First-line tislelizumab combination confers benefit in non-small cell lung cancer subset
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The addition of tislelizumab to chemotherapy led to improvements in PFS among patients with advanced squamous cell non-small cell lung cancer, according to results of the randomized phase 3 study published in JAMA Oncology.
The combination of tislelizumab (BGB-A317, BeiGene), a humanized immunoglobulin G4 anti-PD-1 monoclonal antibody, and chemotherapy also improved objective response rates compared with chemotherapy alone and demonstrated a manageable safety profile among this patient population, regardless of PD-L1 expression, researchers noted.
“The addition of tislelizumab to standard chemotherapy demonstrated a significant reduction to the risk for progression or death among patients with advanced squamous cell NSCLC,” Jie Wang, MD, PhD, researcher in the State Key Laboratory of Molecular Oncology at the National Cancer Center/National Clinical Research Center for Cancer in Beijing, China, and colleagues wrote. “This represents an additional treatment option as first-line treatment for patients with squamous cell NSCLC.”
Researchers assessed the safety and efficacy of the combination among 355 patients (median age, 62 years; range, 34-74; 91.7% men) with treatment-naive, histologically confirmed stage IIIB/stage IV squamous cell NSCLC across 46 sites in China between July 2018 and June 2019. Data cutoff was Dec. 6, 2019.
The investigators randomly assigned patients 1:1:1 to receive 21-day cycles of 200 mg tislelizumab plus 175 mg/m² paclitaxel and carboplatin area under the concentration (AUC) 5 on day 1 (arm A; n = 120); 200 mg tislelizumab on day 1 plus 100 mg/m² nab-paclitaxel (Abraxane, Celgene) on days 1, 8 and 15 and carboplatin AUC 5 on day 1 (arm B; n = 119); or 175 mg/m² paclitaxel on day 1 and carboplatin AUC 5 on day 1 (arm C; n = 121).
Treatment with tislelizumab continued every 3 weeks until lack of clinical benefit or intolerable toxicity. Patients received the chemotherapy regimen until completion of four to six cycles of treatment, disease progression or intolerable toxicity, whichever occurred first. Patients in arm C with independent review committee (IRC)-confirmed disease progression could cross over to tislelizumab monotherapy.
IRC-assessed PFS served as the primary endpoint. OS, investigator-assessed PFS, IRC-assessed ORR and duration of response, as well as the incidence and severity of adverse events, served as secondary endpoints.
One patient in arm B and four patients in arm C who did not receive treatment were included in the intention-to-treat population but not the safety analysis, researchers noted.
At the time of data cutoff, 63 patients in arm A and 66 patients in arm B remained on treatment, whereas 89 patients in arm C were still in follow-up, including 30 patients who crossed over to tislelizumab monotherapy.
Median follow-up was 8.6 months (95% CI, 8.1-9).
Results of the interim analysis showed significant improvements in median PFS for both arm A and arm B (7.6 months for both) compared with chemotherapy alone (arm C, 5.5 months; HR for arm A vs. C = 0.524; 95% CI, 0.37-0.742; HR for arm B vs. C = 0.478; 95% CI, 0.336-0.679). The PFS rate at 9 months was 41.7% (95% CI, 30.9-52.1) for arm A and 47.2% (95% CI, 36.5-57.2) for arm B compared with 17.5% (95% CI, 9.8-26.9) for arm C.
Researchers also observed higher ORRs and a longer duration of response in both arms A (72.5%; 8.2 months) and B (74.8%; 8.6 months) compared with arm C (49.6%; 4.2 months).
Results of a post-hoc PD-L1 interaction analysis showed no association between PD-L1 expression and IRC-assessed PFS or ORR. OS data were not yet mature at the time of data cutoff.
The most common grade 3 or higher treatment-emergent adverse events included decreased neutrophil levels (arm A, 51.7%; arm B, 45.8%; arm C, 45.3%), neutropenia (33.3% vs. 27.1% vs. 40.2%) and decreased white blood cell count (22.5% vs. 27.1% vs. 23.9%). Adverse events led to discontinuation of any treatment by 12.5% of patients in arm A, 29.7% in arm B and 15.4% in arm C. Six patients developed treatment-related adverse events that led to death, including one in arm A, two in arm B and three in arm C; however, none was solely attributed to tislelizumab, according to the researchers.
“To our knowledge, RATIONALE 307 is one of the first phase 3 trials of a PD-1 inhibitor in combination with chemotherapy in squamous cell NSCLC to include patients with stage IIIB disease who were not amendable to curative surgery or chemoradiotherapy,” Wang and colleagues wrote. “Subgroup analyses of PFS demonstrated that tislelizumab plus chemotherapy provided benefits compared with chemotherapy alone, regardless of disease stage.”
Although it remains unknown whether the well-conducted trial will achieve its secondary endpoint of OS, it revealed tislelizumab to be a viable new first-line treatment option for patients with advanced squamous cell NSCLC regardless of PD-L1 expression levels, according to an accompanying editorial by Raymond U. Osarogiagbon, MBBS, researcher in the multidisciplinary thoracic oncology program at Baptist Cancer Center in Memphis, Tenn.
“Confirmation of these results in a more diverse population of patients with squamous cell lung cancer should be quickly sought and lead to acceptance of tislelizumab as a viable alternative immunotherapy choice, which can expand access to the global community of patients with advanced NSCLC,” Osarogiagbon wrote.
References:
Osarogiagbon RU. JAMA Oncol. 2021;doi:10.1001/jamaoncol.2021.0262.
Wang J, et al. JAMA Oncol. 2021;doi:10.1001/jamaoncol.2021.0366.
Perspective
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Edward S. Kim, MD, MBA, FACP, FASCO
This study of tislelizumab plus chemotherapy was conducted in a Chinese population. The researchers also reported only on PFS, and I would still be interested in seeing the OS data. With that said, the data appear on par with approved therapies for patients with squamous cell NSCLC. It is unclear if these results will be similar or different in populations outside of China, as we know that there can be differences in safety and efficacy when treating different racial and ethnic populations. It is hoped that there may be another therapy to add to our armamentarium for the treatment of squamous cell lung cancer; however, these results are not yet transferable to the rest of the world. We need data including Western populations and other ethnic populations. If the results are similar, then we will have more immunotherapy choices for patients with squamous cell lung cancer and it will be up to us to decide what is best and most convenient for our patients, including dosing schedules, toxicities and efficacy.
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