Immunotherapy unleashed: pioneering chemo-free neoadjuvant programmed cell death ligand 1 (PD-L1) inhibition for resectable non-small cell lung cancer (NSCLC)

The standard of care in the treatment of resectable non-small cell lung cancer (NSCLC) involves surgery for complete resection (1), which offers the best opportunity for long-term survival and cure. Unfortunately, recurrence following surgery for NSCLC remains common, ranging from 20–52% in various studies (2-7). Immunotherapies targeting programmed cell death protein 1 (PD-1) and programmed cell death ligand 1 (PD-L1) have shown benefit and are standard treatments for patients with advanced/metastatic NSCLC. The therapeutic landscape for NSCLC continues to evolve rapidly, with immunotherapy and targeted therapies showing remarkable potential to both enhance resectability and improve outcomes in operable NSCLC. A growing body of evidence shows that patients with NSCLC benefit from neoadjuvant therapeutic regimens with improved overall survival, time to distant recurrence, and recurrence-free survival (8-10). The CheckMate 816 trial (nivolumab) (11) and the KEYNOTE-671 trial (pembrolizumab) (12) demonstrated a survival benefit for combination neoadjuvant immunotherapy + chemotherapy for resectable NSCLC. Nevertheless, a consensus on standardized neoadjuvant treatment for resectable NSCLC remains elusive (13).

Zhao and colleagues studied the efficacy and safety of a chemotherapy-free neoadjuvant combined immunotherapeutic regimen with camrelizumab (an anti-PD-1 antibody) and antiangiogenic therapy with apatinib (a VEGF receptor 2 inhibitor) in the management of histologically-confirmed resectable stage IIA–IIB NSCLC (14). They performed a single-center prospective single-arm phase 2 clinical trial between November 9, 2020 and February 16, 2022 including treatment-naïve patients aged 18–70 years old with histologically-confirmed resectable stage IIA–IIB NSCLC. Patients received three cycles of neoadjuvant therapy with IV camrelizumab and oral apatinib prior to planned surgical resection. All tumors were evaluated with positron emission tomography computed tomography (PET-CT) at baseline and after completion of neoadjuvant therapy. Surgically resected tumors were assessed by two senior pathologists for the primary endpoint of major pathologic response (MPR; defined as <10% or less of residual viable tumor cells). Secondary outcomes included pathologic complete response (pCR; no residual viable tumor cells), radiographic objective response rate [proportion of patients with complete response or partial response according to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1], disease control rate (proportion of patients with complete response, partial response, or stable disease according to RECIST v1.1), disease-free survival, event-free survival, and safety. Seventy-eight participants received neoadjuvant therapy, with 65 (83%) that ultimately underwent surgery. Remarkably, R0 resection was achieved in all operations. Examining histologic response in resected samples, 57% achieved MPR and 23% achieved pCR, with superior pathologic response noted in squamous cell NSCLC (58% and 25% with MPR and pCR, respectively) compared to adenocarcinoma (16% and 0% with pCR, respectively). This differential response based on tumor histology may be explained by the overall genetic landscape in squamous vs. adenocarcinoma. TP53 mutation was more common in squamous cell carcinoma (85%) than adenocarcinoma (25% of participants) and appears to modulate response to pembrolizumab, as this mutation was enriched in participants with MPR. The authors further examined DNA expression profiles in tumor samples and found a correlation between pathologic response to treatment and higher baseline PD-L1 expression, HOXA9 and SEPT9 methylation levels, and circulating tumor DNA status before surgery.

Preoperative PET-CT demonstrated partial metabolic response in 52% of participants and complete metabolic response in 2% of patients. Among those patients with at least partial metabolic response on preoperative PET-CT (27 patients, 54% of participants), 93% had MPR on final pathology. Furthermore, there was significant correlation between SUVmax reduction and pathologic regression, demonstrating the potential predictive value of metabolic imaging in determining pathologic response to immune therapy.

Finally, the combination of camrelizumab and apatinib proved to be acceptably safe; although 78% of patients experienced treatment-related adverse events (TRAEs) (most commonly hypoalbuminemia and proteinuria), only 5% of patients had grade 3 TRAEs and there were no observed grade 4 or 5 events.

