The need to optimize chemotherapy regimens for chemo-immunotherapy

The phase 3 CheckMate 816 trial demonstrated that neoadjuvant nivolumab-plus-chemotherapy treatment significantly improved event-free survival compared to neoadjuvant chemotherapy-alone treatment [hazard ratio (HR) for disease progression, disease recurrence, or death, 0.63; 97.38% confidence interval (CI): 0.43–0.91; P=0.005] in patients with IB–IIIA resectable non-small cell lung cancer (NSCLC) (1). The pathological complete response (pCR) rate was 24.0% in the nivolumab-plus-chemotherapy group and 2.2% in the chemotherapy-alone group (odds ratio, 13.94; 99% CI: 3.49–55.75; P<0.001) (1). Based on these results, the U.S. Food and Drug Administration approved nivolumab with platinum-doublet chemotherapy for adult patients with resectable NSCLC in neoadjuvant setting on March 4th, 2022 (2).

Chemo-immunotherapy has emerged as a promising strategy for cancer treatment. Cytotoxic chemotherapy not only kills tumor cells but also augments antitumor immunity by exposing tumor antigens and inducing immunogenic conditions. This antigen-induced effect can result in a dramatic synergy with immunotherapy, which potentially leads to pCR (1). Thus, in chemo-immunotherapy, the essential role of chemotherapy would be antitumor immunoboosting rather than tumor-cell killing. In this situation, metronomic (low-dose frequent administration) chemotherapy has proven to be effective in priming tumors for immunotherapy (3). Nonetheless, most chemo-immunotherapy trials, including the CheckMate 816 trial (1), administer standard full-dose cytotoxic chemotherapy.

We have two concerns about the CheckMate 816 trial (1). First, the discontinuation rate was lower in the nivolumab-plus-chemotherapy group (6.2%) than in the chemotherapy-alone group (15.3%) (1), although most combination therapies, including chemo-immunotherapy (e.g., the KEYNOTE 189 trial) (4), increase discontinuations. Survival benefits were higher in patients receiving less-toxic and more-tolerable carboplatin (HR, 0.31; 95% CI: 0.14–0.67) than in patients receiving cisplatin (HR, 0.71; 95% CI: 0.49–1.03). We speculate that side effects may have caused differences in chemotherapy dose density and intensity between the nivolumab-plus-chemotherapy group and the chemotherapy-alone group. Preferable-interval chemotherapy might contribute to the efficacy of nivolumab-plus-chemotherapy treatment, although the provided data is insufficient to test these hypotheses. Detailed information would help optimize chemotherapy dose density and intensity in neoadjuvant chemo-immunotherapy. Second, survival benefits were higher in patients with pretreatment tumor PD-L1 expression ≥50% (HR, 0.24; 95% CI: 0.10–0.61) than in patients with PD-L1 expression <1% (HR, 0.85; 95% CI: 0.54–1.32) (1). Preclinical and clinical evidence demonstrates that cytotoxic chemotherapy can increase tumor PD-L1 expression (5), sensitizing tumors to nivolumab. Therefore, certain chemotherapeutic agents might particularly enhance the response to nivolumab by increasing tumor PD-L1 expression. We wonder whether chemotherapy increased tumor PD-L1 expression, and if so, whether the transformed tumors responded to nivolumab, and which regimens had this effect. Such information would be valuable in strategizing not only neoadjuvant but also adjuvant and palliative chemo-immunotherapy.

In an emerging era of integrative chemo-immunotherapy, we should not merely apply standard chemotherapy regimens. In order to maximize the efficacy of chemo-immunotherapy, much effort should be made to determine the best treatment regimen for chemotherapy-immunotherapy combinations.

Acknowledgments

Funding: KI was supported financially by JSPS KAKENHI Grant Number 22H02930, the Takeda Science Foundation, the Mochida Memorial Foundation for Medical and Pharmaceutical Research, the Ichiro Kanehara Foundation for the Promotion of Medical Sciences and Medical Care, Grant for Lung Cancer Research, Foundation for Promotion of Cancer Research in Japan, and the Yakult Bio-Science Foundation.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Journal of Thoracic Disease. The article did not undergo external peer review.

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-22-1101/coif). KI serves as an unpaid editorial board member of Journal of Thoracic Disease. YS has no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

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