Defining Earlier Use of Immunotherapy in Patients With NSCLC

Balazs Halmos, MD, MS

Professor of Medicine

Department of Oncology

Department of Medicine

Albert Einstein College of Medicine

Associate Director, Clinical Science

Director, Thoracic Oncology

Director, Clinical Cancer Genomics

Montefiore Einstein Cancer Center

Bronx, NY

Although clinical research has yielded major advances mostly in the treatment of patients with stage 4 non–small cell lung cancer (NSCLC), recently attention has shifted to patients with earlier stage disease, especially in the era of immunotherapy and combination chemotherapy and immunotherapy. Identifying the appropriate candidate to receive these perioperative approaches, such as neoadjuvant or adjuvant
therapy remains the clinical objective, but conflicting data from different studies has the field in flux, with many clinicians and investigators trying to digest, process, and interpret data correctly.

“This is exactly what makes a meeting such as the 18th New York Lung Cancers Symposium® so great,” cochair Balazs Halmos, MD, MS, said during an interview with Targeted Therapies in Oncology prior to the conference. Along with fellow cochair, Mark G. Kris, MD, the William and Joy Ruane Chair in Thoracic Oncology at Memorial Sloan Kettering Cancer Center, in New York, New York, they have identified an
agenda that focuses on 2 main objectives: presentations that deliver the major advances in the field and presentations that focus on how to apply these advances to the patient in the clinic. As a cochair for 3
years and an attendee for the last 10 years, Halmos has observed the meeting evolve from both perspectives. “We want to bring these advances to our colleagues and translate it to optimal patient
care,” Halmos said.

Sunrise Tumor Board

“Perhaps the biggest breakthrough in the past 2 to 3 years has been the perioperative management of patients with lung cancer,” Halmos said, referring to the first session of the day, the “Sunrise Tumor Board on Perioperative Immunotherapy.” The board will feature key investigators and experts as they navigate patient cases, touching on decision crossroads to reach an optimal outcome.

Recently, a perioperative approach that combined neoadjuvant and adjuvant immune checkpoint inhibition was published in the New England Journal of Medicine.¹

In a randomized, double-blind, phase 3 study (NCT03425643), perioperative pembrolizumab (Keytruda) was evaluated in 397 patients with early stage NSCLC. Patients with resectable stage 2, 2A, 3B NSCLC were randomly assigned 1:1 to receive 200 mg of neoadjuvant pembrolizumab and cisplatin-based chemotherapy (4 cycles) or placebo and cisplatin-based chemotherapy (4 cycles). Both groups subsequently underwent surgery and then received adjuvant pembrolizumab (200 mg) or placebo once every 3 weeks for 13 cycles.

The primary end points were event-free survival (EFS), defined as the time from randomization to the first occurrence of local progression, and overall survival (OS). Major pathological response, pathological
complete response, and safety were the secondary end points.

Investigators reported that EFS at 24 months was 62.4% in the experimental arm and 40.6% in the placebo arm (HR for progression, recurrence, or death = 0.58%; 95% CI, 0.46-0.72; P < .001). OS at 24
months was 80.9% in the experimental group and 77.6% in the standard group, although this did not meet pre-defined statistical significance yet. Major pathological response rate was 30.2% in theexperimental arm vs 11.0% in the placebo arm (19.2 percentage point difference; 95% CI, 13.9-24.7; P < .0001) and pathological complete response was moted in 18.1% of patients in the experimental arm and 4.0% in the placebo arm (14.2 percentage point difference; 95% CI, 10.1-18.7; P < .0001).

The investigators concluded that neoadjuvant/adjuvant pembrolizumab administered alongside neoadjuvant platinum-based doublet chemotherapy in the perioperative setting had improved EFS, pathologic response, and pathological complete response vs neoadjuvant chemotherapy alone followed by surgery. However, between the 2 groups, the difference in OS at this early read-out was not statistically significant.

