Adjuvant/Neoadjuvant Therapies Are Addressed in Lung Cancer

The evolving multidisciplinary approach, to be highlighted at the 22nd Annual Winter Lung Cancer Conference® on January 31 to February 2, 2025, in Hollywood, Florida, will leverage the rapidly changing treatment landscape and regulatory approvals for both non–small cell lung cancer (NSCLC) and small cell lung cancer (SCLC). Cochaired by Julie R. Brahmer, MD, MSc; Rogerio C. Lilenbaum, MD; and Mark A. Socinski, MD, the conference will present the latest diagnostic and therapeutic developments for attendees.

“This is a truly multidisciplinary conference that will bring together thoracic surgeons, radiation oncologists, and medical oncologists who treat patients across lung cancer settings,” Brahmer said in an interview prior to the conference. Brahmer is codirector, Upper Aerodigestive Department, Bloomberg~Kimmel Institute for Cancer Immunotherapy and director, Thoracic Oncology, at Johns Hopkins Medicine in Baltimore, Maryland.

The developments in early-stage, locally advanced, and metastatic disease will provide the discussion points for sessions throughout the conference and fuel interesting conversations among attendees.

Neoadjuvant Immunotherapy

“I think the most important advances we have seen recently are in early-stage NSCLC, with the advent of neoadjuvant immunotherapy plus chemotherapy,” Brahmer said.

Key studies in recent years have evaluated combining chemotherapy with neoadjuvant immunotherapy, including CheckMate 816 (NCT02998528), AEGEAN (NCT03800134), CheckMate 77T (NCT04025879), Neotorch (NCT04158440), and KEYNOTE-671 (NCT03425643).

“The data from these trials and others have shown that if patients can achieve a pathologic complete response with neoadjuvant immunotherapy and chemotherapy, these patients do well over time,” Brahmer said.

KEYNOTE-671

The double-blind, phase 3 KEYNOTE-671 trial evaluated perioperative pembrolizumab (Keytruda) in patients with early-stage NSCLC.¹ The study enrolled 786 patients who were randomly assigned 1:1. In the first arm, patients were treated with pembrolizumab 200 mg intravenously (IV) every 3 weeks for up to 4 cycles with chemotherapy as neoadjuvant therapy prior to surgery, followed by pembrolizumab 200 mg IV every 3 weeks for up to 13 cycles as adjuvant therapy post surgery. The second arm of the trial received placebo plus chemotherapy as neoadjuvant therapy prior to surgery, followed by placebo as adjuvant therapy post surgery.

At the first interim analysis, investigators announced that 1 of the dual primary end points, event-free survival (EFS), was met, as well as its key secondary end points of pathological complete response (pCR) and major pathologic response (mPR), according to data presented at the 2023 American Society of Clinical Oncology Meeting.²

The 24-month EFS rate was 62.4% with pembrolizumab plus chemotherapy and adjuvant pembrolizumab vs 40.6% for placebo plus chemotherapy (HR, 0.58; 95% CI, 0.46-0.72; P < .00001). The mPR rate was 30.2% (95% CI, 25.7%-35.0%) with pembrolizumab compared with 11.0% (95% CI, 8.1%-14.5%) with placebo (percentage point change, 19.2%; 95% CI, 13.9%24.7%; P < .00001).

AEGEAN Trial

In the AEGEAN trial,³ a total of 802 patients with resectable stage II to stage IIIB NSCLC were randomly assigned to receive durvalumab (n = 400; Imfinzi) or placebo (n = 402).

Patients received platinum-based chemotherapy plus durvalumab or placebo administered IV every 3 weeks for 4 cycles before surgery, followed by adjuvant durvalumab or placebo IV every 4 weeks for 12 cycles.

EFS was significantly longer with durvalumab than with placebo; the stratified HR for disease progression, recurrence, or death was 0.68 (95% CI, 0.53-0.88; P = .004) at the first interim analysis. Further, the incidence of pCR was 17.2% (95% CI, 13.5%-21.5%) with durvalumab compared with 4.3% (95% CI, 2.5%-6.9%) with placebo.

These findings led to the FDA approval of durvalumab with platinum-containing chemotherapy as neoadjuvant treatment.4 “We are at the point now that we’re trying to figure out different ways to decide what type of therapy patients should receive,” Brahmer said.

CheckMate 77T

This year, Cascone et al5 explored the use of perioperative treatment with nivolumab (Opdivo) in the phase 3 CheckMate 77T trial.

In the study, patients received either neoadjuvant nivolumab given with chemotherapy followed by surgery and adjuvant nivolumab or neoadjuvant chemotherapy and placebo followed by surgery and adjuvant placebo. A total of 452 patients with resectable stage IIA to IIIB NSCLC were enrolled.

At the interim analysis (median follow-up, 25.4 months), the percentage of patients with 18-month EFS was 70.2% in the nivolumab group and 50.0% in the chemotherapy group (HR, 0.58; 97.36% CI, 0.42-0.81; P < .001). A pCR occurred in 25.3% of the patients in the nivolumab group and in 4.7% of those in the chemotherapy group (odds ratio [OR], 6.64; 95% CI, 3.40-12.97); a mPR occurred in 35.4% and 12.1%, respectively (OR, 4.01; 95% CI, 2.48-6.49). Investigators reported no new safety signals during the trial.

