mg/kg and that was derived from a pilot trial where this particular combination and dosing was demonstrated to be among the most effective one. The initial treatment ipi 3 [mg/kg] and nivo 1 [mg/kg] was going up to four doses, followed by nivolumab 480 mg monotherapy every four weeks versus in the control arm lenvatinib 8 [mg] or 12 [mg] depending on weight or sorafenib 400 mg twice a day orally. Overall, we enrolled 335 patients to be treated with nivolumab plus ipilimumab and 333 to be treated with lenvatinib or sorafenib [Citation1]. Bruno, do you want to get right into it and talk about the primary efficacy results and the overall safety profile? BRUNO SANGRO: Certainly. We focused on the primary endpoint. The main conclusion of the study is this objective was met. At a median follow-up of 35.2 months, the median overall survival (OS) with nivolumab plus ipilimumab or nivo, it was 23.7 months versus the control arm of 20.6 months [Citation1]. And this was a statistically significant difference between the two treatment arms, supported by a p value of 0.018 [Citation1]. These longer-term survival data are particularly relevant in the context of immuno-oncology agents where durable benefit is the key treatment goal. From a safety perspective, nivolumab plus ipilimumab showed a manageable safety profile with no new safety concerns [Citation1]. Treatment-related adverse events of any grade occurred in the majority of patients in both treatment arms, that is 84% of patients in the nivo plus ipi arm and 91% of patients in the control arm. Grade 3/4 treatment-related adverse events occurred in 41% of patients in the nivo/ipi arm and 42% in those receiving lenvatinib or sorafenib. We did see treatment-related adverse events leading to discontinuation, and this occurred in 18% of patients in the nivo/ipi arm and 10% of patients in the lenvatinib or sorafenib arm [Citation1]. I think next we can talk a bit more about some of the important secondary endpoints and the patient-reported outcomes that indeed highlight the total ability of this regimen. And, Peter, do you want to start us off? PETER GALLE: Absolutely. Let’s talk about secondary endpoints, so that were objective response rate, duration of response, and time to symptom deterioration [Citation1]. I’d like to focus on objective response rate, so the proportion of participants who had tumor shrinkage. It truly saw a substantially higher rate in patients who received nivo plus ipi versus those who received either lenvatinib or sorafenib and that was specifically 36% versus 13%. And this came with a very highly significant p value of 0.0001 that highlights that there is a true difference between the two treatment arms [Citation1]. This is absolutely clinically meaningful, particularly in a disease where achieving tumor shrinkage can translate into symptom improvement and longer-term outcomes. BRUNO SANGRO: Yeah. And when it comes to patient-reported outcomes, we use the FACT-Hep questionnaire [Citation1]. This stands for Functional Assessment of Cancer Therapy – Hepatobiliary Cancers, quite specific for this disease. And also, the EQ-5D-3 L questionnaire and both are validated and reliable self-reporting questionnaires, well-established in HCC and designed to help measure quality of life. So based on both surveys, we found that patients who received nivo/ipi maintained their health-related quality of life all the time, with a trend toward improvement seen through an overall increase in the mean change from baseline for both scores [Citation1,Citation2]. In contrast, patients receiving lenvatinib or sorafenib experienced a decline in quality-of-life measures seen through an overall decrease in the mean change from baseline for both scores [Citation1,Citation2]. PETER GALLE: And specifically, through the GP5 portion of the FACT-Hep analysis, we also found that patients reported less bother due to side effects of treatment with ipi and nivo when compared to lenva or sorafenib [Citation2]. The overall trend toward improved health-related quality of life really supports the tolerability of this regime in patients with unresectable HCC. BRUNO SANGRO: Yeah. It is a fact that we see a benefit for nivo/ipi versus lenvatinib or sorafenib, but we lack other head-to-head clinical trials comparing other treatment options for unresectable HCC. And to help account for this, we also did a match‑adjusted indirect comparison, or MAIC for short, of CheckMate 9DW versus other HCC studies like HIMALAYA, which evaluated durvalumab plus tremelimumab, and IMbrave150, which evaluated atezolizumab plus bevacizumab, both versus sorafenib [Citation6]. Before we get into the details, it is important to know that MAICs are unanchored cross-trial comparisons with inherent methodological limitations. Despite efforts to adjust for baseline imbalances, these analyses are considered hypothesis-generating rather than providing definitive evidence. PETER GALLE: This is absolutely relevant, Bruno, and thank you for providing that background. We try to avoid cross-trial comparisons if we have no head-to-head evidence. Nevertheless, there are statistical means that MAICs are amongst those who will help us, but l...

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