Trastuzumab Deruxtecan in Patients With HER2-Mutant Metastatic Non–Small-Cell Lung Cancer: Primary Results From the Randomized, Phase II DESTINY-Lung02 Trial

Author(s): Koichi Goto, MD, PhD¹; Yasushi Goto, MD, PhD²; Toshio Kubo, MD, PhD³; Kiichiro Ninomiya, MD, PhD⁴; Sang-We Kim, MD, PhD⁵; David Planchard, MD, PhD⁶; Myung-Ju Ahn, MD, PhD⁷; Egbert F. Smit, MD, PhD⁸; Adrianus Johannes de Langen, MD, PhD⁹; Maurice Pérol, MD¹⁰; Elvire Pons-Tostivint, MD, PhD¹¹; Silvia Novello, MD, PhD¹²; Hidetoshi Hayashi, MD, PhD¹³; Junichi Shimizu, MD, PhD¹⁴; Dong-Wan Kim, MD, PhD¹⁵; Chih-Hsi Kuo, MD, PhD¹⁶; James Chih-Hsin Yang, MD, PhD¹⁷; Kaline Pereira, MD, PhD¹⁸; Fu-Chih Cheng, PhD¹⁸; Ayumi Taguchi, PharmD¹⁹; Yingkai Cheng, MD, PhD¹⁸; Wenqin Feng, PhD¹⁸; Zenta Tsuchihashi, PhD¹⁸; and Pasi A. Jänne, MD, PhD²⁰

Source: DOI: 10.1200/JCO.23.01361 Journal of Clinical Oncology 41, no. 31 (November 01, 2023) 4852-4863.

Dr. Anjan Patel's Thoughts

Preliminary results of DESTINY-Lung02 show strong efficacy with trastuzumab deruxtecan (T-DXd). Overall response rate (ORR) was about 50%, with duration of response of 16.8 months. This is now FDA-approved and is an available therapy for patients with ERBB2 mutations after 1st line platinum-based chemo +/- immunotherapy. This is preferred over traditional trastuzumab or afatinib. Interestingly, some responses were seen in the ERBB2-negative patients who had over-expression by IHC. Please continue to sequence your patients and enroll in targeted therapy trials.

PURPOSE

Trastuzumab deruxtecan (T-DXd) 5.4 and 6.4 mg/kg showed robust antitumor activity in multiple cancer indications; however, T-DXd 5.4 mg/kg has not been evaluated in patients with previously treated human epidermal growth factor receptor 2–mutant (HER2m; defined as single-nucleotide variants and exon 20 insertions) metastatic non–small-cell lung cancer (mNSCLC).

METHODS

DESTINY-Lung02, a blinded, multicenter, phase II study, investigated T-DXd 5.4 mg/kg once every 3 weeks for the first time in previously treated (platinum-containing therapy) patients with HER2m mNSCLC and further assessed T-DXd 6.4 mg/kg once every 3 weeks in this population. The primary end point was confirmed objective response rate (ORR) per RECIST v1.1 by blinded independent central review.

RESULTS

One hundred fifty-two patients were randomly assigned 2:1 to T-DXd 5.4 or 6.4 mg/kg once every 3 weeks. As of December 23, 2022, the median duration of follow-up was 11.5 months (range, 1.1-20.6) with 5.4 mg/kg and 11.8 months (range, 0.6-21.0) with 6.4 mg/kg. Confirmed ORR was 49.0% (95% CI, 39.0 to 59.1) and 56.0% (95% CI, 41.3 to 70.0) and median duration of response was 16.8 months (95% CI, 6.4 to not estimable [NE]) and NE (95% CI, 8.3 to NE) with 5.4 and 6.4 mg/kg, respectively. Median treatment duration was 7.7 months (range, 0.7-20.8) with 5.4 mg/kg and 8.3 months (range, 0.7-20.3) with 6.4 mg/kg. Grade ≥ 3 drug-related treatment-emergent adverse events occurred in 39 of 101 (38.6%) and 29 of 50 (58.0%) patients with 5.4 and 6.4 mg/kg, respectively. 13 of 101 (12.9%) and 14 of 50 (28.0%) patients had adjudicated drug-related interstitial lung disease (2.0% grade ≥ 3 in each arm) with 5.4 and 6.4 mg/kg, respectively.

CONCLUSION

T-DXd demonstrated clinically meaningful responses at both doses. Safety profile was acceptable and generally manageable, favoring T-DXd 5.4 mg/kg.

Author Affiliations

¹National Cancer Center Hospital East, Kashiwa, Japan; ²National Cancer Center Hospital, Tokyo, Japan; ³Center for Clinical Oncology, Okayama University Hospital, Okayama, Japan; ⁴Okayama University Hospital, Okayama, Japan; ⁵Asan Medical Center, Seoul, Republic of Korea; ⁶Gustave Roussy, Department of Medical Oncology, Thoracic Group, Villejuif, France; ⁷Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea; ⁸Leiden University Medical Center, Leiden, the Netherlands; ⁹Netherlands Cancer Institute, Amsterdam, the Netherlands; ¹⁰Léon Bérard Center, Lyon, France; ¹¹Centre Hospitalier Universitaire Nantes, Nantes University, Nantes, France; ¹²Department of Oncology, Azienda Ospedaliero-Universitaria San Luigi Gonzaga, Orbassano, University of Turin, Turin, Italy; ¹³Kindai University Hospital, Osaka, Japan; ¹⁴Aichi Cancer Center Hospital, Aichi, Japan; ¹⁵Seoul National University College of Medicine and Seoul National University Hospital, Seoul, South Korea; ¹⁶Chang Gung Memorial Hospital, Chang Gung University, Taipei, Taiwan; ¹⁷National Taiwan University Hospital and National Taiwan University Cancer Center, Taipei, Taiwan; ¹⁸Daiichi Sankyo Inc, Basking Ridge, NJ; ¹⁹Daiichi Sankyo, Tokyo, Japan; ²⁰Dana-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.