Year in Review: Non-Small Cell Lung Cancer

The top stories in non-small cell lung cancer (NSCLC) for 2024 included practice-changing results in EGFR-mutant disease, an unprecedented gain in progression-free survival (PFS) for ALK-positive tumors, apparent superiority of perioperative versus neoadjuvant PD-(L)1 inhibition, and using novel agents to improve the anticancer activity of immunotherapy.

‘Practice-Changing’ Results for Inoperable Disease

Median PFS in unresectable, stage III EGFR-mutant NSCLC that did not progress after chemoradiation increased from 5.6 months with placebo to an “outstanding” 39.1 months with osimertinib (Tagrisso).

The 84% reduction in the risk of disease progression or death in PFS occurred despite the fact that 81% of patients randomized to placebo crossed over to osimertinib after disease progression, reported Suresh Ramalingam, MD, of Emory University’s Winship Cancer Institute in Atlanta, at the American Society of Clinical Oncology (ASCO) meeting. An interim analysis of overall survival showed 3-year median values of 84% with the EGFR inhibitor versus 74% with placebo.

“Osimertinib will become the new standard of care for patients with locally advanced, non-small cell lung cancer following definitive chemoradiation,” said Ramalingam.

ASCO-designated expert David Spigel, MD, of Sarah Cannon Research Institute in Nashville, Tennessee, added, “This will be practice changing. It really is outstanding.”

The findings came from the international phase III LAURA trial involving 216 patients with unresectable, EGFR-mutant NSCLC and no evidence of disease progression after definitive chemoradiation. They were randomized 2:1 to osimertinib or placebo and followed until disease progression or unacceptable toxicity. The primary endpoint was PFS.

The findings create a mandate for EGFR mutation testing in all patients with stage III disease to identify those who might benefit from osimertinib, said Ramalingam.

The study outcome led directly to expanded FDA approval of osimertinib.

New Standard for First-Line ALK-Positive Disease

The risk of disease progression or death in newly diagnosed ALK-positive NSCLC decreased by 81% at 5 years when patients received the third-generation ALK inhibitor lorlatinib (Lorbrena) instead of crizotinib (Xalkori), the phase III CROWN trial showed.

Median PFS had yet to be reached in the lorlatinib arm as compared with 9.1 months in the crizotinib group. Median PFS values after 5 years were 60% with lorlatinib and 8% for patients randomized to the comparator.

“These results represent the most significant progression-free survival benefit that has been reported in ALK-positive lung cancer to date,” said Benjamin Solomon, MBBS, PhD, of the Peter MacCallum Cancer Centre in Melbourne, Australia, at the ASCO meeting.

ASCO Chief Medical Officer Julie Gralow, MD, called the findings “just unheard of.”

The trial involved 296 patients with previously untreated, advanced NSCLC and test-confirmed ALK mutations. They were randomized to lorlatinib or crizotinib, and the primary endpoint was PFS.

The study outcome should be considered with the recognition that crizotinib is not used as often in the U.S. as in other countries, Spigel pointed out during an ASCO press briefing. How lorlatinib stacks up against newer drugs, such as alectinib (Alecensa) and brigatinib (Alunbrig), remains to be seen.

Meaningful Improvement in EFS With Perioperative Immunotherapy

Patients with resectable NSCLC had a 39% reduction in the risk of disease recurrence or death when treated with nivolumab (Opdivo) before and after surgery as compared with neoadjuvant-only nivolumab and chemotherapy, an exploratory comparison of two randomized trials showed.

The cross-trial comparison of the CheckMate 77T and CheckMate 816 trials likely represents the best, and perhaps last, chance for direct comparison of neoadjuvant versus perioperative immunotherapy in NSCLC, said Patrick Forde, MD, of Johns Hopkins Medicine in Baltimore, during the World Conference on Lung Cancer (WCLC) in San Diego.

