Datopotamab Deruxtecan Versus Docetaxel for Previously Treated Advanced or Metastatic Non–Small Cell Lung Cancer: The Randomized, Open-Label Phase III TROPION-Lung01 Study

Author(s): Myung-Ju Ahn, MD, PhD¹; Kentaro Tanaka, MD, PhD²; Luis Paz-Ares, MD, PhD³; Robin Cornelissen, MD, PhD⁴; Nicolas Girard, MD, PhD⁵; Elvire Pons-Tostivint, MD, PhD⁶; David Vicente Baz, MD⁷; Shunichi Sugawara, MD, PhD⁸; Manuel Cobo, MD, PhD⁹; Maurice Pérol, MD¹⁰; Céline Mascaux, MD, PhD¹¹; Elena Poddubskaya, MD¹²; Satoru Kitazono, MD, PhD¹³; Hidetoshi Hayashi, MD, PhD¹⁴; Min Hee Hong, MD¹⁵; Enriqueta Felip, MD¹⁶; Richard Hall, MD¹⁷; Oscar Juan-Vidal, MD, PhD¹⁸; Daniel Brungs, MBBS¹⁹; Shun Lu, MD, PhD²⁰; Marina Garassino, MD²¹; Michael Chargualaf, PharmD²²; Yong Zhang, MSc²²; Paul Howarth, MD²²; Deise Uema, MD²²; Aaron Lisberg, MD²³; Jacob Sands, MD²⁴

Source: https://doi.org/10.1200/JCO-24-01544

Dr. Anjan Patel's Thoughts

Positive trial for the newest ADC on the block, Dato-DXd, is an ADC that delivers a topoisomerase I inhibitor payload via a TROP2 antibody. PFS was not impressive but favored DDxd at 4.4 vs 3.7 months in the docetaxel arm. This drug is now approved in metastatic breast cancer.

PURPOSE

The randomized, open-label, global phase III TROPION-Lung01 study compared the efficacy and safety of datopotamab deruxtecan (Dato-DXd) versus docetaxel in patients with pretreated advanced/metastatic non–small cell lung cancer (NSCLC).

METHODS

Patients received Dato-DXd 6 mg/kg or docetaxel 75 mg/m² once every 3 weeks. Dual primary end points were progression-free survival (PFS) and overall survival (OS). Objective response rate, duration of response, and safety were secondary end points.

RESULTS

In total, 299 and 305 patients were randomly assigned to receive Dato-DXd or docetaxel, respectively. The median PFS was 4.4 months (95% CI, 4.2 to 5.6) with Dato-DXd and 3.7 months (95% CI, 2.9 to 4.2) with docetaxel (hazard ratio [HR], 0.75 [95% CI, 0.62 to 0.91]; P = .004). The median OS was 12.9 months (95% CI, 11.0 to 13.9) and 11.8 months (95% CI, 10.1 to 12.8), respectively (HR, 0.94 [95% CI, 0.78 to 1.14]; P = .530). In the prespecified nonsquamous histology subgroup, the median PFS was 5.5 versus 3.6 months (HR, 0.63 [95% CI, 0.51 to 0.79]) and the median OS was 14.6 versus 12.3 months (HR, 0.84 [95% CI, 0.68 to 1.05]). In the squamous histology subgroup, the median PFS was 2.8 versus 3.9 months (HR, 1.41 [95% CI, 0.95 to 2.08]) and the median OS was 7.6 versus 9.4 months (HR, 1.32 [95% CI, 0.91 to 1.92]). Grade ≥3 treatment-related adverse events occurred in 25.6% and 42.1% of patients, and any-grade adjudicated drug-related interstitial lung disease/pneumonitis occurred in 8.8% and 4.1% of patients, in the Dato-DXd and docetaxel groups, respectively.

CONCLUSION

Dato-DXd significantly improved PFS versus docetaxel in patients with advanced/metastatic NSCLC, driven by patients with nonsquamous histology. OS showed a numerical benefit but did not reach statistical significance. No unexpected safety signals were observed.

