Neoadjuvant, Adjuvant Therapy for Resectable NSCLC Progresses With Immunotherapy, Targeted Therapy

Non–small cell lung cancer (NSCLC) is a disease state that has undergone substantial advancements in the immunotherapy and targeted therapy spaces, with immune checkpoint inhibitors and tyrosine kinase inhibitors (TKIs) becoming feasible treatment options for advanced or metastatic disease. However, surgery continues to be the preferred treatment approach in resectable NSCLC and has historically been coupled with neoadjuvant or adjuvant chemotherapy.

Neoadjuvant Therapy

To support the use of neoadjuvant chemotherapy in operable disease, the NSCLC Meta-analysis Collaborative Group conducted a comprehensive assessment of 15 randomized, controlled trials that included 2385 patients and compared preoperative chemotherapy vs surgery alone. Ten trials studied neoadjuvant chemotherapy alone, and 5 trials studied neoadjuvant chemotherapy followed by adjuvant chemotherapy (usually in responders). Eight trials included postoperative radiotherapy in addition to the randomized intervention in both treatment arms. The HR for overall survival (OS) across all 15 trials was 0.87 (95% CI, 0.78-0.96; P=.007), corresponding to a 5-year absolute benefit of 5% from neoadjuvant chemotherapy.¹

Neoadjuvant immunotherapy is a recent development in the treatment of early-stage resectable NSCLC. One such therapy is nivolumab (Opdivo; Bristol Myers Squibb), which is a PD-1–blocking human monoclonal antibody that restores the function of existing antitumor T cells and has been proven efficacious in numerous solid tumors, including advanced or metastatic NSCLC. On March 4, 2022, nivolumab in combination with platinum-doublet chemotherapy received FDA approval and is recommended by the National Comprehensive Cancer Network (NCCN) as neoadjuvant therapy for patients with resectable stage IB (tumors ≥4 cm or node positive) to stage IIIA NSCLC (category 2A).^2,3 The approved dosing regimen is nivolumab 360 mg administered on the same day as platinum-doublet chemotherapy every 3 weeks for 3 cycles.

This approval is based on the randomized, open-label, phase 3 CheckMate 816 trial (NCT02998528), which randomly assigned 358 patients with resectable stage IB (≥4 cm tumor size) to stage IIIA NSCLC in a 1:1 ratio to receive either neoadjuvant nivolumab plus platinum-doublet chemotherapy or platinum-doublet chemotherapy alone. During the trial, each patient underwent 3 cycles of their respective treatment followed by resection. The primary efficacy end points of CheckMate 816 included event-free survival (EFS) and pathological complete response of 0% viable tumor in resected lung and lymph nodes.⁴

The neoadjuvant nivolumab-plus-chemotherapy treatment arm had a median EFS of 31.6 months (95% CI, 30.2–not estimable [NE]), whereas the chemotherapy-alone treatment arm had a median EFS of 20.8 months (95% CI, 14.0-26.7). The HR for disease recurrence, disease progression, or death was 0.63 (97.38% CI, 0.43- 0.91; P=.005). Additionally, 24.0% of patients in the nivolumab-plus-chemotherapy arm had a pathological complete response (95% CI, 18.0-31.0) compared with 2.2% of patients in the chemotherapy-alone arm (95% CI, 0.6-5.6); the odds ratio of this finding was 13.94 (99% CI, 3.49-55.75; P<.001). Further, 33.5% of patients in the nivolumab-plus-chemotherapy group and 36.9% of patients in the chemotherapy-alone group experienced a grade 3 or 4 treatment-related adverse event.⁴

Adjuvant Therapy

To support the use of adjuvant chemotherapy in completely resected NSCLC, the Lung Adjuvant Cisplatin Evaluation Collaborative Group analyzed the 5 largest randomized, controlled trials (4584 patients) of cisplatin-based postoperative chemotherapy vs surgery alone. Patients who received postoperative radiotherapy in addition to their randomized intervention were also included. Over a 5-year horizon, the HR for OS was 0.89 (95% CI, 0.82-0.96; P=.005), corresponding to a 5-year absolute benefit of 5.4% from adjuvant chemotherapy.⁵

Currently, adjuvant therapy in resectable NSCLC consists of platinum-based chemotherapy followed by a targeted agent or immunotherapy, if eligible. Patients may be treated with certain agents if the surgical tissue or biopsy meets specific biomarker thresholds or if they have confirmed genetic mutations. Thus, because of the potential for targeted therapy or immunotherapy use in resected NSCLC with negative margins, biomarker testing for EGFR mutation (stage IB-IIIA) and PD-L1 status (stage II-IIIA) on surgical tissue or biopsy is recommended.³

