Tetsuya Mitsudomi, MD
Neoadjuvant chemotherapy with vs without the PD-1 inhibitor nivolumab conferred a higher pathologic complete response rate and long-term event-free survival benefit in Asian patients with resectable non–small cell lung cancer (NSCLC), according to the global phase III CheckMate 816 trial. At the International Association for the Study of Lung Cancer (IASLC) 2024 Asia Conference on Lung Cancer (ACLC), former President of IASLC Tetsuya Mitsudomi, MD, Professor at Kindai University in Osaka, Japan, and colleagues presented these 4-year data from this racial subpopulation.1
“[This is] consistent with the findings in the global population,” Dr. Mitsudomi remarked. “[Overall], the 4-year results provide the first understanding of the long-term benefits of neoadjuvant immunotherapy plus chemotherapy and reinforce nivolumab plus chemotherapy as the standard of care for patients with resectable NSCLC.”
About CheckMate 816
In the CheckMate 816 trial, patients with stage IB to IIIA resectable NSCLC were randomly assigned to receive neoadjuvant platinum-based chemotherapy with or without nivolumab. A total of 177 patients (chemoimmunotherapy: n = 85; chemotherapy: n = 92) and 179 patients (chemoimmunotherapy: n = 93; chemotherapy: n = 86) identified as Asian and non-Asian, respectively.
Although the baseline characteristics were generally found to be similar between the global and Asian patients, the Asian vs non-Asian subpopulation included more patients with an Eastern Cooperative Oncology Group performance status score of 0, squamous histology, and high PD-L1 expression, as well as more males. Dr. Mitsudomi thus emphasized “there are some favorable factors present in the Asian population.”
The primary endpoints were event-free survival and pathologic complete response. In a prior analysis, with a median follow-up of 29.5 months, neoadjuvant nivolumab plus chemotherapy vs chemotherapy alone was found to result in a significantly longer median duration of event-free survival (31.6 vs 20.8 months; hazard ratio [HR] = 0.63; P = .005) and a higher pathologic complete response rate (24.0% vs 2.2%; odds ratio = 13.94; P < .001).2
“Earlier this year, the 4-year update of the data was presented, and the difference between the arms was still maintained [(event-free survival: median, 43.8 vs 18.4 months; HR = 0.66)],” Dr. Mitsudomi commented.3 “Overall survival showed a very nice trend favoring the neoadjuvant immunochemotherapy arm, but there has not been significance yet [(median, not reached vs not reached; HR = 0.71; P = .0451)].”
Event-Free Survival and Pathologic Complete Response
At 4 years, treatment with nivolumab plus chemotherapy vs chemotherapy alone was found to result in a similar improvement in event-free survival between the global population (49% vs 38%; median, 43.8 vs 18.4 months; HR = 0.66) and Asian subpopulation (51% vs 32%; median, not reached vs 15.7 months; HR = 0.53). Dr. Mitsudomi highlighted that the hazard ratio was “more favorable” in the Asian subpopulation.
In the non-Asian subpopulation, the 4-year event-free survival rate was 48% with nivolumab plus chemotherapy and 45% with chemotherapy alone. The median durations were 40.4 and 31.8 months, respectively. According to Dr. Mitsudomi, with a hazard ratio of 0.82, the non-Asian vs Asian subpopulation showed a less favorable treatment effect.
KEY POINTS
- Neoadjuvant chemotherapy with vs without nivolumab conferred a higher pathologic complete response rate and long-term event-free survival benefit in Asian patients with resectable NSCLC, which appeared to be consistent with findings from the global population of the CheckMate 816 trial.
- The safety profile of the combination was found to be consistent with previous reports.
- Taken together with the global data, these results seem to reinforce neoadjuvant nivolumab plus chemotherapy as the standard of care.
In the nivolumab-plus-chemotherapy arm, the pathologic complete (28.2% vs 20.4% and 24.0%) and major pathologic (38.8% vs 35.5% and 36.9%) response rates by blinded independent pathologic review were higher in the Asian vs non-Asian and global patients. Nivolumab with vs without chemotherapy showed higher pathologic complete response rates by 25.0% in the Asian subpopulation, 19.2% in the non-Asian subpopulation, and 21.6% in the global population. The combination also resulted in greater major pathologic complete response rates by 30.1%, 27.4%, and 27.9%, respectively.
The pathologic complete response rate in patients with evidence of circulating tumor DNA (ctDNA) clearance on the first day of the third cycle of chemoimmunotherapy was 46% in the global population and 40% in the Asian subpopulation. In both populations, those without ctDNA clearance showed a pathologic complete response rate of 0%. These findings indicate that “ctDNA clearance is a necessary—but not sufficient—condition for pathologic complete response,” according to Dr. Mitsudomi.
Safety Summary
Asian patients appeared to experience more treatment-related adverse events. The incidence rates of any-grade and grade 3 to 4 treatment-related adverse events with nivolumab plus chemotherapy were 90% and 46% in Asian patients and 77% and 27% in non-Asian patients, respectively.