Author Affiliations

¹Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea ²Kyushu University Hospital, Fukuoka, Japan ³Hospital Universitario 12 de Octubre, Madrid, Spain ⁴Erasmus MC Cancer Institute, Rotterdam, the Netherlands ⁵Institut Curie, Paris, France ⁶University Hospital of Nantes, Nantes, France ⁷Hospital Universitario Virgen Macarena, Seville, Spain ⁸Sendai Kousei Hospital, Sendai, Japan ⁹Medical Oncology Intercenter Unit, Regional and Virgen de la Victoria University Hospitals, IBIMA, Málaga, Spain ¹⁰Centre Léon Bérard, Lyon, France ¹¹Hopitaux Universitaire de Strasbourg, Strasbourg, France ¹²VitaMed LLC, Moscow, Russia ¹³The Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo, Japan ¹⁴Kindai University Hospital, Osaka, Japan ¹⁵Yonsei Cancer Center, Severance Hospital, Seoul, Republic of Korea ¹⁶Vall d’Hebron Hospital Campus, Vall d’Hebron Institute of Oncology, Universitat Autònoma de Barcelona, Spain ¹⁷University of Virginia Health System, Charlottesville, VA ¹⁸Hospital Universitari i Politecnic La Fe, Valencia, Spain ¹⁹Southern Medical Day Care Centre, University of Wollongong, Wollongong, Australia ²⁰Shanghai Lung Cancer Center, Shanghai Chest Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China ²¹Department of Medicine, Hematology-Oncology Section, Thoracic Oncology Program, The University of Chicago Medicine & Biological Sciences, Chicago, IL ²²Daiichi Sankyo, Basking Ridge, NJ ²³Department of Medicine, Division of Hematology and Oncology, David Geffen School of Medicine, University of California Los Angeles (UCLA), Los Angeles, CA ²⁴Dana-Farber Cancer Institute, Boston, MA

Amivantamab Plus Lazertinib in Atypical EGFR-Mutated Advanced Non–Small Cell Lung Cancer: Results From CHRYSALIS-2

The CHRYSALIS-2, the cohort C analysis of patients with atypical EGFR mutations showed meaningful and durable activity. Atypical mutations can be difficult to deal with as a clinician, and having concrete data on these (S768I, L861Q and G719ZX) mutations gives assurance that this doublet is active. Overall response rate (ORR) was 52% and median progression-free survival (PFS) was 11.1 months in refractory patients and 19.5 months in the treatment-naive population.

Survival with Osimertinib plus Chemotherapy in EGFR-Mutated Advanced NSCLC

The final overall survival (OS) analysis from the FLAURA2 confirms the well-published findings that Osi + chemo improves survival over Osi monotherapy. OS difference was about 10 months at 47 vs 37 months, with a predictable toxicity tradeoff.

Updated Overall Survival Analysis From the Phase II PHAROS Study of Encorafenib Plus Binimetinib in Patients With BRAF V600E-Mutant Metastatic Non–Small Cell Lung Cancer

This update demonstrated that encorafenib plus binimetinib was associated with the longest median overall survival (mOS) reported to date among targeted therapies in patients with treatment-naïve BRAF V600E–mutant metastatic NSCLC (mNSCLC). Median OS was 47.6 months in treatment-naïve patients. By the way check the authors there 😊.

Simultaneous Durvalumab and Platinum-Based Chemoradiotherapy in Unresectable Stage III Non–Small Cell Lung Cancer: The Phase III PACIFIC-2 Study

PACIFIC-2 was a phase III trial testing durva given concurrently with cCRT (and continued as consolidation) versus placebo + cCRT in unresectable stage III NSCLC, and it did not meet its primary endpoint. The overall response rate (ORR) was essentially identical (60.7% vs 60.6%), and pneumonitis rates were similar (any grade 28.8% vs 28.7%; grade ≥3: 4.6% vs 5.6%), but adverse events (AEs) leading to discontinuation and fatal AEs were higher with durva (25.6% vs 12.0%; 13.7% vs 10.2%), especially early on. Starting IO up front with cCRT didn’t improve outcomes and added early toxicity—consolidation durva after cCRT is still the way to go.

Sevabertinib in Advanced HER2-Mutant Non–Small-Cell Lung Cancer

Sevabertinib shows strong efficacy in HER2-mutant NSCLC, with an overall response rate (ORR) of 64% and median progression-free survival (PFS) of 8.3 months in previously treated, HER2-TKI–naive patients, and an overall response rate (ORR) of 71% with a duration of response (DOR) of 11.0 months in first-line therapy. Activity is highest in TKD mutations, especially Y772_A775dupYVMA, and intracranial responses are seen. Safety is manageable: diarrhea is common but mostly low grade, with grade ≥3 in 5–23% and rare discontinuations. Notably, interstitial lung disease (ILD) was not observed. These data position sevabertinib as a viable oral TKI alongside ADCs for HER2-mutant NSCLC, particularly for TKD/YVMA disease.