These findings led to the FDA approval of perioperative nivolumab in the resectable NSCLC setting. At a median follow-up of 33.3 months (range, 23.6-52.1), those given perioperative nivolumab (n = 229) had a median EFS of 40.1 months (95% CI, 33.7not reached) vs 17.0 months (95% CI, 13.628.1) in the placebo arm (n = 232; HR, 0.59; 95% CI, 0.45-0.79).⁶

“None of these combinations are clear front-runners yet, but I think that over time, we’ll have a better idea of different combinations with immunotherapy and chemotherapy,” Brahmer said.

Adjuvant Setting

In the adjuvant setting, for patients with EGFR exon 19 deletions or exon 21 L858R mutations, osimertinib (Tagrisso) is a mainstay based on efficacy results from the ADAURA trial (NCT02511106) in patients who underwent complete resection, with or without prior adjuvant therapy.⁷

For patients with ALK-positive NSCLC, alectinib (Alecensa) has emerged as a viable treatment option based on the ALINA trial (NCT03456076).^8,9 In the trial, patients were randomly assigned to receive oral alectinib (600 mg twice daily; n = 130) for 24 months or IV platinum-based chemotherapy (n = 127) in four 21-day cycles. The primary end point was disease-free survival.

According to investigators, the percentage of patients alive and disease-free at 2 years was 93.8% in the alectinib group and 63.0% in the chemotherapy group (HR, 0.24; 95% CI, 0.13-0.45; P < .001) and 93.6% and 63.7%, respectively, in the intention-to-treat population (HR, 0.24; 95% CI, 0.130.43; P < .001).

Metastatic Disease

A number of recent findings of trials focused on the metastatic disease setting have encouraging signs. For example, frontline treatment with ivonescimab led to a 49% reduction in the risk of disease progression or death vs pembrolizumab in patients with PD-L1–positive advanced NSCLC, according to findings from the primary analysis of the phase 3 HARMONi-2 trial (AK112-303; NCT05499390) presented at the 2024 International Association for the Study of Lung Cancer World Conference on Lung Cancer.¹⁰

At a median follow-up of 8.67 months, the median progression-free survival (PFS) was 11.14 months (95% CI, 7.33-not estimable [NE]) among patients treated with ivonescimab (n = 198) vs 5.82 months (95% CI, 5.03-8.21) for those treated with pembrolizumab (n = 200; stratified HR, 0.51; 95% CI, 0.38-0.69; P < .0001). The 9-month PFS rates with ivonescimab and pembrolizumab were 56% (95% CI, 47%-64%) and 40% (95% CI, 32%-48%), respectively.¹⁰

“It was exciting to see this improvement over single-agent pembrolizumab,” Brahmer said, “but we’ll see [whether] this could lead to a change of practice in the United States down the road.”

With the ongoing advancements in this disease setting, the 22nd Annual Winter Lung Cancer Conference will deliver insightful feedback and direction for attendees. “I’m excited to see how all these changes can be synthesized to help me best treat my patients in clinic,” Brahmer concluded.

REFERENCES:

1.Wakelee H, Liberman M, Kato T, et al; KEYNOTE-671 Investigators. Perioperative pembrolizumab for early-stage non-small-cell lung cancer. N Engl J Med. 2023;389(6):491-503. doi:10.1056/NEJMoa2302983

2.Wakelee HA, Liberman M, Kato T, et al. KEYNOTE-671: randomized, double-blind, phase 3 study of pembrolizumab or placebo plus platinum-based chemotherapy followed by resection and pembrolizumab or placebo for early stage NSCLC. J Clin Oncol. 2023;41 (suppl 17):LBA100. doi:10.1200/JCO.2023.41.17_suppl.LBA100

3.Heymach JV, Harpole D, Mitsudomi T, et al; AEGEAN Investigators. Perioperative durvalumab for resectable non-small-cell lung cancer. N Engl J Med. 2023;389(18):1672-1684. doi:10.1056/NEJMoa2304875

4.FDA approves neoadjuvant/adjuvant durvalumab for resectable non-small cell lung cancer. FDA. August 15, 2024. Accessed October 4, 2024. https://tinyurl.com/yy76bynr

5.Cascone T, Awad MM, Spicer JD, et al. Perioperative nivolumab in resectable lung cancer. N Engl J Med. 2024;390(19):1756-1769. doi:10.1056/NEJMoa2311926

6.FDA approves neoadjuvant/adjuvant nivolumab for resectable non-small cell lung cancer. FDA. October 3, 2024. Accessed October 3, 2024. https://tinyurl.com/5475fws4

7.Wu YL, Tsuboi M, He J, et al; ADAURA Investigators. Osimertinib in resected EGFR-mutated non-small-cell lung cancer. N Engl J Med. 2020;383(18):1711-1723. doi:10.1056/NEJMoa2027071

8.Wu YL, Dziadziuszko R, Ahn JS, et al; ALINA Investigators. Alectinib in resected ALK-positive non-small-cell lung cancer. N Engl J Med. 2024;390(14):1265-1276. doi:10.1056/NEJMoa2310532

9.FDA approves alectinib as adjuvant treatment for ALK-positive non-small cell lung cancer. FDA. April 18, 2024. Accessed October 4, 2024. https://tinyurl.com/yc5abfn6

10.Zhou C, Chen J, Wu L, et al. Phase 3 study of ivonescimab (AK112) vs pembrolizumab as first-line treatment for PD-L1-positive advanced NSCLC: HARMONi-2. Presented at: 2024 International Association for the Study of Lung Cancer World Conference on Lung Cancer; September 7-10, 2024; San Diego, CA. Abstract PL02.04.