Atezolizumab (Tecentriq; Genentech, Inc) is a PD-L1 inhibitor that is FDA approved and recommended by National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for patients with completely resected stage IIB to IIIA NSCLC or high-risk stage IIA NSCLC with PD-L1 of 1% or greater who received previous adjuvant chemotherapy (category 2A).^3,6 This approval is based on the randomized, open-label, phase 3 IMpower010 trial (NCT02486718), in which 1005 patients with completely resected stage IB to IIIA NSCLC were randomly assigned 1:1 to receive either atezolizumab 1200 mg every 21 days for 1 year or best supportive care alone after 1 to 4 cycles of adjuvant platinum-based chemotherapy. The primary end points of IMpower010 were disease-free survival (DFS) in stage II to IIIA NSCLC with PD-L1 expression of 1% or greater, DFS in all stage II to IIIA NSCLC regardless of PD-L1 expression, and DFS in the intention-to-treat (ITT) population.⁷

In the subpopulation with stage II to IIIA NSCLC with PD-L1 of 1% or greater (n=476), atezolizumab improved median DFS compared with best supportive care alone (HR, 0.66; 95% CI, 0.50-0.88; P=.0039). In the entire stage II to IIIA population (n=882), regardless of PD-L1 expression, atezolizumab similarly improved median DFS compared with best supportive care alone (HR, 0.79; 95% CI, 0.64-0.96; P=.020). In the ITT population encompassing stage IB to IIIA NSCLC (n=1005), the HR for median DFS was 0.81 (95% CI, 0.67-0.99; P=.040). Although the upper boundary for the 95% CI was not technically crossed, the authors did not consider this HR statistically significant. OS analyses were not formally conducted because the primary end point of DFS in the ITT population was not met and median OS data were immature.⁷

Osimertinib (Tagrisso; AstraZeneca) is an EGFR TKI that is FDA approved and recommended by NCCN Guidelines for patients with completely resected stage IB to IIIA EGFR-mutated (exon 19 deletion or exon 21 L858R) NSCLC who have received previous adjuvant chemotherapy or are ineligible to receive platinum-based chemotherapy (category 2A).^3,8 This approval is based on the randomized, double-blind, phase 3 ADAURA trial (NCT02511106), in which 682 patients with completely resected EGFR mutation–positive NSCLC were randomly assigned 1:1 to receive either osimertinib 80 mg orally daily or placebo for 3 years. Each stage of NSCLC (stage IB, II, and IIIA) was evenly represented in the overall study population. The prevalence of EGFR exon 19 deletion or EGFR exon 21 L858R mutations was 55% and 45%, respectively, with approximately 60% of patients in both treatment arms receiving platinum-based adjuvant chemotherapy prior to randomization.⁹

The primary efficacy end point of DFS in the stage II to IIIA NSCLC subpopulation (n=470) was met. Further, 90% of patients in the osimertinib treatment arm were alive and disease free at 24 months compared with 44% in the placebo treatment arm (HR, 0.17; 99.06% CI, 0.11-0.26; P<.001). The median DFS was not reached in the osimertinib arm (95% CI, 38.8-NE), and the median DFS in the placebo arm was 19.6 months (95% CI, 16.6-24.5). In the overall population encompassing stage IB to IIIA disease (n=682), there was a similarly statistically significant survival benefit in DFS at 24 months with osimertinib vs placebo (HR, 0.20; 99.12% CI, 0.14-0.30; P<.001).⁹

Among patients who received platinum-based adjuvant chemotherapy prior to randomization, osimertinib significantly improved DFS at 24 months vs placebo (HR, 0.16; 95% CI, 0.10-0.26). Similarly, patients who did not receive previous adjuvant chemotherapy had improved DFS at 24 months with osimertinib vs placebo (HR, 0.23; 95% CI, 0.13-0.40). Regardless of prior treatment with platinum-based adjuvant chemotherapy, osimertinib following surgery demonstrated clinical superiority vs placebo in completely resected stage IB to IIIA EGFR mutation–positive NSCLC.⁹

Conclusion

Significant advancements in neoadjuvant therapy and adjuvant therapy were made recently, which ultimately have changed clinical practice procedures. Neoadjuvant therapy consists of platinum-doublet chemotherapy but now may be supplemented with an immunotherapy. Further, patients who received neoadjuvant nivolumab plus chemotherapy were found to experience an improved median EFS and an improved pathological complete response of 0% viable tumor upon resection compared with neoadjuvant chemotherapy alone.⁴

Additionally, the available adjuvant treatment options have expanded to include either an immunotherapy or an EGFR TKI for eligible patients. Atezolizumab has demonstrated significant improvements vs best supportive care alone in median DFS for patients with completely resected stage II to IIIA NSCLC who received previous adjuvant chemotherapy.⁷ Also, osimertinib has demonstrated clinical superiority vs placebo in DFS at 24 months for patients with completely resected stage IB to IIIA EGFR-mutated NSCLC, regardless of prior treatment with platinum-based adjuvant chemotherapy.⁹ Further improvements in the treatment landscape of resectable NSCLC are underway with additional well-designed clinical trials in the neoadjuvant or adjuvant treatment setting.

About The Authors

Kevin Pang, PharmD, is an associate oncology scientist and medical writer at the National Comprehensive Cancer Network.

Noni Theocharides is a PharmD candidate at Rutgers University Ernest Mario School of Pharmacy.

References

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