With an estimated 2.2 million new cancer cases and 1.8 million deaths, lung cancer is the second most commonly diagnosed cancer and the leading cause of cancer death in 2020, and accounts for approximately one in 10 (11.4%) cancers diagnosed and one in 5 (18.0%) deaths (1). Over the last decade, stunning advances in lung cancer treatment and research, including the development of targeted therapies and immune-based strategies, have dramatically improved the outlook for lung cancer.
“The advent of personalized medicine has undoubtedly changed the treatment landscape of lung cancer, but we still have a long road to travel in order to extend the promise of precision oncology to an increasing number of our patients, and overcome the many obstacles that currently hamper our efforts aimed at more effectively combatting this disease,” observes Enriqueta Felip, Principal Investigator of the Vall d’Hebron Institute of Oncology’s (VHIO) Thoracic Tumors Group and Head of Section, the Vall d’Hebron University Hospital’s (HUVH) Medical Oncology Department (Vall d’Hebron Barcelona Hospital Campus).
Two of the major remaining challenges include combating cancer drug resistance and disease progression. Presented at the 2023 Annual Meeting of the American Society of Clinical Oncology (ASCO), 2-6 June (Chicago, IL), just some of the many studies and invited talks that reported advances in more effectively anticipating and overcoming resistance to treatment and halting cancer cell spread included those (co) led by VHIO investigators.
Identifying predictive biomarkers of response
Alterations in the EGFR and MET genes are oncogenic driver mutations in lung cancer that promote tumor growth through increased cell proliferation, invasion, and metastasis. Led by Benjamin Besse at the Insitut Gustave Roussy in Villejuif (France), the phase I/Ib CHRYSALIS-2 ongoing clinical trial is evaluating the efficacy of amivantamab—a bispecific antibody targeting EGFR and MET with immune cell-directing activity—combined with third-generation EGFR tyrosine kinase inhibitor lazertinib, in patients with EGFR-mutated non-small cell lung cancer (NSCLC) refractory to standard treatment.
“Based on the results of previous exploratory analyses, we conducted a prospective study to further explore the study data, analyzing both tumor tissue characteristics and circulating tumor DNA by next-generation sequencing to identify those patients who would most likely benefit from this novel combination. Data from our tumor tissue analysis suggest that patients with MET-positive tumors could benefit most,” says Enriqueta Felip, co-lead author of this present study (2).
The overall objective response rate of these patients was 61% versus 12% in MET- patients. Progression-free survival of MET+ patients was not reached during the study and was 4.1 months in MET- patients.
“This drug combination could therefore be a chemotherapy-free therapeutic option for patients with EGFR-mutated advanced non-small cell lung cancer who have progressed on standard treatment with tyrosine kinase inhibitor osimertinib and are also MET-positive,” concludes Enriqueta Felip.
Putting novel KRAS inhibitor JDQ443 to the test in NSCLC and other solid tumors
The phase Ib/II open-label, multicenter KontRASt-01 study, directed by Philippe Alexandre Cassier at the Centre Léon Bérard in Lyon (France), was designed to assess the safety and efficacy of JDQ443—a novel selective inhibitor of the KRASG12C oncogene —in KRASG12C-mutated solid tumors including non-small cell lung cancer (NSCLC).
KRASG12C mutations occur in approximately 13% of NSCLCs and up to 4% of other solid tumors. The first part of this study sought to assess the safety and tolerability of this novel agent as monotherapy in 84 enrolled patients with advanced solid tumors (including 38 NSCLC patients), previously treated with standard-of-care. First results of this currently recruiting study (3), presented at ASCO 2023 by María José de Miguel Luken from the START-CIOCC Hospital Universitario HM Sanchinarro in Madrid (Spain), show an acceptable safety and tolerability, with clinical activity in patients with NSCLC.
“Initial data point to the promise of JDQ443 as monotherapy in these patients, showing an overall response rate of 41.7%. Enrollment is ongoing to the JDQ443 monotherapy dose escalation and the two combination arms of this agent with an SHP2 inhibitor, TNO155, and anti-PD-1 monoclonal antibody tislelizumab,” says co-author Enriqueta Felip.
Long-term outcomes of VISION: further defining the use of MET inhibitor tepotinib in clinical practice
Between 3%-4% of patients with NSCLC present a series of mutations in the MET oncogene that trigger its role as an initiator of cancer development in this tumor type. as a tumor promoter in this type of cancer. These mutations known generically as MET Exon 14 produce alterations that drive tumor growth through increased cell proliferation, invasion, and metastasis.
Presented at ASCO 2023 by first author Paul K. Paik, Memorial Sloan-Kettering Cancer Center in New York (USA) (4), long-term outcomes from the phase II VISION study further demonstrate the robust and durable clinical activity and manageable safety profile of oral and highly selective MET inhibitor tepotinib in patients with advanced MET exon 14 skipping NSCLC.
The 313 patients included in the trial were followed-up for a median of 32.6 months and the investigators observed a overall response rate of 51.4%. The median duration of response was 18 months, and the median progression-free survival was 11.2, with median overall survival of 19.6 months. No new safety concerns were observed and grade 3 treatment-related adverse events occurred in 34.8% of patients.
“Globally, these long-term data support the safety, efficacy and durable clinical activity of tepotinib, particularly in patients receiving first-line treatment, and further define its use in clinical practice,” concludes co-lead author Enriqueta.
A masterclass on antibody-drug conjugates for lung cancer
VHIO’s Enriqueta Felip was also an invited as an expert speaker for an ASCO Education Session entitled: Antibody-Drug Conjugates for Lung Cancer: Payloads and Progress (5), chaired by Benjamin Solomon at the Peter MacCallum Cancer Centre in Melbourne (Australia). During her masterclass on ADCs, she presented both the pros and the cons of these emerging anti-cancer therapies across a range of lung cancer subtypes.
“Antibody drug-conjugates selectively target cancer cells and deliver concentrated cytotoxic payloads through an antibody-mediated process, effectively sparing health tissue and delivering mighty blows against tumor cells. In addition to direct cytotoxic effects, additional innate and adaptive immune mechanisms can further potentiate anticancer activity both locally and systemically,” explains Enriqueta Felip.
Advances in chemistry, pharmacology, and immunology have led to the development of ADCs that are increasingly demonstrating significant clinical activity in subgroups of lung cancer patients.
In August 2022, the FDA approved T-DXd 5.4 mg/kg for patients with previously treated HER2-mutant metastatic NSCLC, marking the first approval of an ADC for lung cancer. This accelerated approval was based on results from the DESTINY Lung01 and DESTINY-Lung02 trials, which demonstrated frequent and durable tumor responses in this patient population.
Additional ADCs targeting TROP-2, HER2, HER3, MET, and CEACAM5, are currently being evaluated as monotherapy and in combination with other agents.
“By uncovering the nuances of ADC and tumor cross-talk and refining the development of these drugs, we will identify new strategies for patient selection, more effectively manage associated toxicity and achieve a deeper understanding of drug-resistance mechanisms. In so doing, ADCs will likely continue to step up in the treatment of a wider spectrum of patients with non-small cell lung cancer,” concludes Felip.
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