The findings from Zhao et al.’s study contribute to the emerging literature examining the use of neoadjuvant therapy in the treatment of NSCLC as a combination therapy. Camrelizumab and apatinib have been studied most widely in the treatment of hepatocellular carcinoma (15) and have demonstrated efficacy in the treatment of several other cancers¹. The combination therapy is based on the theoretical synergistic mechanism of action between camrelizumab as a cytotoxic agent and apatinib as an anti-angiogenic agent that may enhance immune cell infiltration and antitumor response. Both drugs are produced by the Chinese pharmaceutical company Jiangsu Hengrui Medicine Co. Ltd. and the majority of clinical studies have been in Chinese patient cohorts. With regard to lung cancer therapy, original proof-of-concept studies in mice explored the benefit of combination PD-1 blockade with inhibition of angiogenesis and demonstrated that low-dose apatinib + anti-PD-1 agents decreased tumor growth, reduced the number of metastasis, and prolonged overall survival in a mouse model of lung cancer (16). Human subject clinical studies of camrelizumab + apatinib have demonstrated promising results with prolonged progression-free survival and overall survival, decreased symptom burden, and manageable safety profile (including hypertension, proteinuria, and palmar-plantar erythrodysaesthesia syndrome) in patients with locally advanced or advanced NSCLC (16-22). The study by Zhao et al. is novel in applying this combination therapy in the neoadjuvant setting for clinically resectable disease.

These results build on findings from the KEYNOTE-671 Trial, a multi-national randomized, double-blinded, phase 3 clinical trial study with 397 participants from the United States, Canada, Japan, South Korea, China, Belgium, Spain, Germany, Argentina, France, and Italy. Participants received neoadjuvant pembrolizumab + chemotherapy (cisplatin and gemcitabine or pemetrexed) compared to neoadjuvant chemotherapy alone in patients with resectable stage II–IIIB NSCLC. Participants who received neoadjuvant pembrolizumab + chemotherapy had improved event-free survival, overall survival, and higher pathologic response rates in patients treated with neoadjuvant pembrolizumab compared to those who received neoadjuvant chemotherapy alone.

Zhao and colleagues should be congratulated for their contribution to the evolving evidence for neoadjuvant therapy in resectable NSCLC. The present study showcases the potential for using a well-tolerated neoadjuvant regimen to improve therapeutic outcomes. Additionally, the sequence of systemic therapy prior to resection makes it much more likely that patients will tolerate and complete treatment. Finally, this approach also allows assessment of biologic response of the tumor and may guide treatment in the event of a future recurrence. However, several aspects of the study warrant further consideration: as a phase 2 trial, the sample size is modest with only 78 total participants. The study was conducted at a single center in China, and participants were enrolled to a single treatment arm in an unblinded fashion without a control group. Larger studies with blinded treatment arms are needed to validate the promising results of this study and/or identify specific patient subgroups that benefit the most from this regimen.

Acknowledgments

Funding: This work was supported by the Washington University School of Medicine StARR Program in Cross-Disciplinary Oncology Clinician-Scientist Training (No. R38CA255575) from the National Cancer Institute (NCI). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, AME Clinical Trials Review. The article has undergone external peer review.

Peer Review File: Available at https://actr.amegroups.com/article/view/10.21037/actr-23-34/prf

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://actr.amegroups.com/article/view/10.21037/actr-23-34/coif). N.E.R. was supported by the Washington University School of Medicine StARR Program in Cross-Disciplinary Oncology Clinician-Scientist Training (No. R38CA255575) from the National Cancer Institute (NCI). V.P. reports the following grant for projects (No. R01CA258681), and consulting fees from PrecisCa. His spouse owns stock in Intuitive Surgical. The authors have no other 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/.

¹including small cell lung cancer, hepatocellular carcinoma, cholangiocarcinoma, gallbladder carcinoma, oral and esophageal squamous cell carcinoma, esophageal neuroendocrine carcinoma, gastric and gastroesophageal junction adenocarcinoma, nasopharyngeal carcinoma, thyroid carcinoma, triple negative breast cancer, cervical cancer, ovarian carcinoma, gestational trophoblastic neoplasia, osteosarcoma, soft tissue sarcoma, clear cell sarcoma, colorectal adenocarcinoma, acral melanoma, peripheral T cell lymphoma.

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