“In the near future, we will not have a randomized trial available to use to try to make clinical decisions,” said Forde. “And this analysis, at present, represents the only comparison of perioperative versus neoadjuvant-only immunotherapy treatments with resectable lung cancer.”

Together, the results of CheckMate 77T and CheckMate 816 support perioperative therapy as a treatment option for eligible patients with resectable NSCLC, said invited discussant Nan Wu, MD, of Peking University Cancer Hospital in Beijing. Nonetheless, “phase III randomized clinical trials are needed for further validation.”

CheckMate 77T showed an 18-month event-free survival (EFS) of 70% with perioperative therapy with nivolumab versus 50.0% with neoadjuvant-only chemotherapy, representing a 42% reduction in the hazard ratio. CheckMate 816 compared neoadjuvant nivolumab plus chemotherapy versus chemotherapy alone and showed a median EFS of 31.6 months with nivolumab versus 20.8 months without, representing a 37% reduction in the EFS hazard.

At the WCLC, Forde reported findings from a propensity-matched analysis of the two randomized trials. The indirect comparison yielded a hazard ratio of 0.61 in favor of perioperative therapy. The results favored perioperative therapy regardless of disease stage and among patients with and without pathologic complete response to neoadjuvant therapy.

“However, we know that PD-L1-positive tumors tend to benefit from either neoadjuvant or perioperative or adjuvant therapy, so it’s quite possible we need longer follow-up in this group,” Forde observed.

Novel Agents Build on Activity of Neoadjuvant Immunotherapy

Three novel agents, an antibody-drug conjugate (ADC) and two monoclonal antibodies, showed promise for improving response to neoadjuvant durvalumab (Imfinzi) in resectable NSCLC.

Pairing the ADC datopotamab deruxtecan (Dato-DXd) with durvalumab and chemotherapy led to pathologic complete response (pCR) in 34% of patients and major pathologic response (mPR) in 65.9%. The anti-NKG2A antibody monalizumab plus durvalumab and chemotherapy resulted in a pCR rate of 26.7% and mPR of 53.3%. The addition of the anti-CD73 antibody oleclumab achieved a pCR rate of 20% and mPR of 45%.

For comparison, investigators used results of the phase III AEGEAN trial, which showed pCR and mPR rates of 17.2% and 33.0%, respectively with perioperative durvalumab plus chemotherapy, reported Tina Cascone, MD, PhD, of the University of Texas MD Anderson Cancer Center at the WCLC.

“This is the first global phase II study showing encouraging efficacy and manageable safety profile of antibody-drug conjugate in the neoadjuvant setting for patients with resectable non-small cell lung cancer,” she said.

The results compared favorably with CheckMate 77T (pCR 25%) and CheckMate 816 (pCR 24%), Wu said during his discussion of the results. The findings require confirmation in randomized, phase III trials, he added.

Cascone reported findings from the NeoCOAST-2 trial, which represented a rational progression of clinical evaluation following earlier studies of durvalumab plus oleclumab or monalizumab in unresectable NSCLC and as neoadjuvant therapy for resectable disease. The trial involved a total of 202 patients, all of whom received neoadjuvant chemotherapy and were randomized to perioperative oleclumab-durvalumab, perioperative monalizumab-durvalumab, or neoadjuvant Dato-DXd and durvalumab followed postoperatively by durvalumab.

Other Newsworthy Developments in NSCLC

ACS Guidelines Expand Lung Cancer Screening Eligibility — Is That a Good Thing?

Frontline EGFR/VEGF Inhibition Slows Advanced EGFR-Positive Lung Cancer

Trial Questions Role of Dual Immunotherapy in First-Line NSCLC

FDA Panel Supports More Clarity in NSCLC Perioperative Immunotherapy Trials

Novel Bispecific in EGFR-Mutant Lung Cancer Boosts PFS After Targeted Agents

Changing the Surgical Paradigm in Oligometastatic NSCLC

Futile Immunotherapy for Cancer Grows More Common