Targeted therapies have significantly improved outcomes for patients with non-small cell lung cancer (NSCLC) with actionable mutations. However, many tumors inevitably develop drug resistance and progress. (1) Metastatic disease develops in about 50% of patients with surgically resected early-stage NSCLC and is a driving factor for why it remains the leading cause of cancer-related deaths in the United States. (2) (3)
Thoracic medical oncologists and early drug development specialists at Memorial Sloan Kettering Cancer Center (MSK) continue to investigate new ways to improve outcomes for this patient population.
This article highlights three clinical trials of new treatment approaches for patients with epidermal growth factor receptor (EGFR)-mutated lung cancer metastases. It also shares key findings from preclinical research and evidence from three case studies from the ongoing phase 1/2 ALKOVE-1 clinical trial, the first study to evaluate a brain-penetrant anaplastic lymphoma kinase (ALK)-selective inhibitor for patients with heavily pretreated ALK fusion-positive NSCLC.
EGFR-Mutated Lung Cancer
EGFR pathway activation is found in 15% to 40% of NSCLC, and the incidence of brain metastases in patients with EGFR-mutant NSCLC is estimated to be up to 70%. (4)
MSK thoracic medical oncologist and early drug development specialist Helena A. Yu, MD, is leading three clinical trials evaluating new targeted therapies for EGFR-mutated metastatic NSCLC:
1. Amivantamab plus lazertinib improved responses in EGFR-mutated lung cancer with active brain metastases and leptomeningeal disease
Amivantamab is a bispecific antibody that targets EGFR and MET protein and also causes antibody-dependent cellular cytotoxicity. (5) Lazertinib is an oral third-generation selective inhibitor of EGFR. (6)
The MSK-exclusive study (NCT04965090) enrolled 20 adults with brain metastases and 21 with leptomeningeal disease. Patients received a median of two prior lines of therapy before treatment with amivantamab plus lazertinib.
For the brain metastases group, the systemic objective response rate (ORR) was 30%, and the intracranial ORR was 40%, with a median time on treatment of 3.9 months. In the leptomeningeal disease group, the systemic ORR was 32%, and the intracranial ORR was 23%, with a median time on treatment of 8.1 months. (7)
No serious side effects occurred, underscoring the importance of including patients with brain metastases and leptomeningeal disease in clinical trials testing EGFR-targeted therapies.
The study was funded by Janssen Oncology. Access disclosures for Dr. Yu.
2. Osimertinib alone or with chemotherapy for EGFR-mutated metastatic lung cancer
Osimertinib, an oral selective third-generation EGFR inhibitor, (8) is the usual treatment for EGFR-mutated NSCLC. This phase 2 study is evaluating whether adding carboplatin and pemetrexed to osimertinib can improve response rates and progression-free survival (PFS).
Only patients with persistent EGFR in circulating tumor DNA (ctDNA) after initiating therapy with osimertinib are randomized to either continuing osimertinib alone versus adding chemotherapy to osimertinib.
Dr. Yu is the principal investigator of the study (NCT04410796), which is open at 10 sites across the U.S. and seeks to enrol more than 570 patients. The aim of the study is to risk-stratify patients and match them to the appropriate therapy for their cancer.
3. Osimertinib alone or with bevacizumab as initial treatment for EGFR-mutated metastatic NSCLC
Dr. Yu is the lead principal investigator for the multisite phase 3 trial of osimertinib with or without the antiangiogenic agent bevacizumab. Sponsored by the National Cancer Institute, the study includes more than 590 U.S. locations and seeks to enroll 300 participants (NCT04181060).
This clinical trial builds on earlier work by Dr. Yu and other MSK researchers that found intracranial response to osimertinib was excellent for patients with EGFR-mutant NSCLC with de novo, previously untreated brain metastases. (9)
The primary endpoint is PFS, and the secondary study objectives include overall survival (OS), ORR, duration of objective response, time to central nervous system (CNS) progression and CNS PFS, and toxicity. Recruiting continues at MSK and other locations. The estimated trial completion date is December 2026. Read more.
ALK-Fusion Positive Lung Cancer
ALK fusions occur in up to 5% of patients diagnosed with NSCLC. (10) Six tyrosine kinase inhibitors (TKIs) spanning three generations have been approved for ALK fusion-positive NSCLC. As initial therapy, all of these agents produce ORRs from 70% to 80%, and each successive generation has improved CNS activity and median PFS.
However, effective treatment strategies following disease relapse remain limited. For example, the third-generation drug lorlatinib after a second-generation ALK TKI is associated with a broad range of CNS effects that occur in 52% of patients, including psychotic effects, dizziness, gait disturbances, and changes in mood, cognitive function, and mental status. These CNS effects are caused by the off-target inhibition of tropomyosin receptor kinase (TRK). (11)
Neladalkib shows promising activity in heavily pretreated ALK fusion-positive NSCLC
Preclinical and translational research by thoracic medical oncologist Alexander Drilon, MD, Chief of MSK’s Early Drug Development Service, in collaboration with Nuvalent, has culminated in the first-in-human clinical trial of neladalkib (NVL-655), a novel, brain-penetrant ALK-selective inhibitor.
Neladalkib is a rationally designed TKI with a greater than 50 times selectivity for ALK over 96% of the kinome tested. It was created to provide activity against ALK single and compound mutations that have developed resistance to previous-generation ALK inhibitors, avoid inhibition of the TRK proteins, and address brain metastases. (12)
In a paper published in Cancer Discovery in December 2024, Dr. Drilon and colleagues reported their preclinical research findings and supporting evidence from three case studies from the ongoing international phase 1/2 ALKOVE-1 clinical trial. Highlights of their findings are as follows: (12)
- In vitro, neladalkib inhibited diverse ALK fusions, activating alterations, and resistance mutations, including a more than 100-fold improved potency against ALKG120SR mutations compared to approved ALK TKIs.
- In vivo, neladalkib induced regression across 12 tumor models, including intracranial and patient-derived xenografts. Neladalkib inhibited ALK over TRK with a 22-fold to 874-fold greater selectivity.
- The case studies showed that neladalkib induced responses without accompanying CNS effects. However, longer follow-up assessment in more patients is underway to confirm this finding.
The ALKOVE-1 study (NCT05384626) is currently recruiting patients at 70 institutions, including five cohorts of patients with locally advanced or metastatic NSCLC with an ALK rearrangement or activating ALK mutation and one cohort of patients with other solid tumors with ALK mutations. Dr. Drilon is the principal investigator for the study at MSK, which is enrolling patients at seven locations. Read more.
Based on early data, the U.S. Food and Drug Administration granted neladalkib breakthrough designation in May 2024 for the treatment of patients with locally advanced or metastatic ALK-positive NSCLC who have been previously treated with two or more TKIs. (12)
The ALKOVE-1 study is sponsored by Nuvalent. Access disclosures for Dr. Drilon.
Read more about MSK’s research into new treatment approaches for patients with lung cancer metastatic disease: