Trastuzumab Deruxtecan in HER2-Mutant Non–Small-Cell Lung Cancer

Author(s): Bob T. Li, M.D., Ph.D., M.P.H., Egbert F. Smit, M.D., Ph.D., Yasushi Goto, M.D., Ph.D., Kazuhiko Nakagawa, M.D., Hibiki Udagawa, M.D., Julien Mazières, M.D., Misako Nagasaka, M.D., Ph.D., Lyudmila Bazhenova, M.D., Andreas N. Saltos, M.D., Enriqueta Felip, M.D., Ph.D., Jose M. Pacheco, M.D., Maurice Pérol, M.D., et al., for the DESTINY-Lung01 Trial Investigators*

Source: January 20, 2022 N Engl J Med 2022; 386:241-251 DOI: 10.1056/NEJMoa2112431

Dr. Lucio Gordan's Thoughts

Interesting and encouraging development in this setting. The science and applicability of this drug in the scenario of no/low HER-2 expression will be thought-provoking. Interstitial pneumonitis is a concern.

BACKGROUND

Human epidermal growth factor receptor 2 (HER2)–targeted therapies have not been approved for patients with non–small-cell lung cancer (NSCLC). The efficacy and safety of trastuzumab deruxtecan (formerly DS-8201), a HER2 antibody–drug conjugate, in patients with HER2-mutant NSCLC have not been investigated extensively.

METHODS

We conducted a multicenter, international, phase 2 study in which trastuzumab deruxtecan (6.4 mg per kilogram of body weight) was administered to patients who had metastatic HER2-mutant NSCLC that was refractory to standard treatment. The primary outcome was objective response as assessed by independent central review. Secondary outcomes included the duration of response, progression-free survival, overall survival, and safety. Biomarkers of HER2 alterations were assessed.

RESULTS

A total of 91 patients were enrolled. The median duration of follow-up was 13.1 months (range, 0.7 to 29.1). Centrally confirmed objective response occurred in 55% of the patients (95% confidence interval [CI], 44 to 65). The median duration of response was 9.3 months (95% CI, 5.7 to 14.7). Median progression-free survival was 8.2 months (95% CI, 6.0 to 11.9), and median overall survival was 17.8 months (95% CI, 13.8 to 22.1). The safety profile was generally consistent with those from previous studies; grade 3 or higher drug-related adverse events occurred in 46% of patients, the most common event being neutropenia (in 19%). Adjudicated drug-related interstitial lung disease occurred in 26% of patients and resulted in death in 2 patients. Responses were observed across different HER2 mutation subtypes, as well as in patients with no detectable HER2 expression or HER2 amplification.

CONCLUSIONS

Trastuzumab deruxtecan showed durable anticancer activity in patients with previously treated HER2-mutant NSCLC. The safety profile included interstitial lung disease that was fatal in two cases. Observed toxic effects were generally consistent with those in previously reported studies. (Funded by Daiichi Sankyo and AstraZeneca; DESTINY-Lung01 ClinicalTrials.gov number, NCT03505710. opens in new tab.)

Author Affiliations

From Memorial Sloan Kettering Cancer Center and Weill Cornell Medicine, New York (B.T.L.); the Netherlands Cancer Institute, Amsterdam (E.F.S); the National Cancer Center Hospital, Tokyo (Y.G.), Kindai University Hospital, Osaka (K.N.), and the National Cancer Center East, Kashiwa (H.U.) — all in Japan; Centre Hospitalier Universitaire, Toulouse (J.M.), Centre Léon Bérard, Lyon (M.P.), and the Department of Medical Oncology, Thoracic Group, Gustave Roussy, Villejuif (D.P.) — all in France; Karmanos Cancer Institute, Detroit (M.N.); the University of California, San Diego, Moores Cancer Center, San Diego (L.B.); Moffitt Cancer Center, Tampa, FL (A.N.S.); Vall d’Hebron University Hospital and Vall d’Hebron Institute of Oncology, Barcelona (E.F.); University of Colorado, Aurora (J.M.P.); Hospital Universitario 12 de Octubre, H12O–Centro Nacional de Investigaciones Oncológicas (CNIO) Lung Cancer Clinical Research Unit, and Complutense University, Madrid (L.P.-A.); Daiichi Sankyo, Basking Ridge, NJ (K.S., R.S., Y.C., S.A., P.V., J.S.); and Dana–Farber Cancer Institute and the Belfer Center for Applied Cancer Science, Boston (P.A.J.).

Navigational Bronchoscopy or Transthoracic Needle Biopsy for Lung Nodules

Non-inferior in diagnosing malignant or benign lesions, and safer (less pneumothorax). The question remains about the amount of tissue for further testing.

Plasma Proteome–Based Test for First-Line Treatment Selection in Metastatic Non–Small Cell Lung Cancer

FCS medical oncologist and hematologist Ernesto Bustinza-Linares, MD has co-authored an abstract published in the American Society of Clinical Oncology Journal, JCO Precision Oncology, that uncovers a new testing method to determine personalized care options for patients with metastatic non-small cell lung cancer (NSCLC). The abstract’s authors address the limitations of existing guidelines that recommend checkpoint immunotherapy, sometimes in combination with chemotherapy, for treating NSCLC, which often discounts patient variability and immune factors. The findings from the study show that by incorporating additional plasma proteome-based testing, combined with the standard protein inhibitor testing, clear differences in patient outcomes were observed after applying targeted treatments based on the testing results.

Phase II, Open-Label Study of Encorafenib Plus Binimetinib in Patients With BRAFV600-Mutant Metastatic Non–Small-Cell Lung Cancer

Targeted therapy in NSCLC, FCS was part of this trial.

Burden of chemotherapy-induced myelosuppression among patients with extensive-stage small cell lung cancer: A retrospective study from community oncology practices

FCS medical oncologist and hematologist Lowell L. Hart, MD, FACP was first-author a study with FCS co-authors President and Managing Physician Lucio N. Gordan, MD, Director of Pharmacy Operations Kristen Boykin, Senior Vice President & Data Officer Trevor Heritage, PhD, and (Retired) Vice President of Pharmacy Services Ray Bailey BPharm, RPh, that evaluated ES-SCLC patients with chemotherapy-induced myelosuppression over a seven-year period, from January 2013 through December 2020. Within this cohort, 98% of the patients experienced at least one myelosuppressive episode following chemotherapy treatment, leading to the need for supportive care, creating additional costs in health care management and time lost in treatment for ES-SCLC.

Durvalumab With or Without Tremelimumab in Combination With Chemotherapy as First-Line Therapy for Metastatic Non–Small-Cell Lung Cancer: The Phase III POSEIDON Study

Suddenly met-NSCLC is a crowded space. This study did not conclude that T+D+CT was better than D+CT, the findings showed that D+CT was better than CT alone. The addition of T to D+CT improved the PFS and OS trend but I don’t think this was a homerun result. There was not a significant OS benefit and further follow-up will declare these results. Also an improved outcomes were not seen in the non-squamous population. The pembrolizumab studies have 5+ years of follow-up and an improvement in PFS and OS across NSCLC subtypes.