No QoL Downside With Adding Nivo to Chemo in Urothelial Cancer

BARCELONA, Spain — Health-related quality of life (HRQoL) is not further compromised by the addition of nivolumab (Opdivo) immunotherapy to first-line cisplatin-based chemotherapy in patients with unresectable or metastatic urothelial carcinoma, according to an analysis of a phase 3 randomized trial.

Jens Bedke, MD, presented this and other findings of the analysis of CheckMate 9src1 at the European Society for Medical Oncology (ESMO) Annual Meeting 2src24 on September 16.

Indeed, the percentage of patients experiencing clinically meaningful changes in HRQoL was similar between the nivolumab plus gemcitabine and cisplatin (GC) and GC alone treatment arms, said Bedke, of the Department of Urology and Transplantation Surgery, Klinikum Stuttgart, in Stuttgart, Germany.

“These findings further support nivolumab plus GC as a standard first-line treatment option for cisplatin-eligible patients with unresectable or metastatic urothelial carcinoma,” he said.

At the same time, Bedke acknowledged that more data had been collected for the control arm. Patient-reported outcome (PRO)/HRQoL data were available from the GC alone control arm only up until week 24, while patients in the combination arm continued to fill out the questionnaires for longer, he said.

He also noted that, while PRO/HRQoL completion rates were comparable between the treatment arms at most timepoints, there was a noticeable imbalance at week 16, with rates dropping below 5src% in the combination therapy.

Overall, Bedke believes that the “continued exploration and development of PRO/HRQoL tools for patients with metastatic urothelial carcinoma is warranted.”

HRQoL Assessment Shortfalls

Session co-chair Shilpa Gupta, MD, expressed disappointment with some aspects of the way in which HRQoL was assessed.

She said that the main analysis, which looked at changes from baseline to week 16, “was not really based on any science, but really the logistics of the completion of four to six cycles of chemo.”

Gupta, director of the Genitourinary Medical Oncology at Taussig Cancer Institute, Cleveland Clinic, Cleveland, who was not involved in the study, also compared the HRQoL assessments for the EV-3src2 trial with the current analysis of CheckMate 9src1. In the EV-3src2 trial, enfortumab vedotin and pembrolizumab were compared with platinum-based chemotherapy in patients with previously untreated locally advanced or metastatic urothelial carcinoma.

In this trial, in which Gupta served as an investigator, PRO data were collected not only weekly during the treatment but also every 3 weeks after treatment was completed, through to survival follow-up. Moreover, HRQoL measures were prespecified endpoints included in the hierarchical statistical testing plan, rather than tested after the fact.

Gupta went on to highlight that HRQoL tools “unfortunately, so far, have not evolved with the tremendous advances that we have made in cancer therapies.”

She said that the current tools are “very static” and measure the same questions, regardless of the stage. Consequently, “we cannot really differentiate between the disease symptoms, the treatment toxicity, and the physical function.”

However, Gupta said that more recent tools such as the US National Cancer Institute’s Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events and the Functional Assessment of Chronic Illness Therapy — Item GP5 are more useful measures.

She also urged investigators to “harmonize PRO assessment across trials” and “move away from exploratory endpoints and make this a primary endpoint.”

Gupta also said it is important to include symptomatic patients in trials to see the impact of treatment on symptoms and also to consider PRO assessment “throughout a patient’s journey and not just during active treatment.”

She called for the incorporation of medical devices and artificial intelligence to assess pain, sleep, and physical activity rather than via repeated questionnaires, which could help to reduce so-called “survey fatigue” among patients.

Survival Data for CheckMate 9src1

Results from CheckMate 9src1 demonstrated that nivolumab plus GC was associated with a 22% improvement in overall survival and a 28% increase in progression-free survival vs GC alone in previously untreated unresectable metastatic urothelial carcinoma.

As reported by Medscape Medical News, it was the first time that adding immunotherapy to first-line chemotherapy had been shown to improve survival in metastatic urothelial carcinoma.

The combination was subsequently approved by the US Food and Drug Administration for the first-line treatment of adults with unresectable or metastatic urothelial carcinoma, followed soon after in Europe by the European Medicines Agency.

Alongside standard objective outcome measures, patients in the trial had their global health status assessed using the EORTC QLQ-C3src, with individual domains of the questionnaire also examined separately, alongside the EQ-5D-5L visual analogue scale.

The tools were administered on day 1 of cycle 1, then every other 3-week cycle for the first 6 months, during the main treatment phase of the trial. They were then continued every 4 weeks, then every 12 weeks, but only in patients in the combination therapy arm who continued with nivolumab maintenance therapy.

The current analysis included 276 patients from the nivolumab plus GC arm and 248 who were treated with GC alone. As in the main trial analysis, the two groups were well balanced.

Bedke reported that, looking at least squares mean changes from baseline to week 16, the combination of nivolumab plus GC showed non-inferiority vs GC alone on all of the PRO measures.

The proportion of patients at the same timepoint who had a clinically meaningful improvement or deterioration in their HRQoL was also similar between the combination and control arms on all assessments.

For example, 29% vs 23% showed a clinically meaningful improvement in their global health status at week 16, while 28% and 3src%, respectively, experienced a clinically meaningful deterioration.

He went on to show that, while there was no clinically meaningful change over time in global health status on the EORTC QLQ-C3src in either treatment arm, there was a trend toward improvement with nivolumab plus GC.

Again, there was no clinically meaningful change in visual analogue scores in either the experimental or control arms.

Bedke told the audience that, during the nivolumab monotherapy phase, any-grade, all-cause adverse events were reported by 91.src% of patients, but just 31.6% experienced grade 3/4, all-cause adverse events.

The study was funded by Bristol Myers Squibb.

Bedke declared relationships with AstraZeneca, Astellas, BMS, Eisai, Ipsen, MSD, MSD Oncology, Pfizer, Roche, Janssen, Ipsen, Novartis, Nektar, and Seagen.

Gupta declared relationships with Merck, Bristol Myers Squibb, Gilead Sciences, Pfizer, EMD Serono, Seattle Genetics, Natera, Novartis, EMD Serono, Astellas, Roche, Tyra Biosciences, Acrivon Therapeutics, Flare Therapeutics, Exelixis, Nektar Therapeutics, and BioNTech.