Picking the Right Therapy Up Front

Presenters from a diverse group of leading healthcare institutions in the New York tristate area will provide a balanced perspective that ensures that the conference delivers rich content and expertise.

Halmos noted that much of the agenda addresses how to integrate immunotherapy into patient management.

Key questions to be answered include how to choose single-agent vs combination agents in NSCLC, combination immunotherapies, new immunotherapy agents, managing the adverse events that accompany immunotherapy regimens, and duration of therapy. “These are all the key elements that a clinician has to know about immunotherapy that covers patient selection, administration and optimal usage,” Halmos said.

Attendees can also look forward to sessions that focus on recent novel developments and anticipated breakthroughs, such as antibody-drug conjugates, new developments in the squamous cell lung cancer
field, and targeted therapies that amongst others focus on KRAS, EGFR, and acquired resistance challenges.

ADAURA

One of the key presentations from the 2023 American Society of Clinical Oncology Annual Meeting featured the phase 3 ADAURA study (NCT02511106).²

“Findings from ADAURA were significant, and its implications will be [highlighted] during many different sessions,” Halmos said.

The final OS analysis demonstrated that adjuvant osimertinib (Tagrisso) had unprecedented, highly statistically significant, and clinically meaningful outcomes in patients with EGFR-mutated, stage IB to IIIA
NSCLC after complete tumor resection with or without adjuvant chemotherapy.

Patients were randomly assigned 1:1 to receive 80 mg of osimertinib (n = 339) once daily or placebo (n = 343) until disease recurrence, treatment completion, or therapy discontinuation, according to the investigators.

For patients with stage II to IIIA disease, the OS HR was 0.49 (95% CI, 0.33-0.73; P = .004), and the 5-year OS rate was 85% in the treatment arm vs 73% in the placebo arm.

Biomarker Testing

The role of biomarker testing cannot be emphasized enough, according to Halmos. “We cannot bring the best treatments to our patients unless we implement biomarker testing,” he said.

Two sessions in particular will highlight biomarker testing: “ctDNA in Lung Cancer” and “MRD Assessment in Lung Cancer.”

Charu Aggarwal, MD, MPH, the Leslye M. Heisler Associate Professor for Lung Cancer Excellence, physician leader for Airways Malignancies Research, and director of precision medicine innovation at the Penn Center for Cancer Care Innovation at Penn Medicine in Philadelphia,
Pennsylvania, will deliver the circulating tumor DNA presentation. Bruna Pellini, MD, assistant professor at Morsani College of Medicine at University of South Florida and assistant member of the Department
of Thoracic Oncology at H. Lee Moffitt Cancer Center in Tampa, Florida, will discuss minimal residual disease.

Chemotherapy Shortage

There is currently a chemotherapy drug shortage, which Halmos described as “eye opening and sobering.”

Although the shortage has negatively impacted clinical trial research and care delivery, resulting in the use of triage techniques, Halmos said the shortage has spurred the oncology community and regulatory agencies to develop long-term plans to safeguard against a similar situation arising in the future.

“It has resulted in proactive developments, in terms of figuring out supply chain issues on a national level,” Halmos said. “These developments should ensure there is a buffer [in the supply chain] so that critical, lifesaving drugs are available for our patients.”

REFERENCES:

1. Wakelee H, Liberman M, Kato T, et al. Perioperative pembrolizumab for early-stage non-small-cell lung cancer. N Engl J Med. 2023;10.1056/NEJMoa2302983. doi:10.1056/ NEJMoa2302983

2. Herbst RS, Tsuboi M, John T, et al. Overall survival analysis from the ADAURA trial of adjuvant osimertinib in patients with resected EGFR-mutated (EGFRm) stage IB–IIIA non–small cell lung cancer (NSCLC). J Clin Oncol. 2023;41(suppl17):LBA3-LBA3. doi:10.1200/JCO.2023.41.17_suppl.LBA3