“There appears to be a big difference [in the incidence of surgery-related adverse events between the Asian and non-Asian subpopulations, but] I do not know why such a difference is present,” Dr. Mitsudomi remarked. The rate with chemoimmunotherapy was found to be more than three times higher in Asian patients. Anemia, pain, wound complication, and procedural pain were among the most frequently reported surgery-related adverse events in this subpopulation; the majority were grade 1 or 2.
Dr. Mitsudomi concluded: “Neoadjuvant nivolumab plus chemotherapy showed a higher pathologic complete response rate and long-term event-free survival benefit vs chemotherapy, [which was] consistent with the findings in the global population. The safety profile was consistent [with previous reports] except that the surgical adverse events were a bit more frequent in the Asian population.”
EXPERT POINT OF VIEW
Nan Wu, MD
“Asian patients represented 49% of the global [population of the CheckMate 816 trial],” commented formal discussant of the Asian subpopulation analysis Nan Wu, MD, of Peking University Cancer Hospital, Beijing. “We needed to know whether a consistent effect of neoadjuvant nivolumab plus chemotherapy in Asian patients exists, [as this] subpopulation may have a significantly different genetic background than the Western population.”
Dr. Wu highlighted some of the favorable baseline characteristics of the Asian vs non-Asian population: fewer patients with PD-L1 negativity; more with a PD-L1 expression level of higher than 50%; and more with squamous histology. Because of the former two factors, he stated: “Asian patients may experience a lower risk of relapse with induction chemoimmunotherapy, and they may achieve a higher pathologic complete response rate.”
Squamous Histology and Geographic Location
Furthermore, Dr. Wu subsequently posed the following question: In addition to PD-L1, is squamous histology a player in improving outcomes? He noted that both patients with squamous and nonsquamous disease were found to derive an event-free survival benefit in several clinical trials; however, more significant differences were documented in those with the former subtype. A meta-analysis demonstrated that, although those with nonsquamous vs squamous histology achieved a numerically higher risk ratio of pathologic complete response (6.01 vs 4.76), they demonstrated a higher risk of relapse (hazard ratio = 0.63 vs 0.54).4
In addition, geographic location may contribute to improved event-free survival outcomes after neoadjuvant or perioperative immunotherapy, according to Dr. Wu. In the same meta-analysis, the hazard ratios of event-free survival with neoadjuvant chemoimmunotherapy vs chemotherapy were 0.51, 0.65, and 0.69 in patients treated in Asia, Europe, and North America, respectively.1
Looking Ahead
“Neoadjuvant immunotherapy plus chemotherapy with or without adjuvant immunotherapy achieved a significant survival benefit, being a standard of care for patients with resectable NSCLC,” Dr. Wu concluded. Looking forward in the treatment paradigm, he added that a related abstract presented during this session found “minimally invasive procedures, such as robotic and video-assisted thoracoscopic surgery, [to] remain promising solutions for achieving better surgical and oncologic outcomes [after induction chemoimmunotherapy].”5
DISCLOSURE: Dr. Mitsudomi has served as a consultant or advisor to AstraZeneca, Chugai, Taiho, Eli Lilly, Daiichi Sankyo, ThermoFisher Scientific, Janssen, Merck Sharp & Dohme, Merck Biopharma, Novartis, Pfizer, Amgen, Regeneron, Ono, Bristol Myers Squibb, Amgen, Guardant, Eisai, and Bayer; has received honoraria from Amgen, AstraZeneca, Boehringer Ingelheim, Chugai, Eli Lilly, Merck KGaA, Merck Sharp & Dohme, Novartis, Ono, Pfizer, Taiho, Takeda, and Invitae; and has received institutional research support from AstraZeneca, Chugai, Daiichi Sankyo, Eli Lilly, Merck Sharp & Dohme, Pfizer, Boehringer Ingelheim, Bridge Biopharma, Natera, and Ono. Dr. Wu reported no conflicts of interest.
REFERENCES
1. Mitsudomi T, Spicer J, Girard N, et al: Neoadjuvant nivolumab + chemotherapy in resectable NSCLC. 2024 Asia Conference on Lung Cancer. Abstract LBA PL03.02. Presented October 19, 2024.
2. Forde PM, Spicer J, Lu S, et al: Neoadjuvant nivolumab plus chemotherapy in resectable lung cancer. N Engl J Med 386:1973-1985, 2022.
3. Spicer J, Girard N, Provencio M, et al: Neoadjuvant nivolumab + chemotherapy vs chemotherapy in patients with resectable NSCLC: 4-year update from CheckMate 816. 2024 ASCO Annual Meeting. Abstract LBA8010. Presented June 2, 2024.
4. Sorin M, Prosty C, Ghaleb L, et al: Neoadjuvant chemoimmunotherapy for NSCLC: A systematic review and meta-analysis. JAMA Oncol 10:621-633, 2024.
5. Li X: Comparative analysis of perioperative outcomes in robotic-assisted versus video-assisted thoracic surgery following neoadjuvant therapy for non-small cell lung cancer. 2024 Asia Conference on Lung Cancer. Abstract PL03.01. Presented October 19, 2024.
