Trastuzumab Deruxtecan Receives CHMP Recommendation for Approval in HER2-Mutant NSCLC

The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended fam-trastuzumab deruxtecan-nxki (Enhertu) for use as a single agent in adult patients with HER2-mutated, advanced non–small cell lung cancer (NSCLC) who require systemic treatment after platinum-based chemotherapy with or without immunotherapy.¹

The positive opinion is supported by primary data from the phase 2 DESTINY-Lung02 trial (NCT04644237), which were shared during the 2023 IASLC World Conference on Lung Cancer. When the antibody-drug conjugate (ADC) was given at a dose of 5.4 mg/kg once every 3 weeks (n = 102), it elicited a confirmed objective response rate (ORR) of 49.0% (95% CI, 39.0%-59.1%) by blinded independent central review (BICR) in this population.²

Specifically, 1% of patients had a complete response (CR), 48% had a partial response (PR), and 44.1% had stable disease (SD); 3.9% experienced disease progression (PD) and 2.9% were not evaluable for response. The disease control rate (DCR) was 93.1% (95% CI, 86.4%-97.2%). The median duration of response (DOR) was 16.8 months (95% CI, 6.4-not evaluable) and the median time to initial response (TTIR) was 1.8 months (range, 1.2-7.0).

“[Trastuzumab deruxtecan] is the first therapy to demonstrate a strong and durable tumor response in patients with previously treated HER2-mutant advanced NSCLC, validating HER2 as an actionable target in lung cancer and supporting the potential to provide a much-needed option for these patients,” Ken Takeshita, MD, global head of R&D at Daiichi Sankyo, stated in a press release.¹ “This CHMP opinion is a positive step forward in advancing this HER2-directed ADC for these patients, and we look forward to the European Commission’s decision.”

The blinded, multicenter, 2-cohort phase 2 study enrolled patients with a diagnosis of metastatic NSCLC and a known activating HER2 mutation who were at least 18 years of age and who had previously received at least 1 line of platinum-based chemotherapy in the metastatic or locally advanced setting.2 Patients needed to have at least 1 measurable lesion by BICR, and they could not be candidates for curative surgery or radiation.

Key exclusion criteria included having known driver mutations in EGFR, BRAF, or MET exon 14 gene or known ALK/ROS1/RET/NTRK fusions; a history of noninfectious interstitial lung disease (ILD) requiring steroids or current or suspected ILD; or having spinal cord compression or active brain metastases defined as being untreated or symptomatic. Notably, those with stable brain metastases were permitted.

Study participants underwent a 2:1 randomization to trastuzumab deruxtecan at a dose of 5.4 mg/kg once every 3 weeks or 6.4 mg/kg once every 3 weeks (n = 50). They were stratified based on previous anti–PD-1/PD-L1 therapy.

ORR served as the trial’s primary end point and was evaluated by BICR and in accordance with RECIST V1.1 criteria. Key secondary end points included confirmed ORR by investigator assessment, DCR by BICR and investigator, DOR by BICR and investigator, progression-free survival (PFS) by BICR and investigator, and overall survival (OS). Exploratory end points included time to response, best percentage change in sum of diameters of tumor lesions, and biomarkers. Safety was also evaluated.

Regarding baseline characteristics, most patients in the 5.4 mg/kg arm and the 6.4 mg/kg arm had HER2 mutations predominantly in the kinase domain, at 97.1% and 100%, respectively. Slightly more than half of patients in both arms were never smokers, at 53.9% and 58.0%, respectively; 34.3% and 44.0% of patients had baseline stable central nervous system (CNS) metastases. The median number of prior regimens received for both arms was 2, with a range of 1 to 12. All patients enrolled in the trial had prior exposure to platinum-based chemotherapy and the majority (73.5% and 78.0%) previously received immunotherapy.

Additional data showed that in the 6.4 mg/kg arm, trastuzumab deruxtecan elicited a confirmed ORR of 56.0% (95% CI, 41.3%-70.0%), which included a CR rate of 4%, a PR rate of 52%, and a SD rate of 36%; 4% had PD and 4% were not response evaluable. The DCR in this group was 92% (95% CI, 80.8%-97.8%). Moreover, the median DOR was not evaluable (95% CI, 8.3-NE) and the median TTIR was 1.6 months (95% CI, 1.2-11.2).

Responses with the ADC were reported across the arms, and irrespective of number or type of prior systemic treatment and baseline CNS metastases. Moreover, patients in both arms experienced tumor reduction from baseline, which was noted to be sustained over time.

For the 5.4 mg/kg arm, the estimated proportion of responders maintaining a response at 1 year was 54.4% (95% CI, 37.6%-68.5%); in the 6.4 mg/kg arm, this rate was 64.1% (95% CI, 38.2%-81.4%). The investigator-assess ORR and DCR were in line with what was reported in the BICR assessments.

The median follow-up for those in the 5.4 mg/kg and 6.4 mg/kg groups was 11.5 months (range, 1.1-20.6) and 11.8 months (range, 0.6-21.0), respectively. The median PFS by BICR for the 5.4 mg/kg arm was 9.9 months (95% CI, 7.4-NE) vs 15.4 months (95% CI, 8.3-NE) in the 6.4 mg/kg arm; the estimated 12-month PFS rates by BICR were 45% (95% CI, 33%-56%) and 53% (95% CI, 36%-67%), respectively. Additionally, the median OS when trastuzumab deruxtecan was given at 5.4 mg/kg was 19.5 months (95% CI, 13.6-NE); it was NE (95% CI, 12.1-NE) when given at 6.4 mg/kg. The estimated 12-month OS rates were 67% (95% CI, 56%-76%) and 73% (95% CI, 57%-84%).

The median treatment duration in the 5.4 mg/kg and 6.4 mg/kg arms was 7.7 months (range, 0.7-20.8) and 8.3 months (range, 0.7-20.3), respectively.

The toxicity profile of trastuzumab deruxtecan at both doses observed proved to be in line with what has been previously reported with the ADC. No new safety signals were observed.¹

Treatment-emergent adverse effects that were grade 3 or higher occurred in 38.6% of those who received the ADC at 5.4 mg/kg, and the most common of these effects included neutropenia (18.8%) and anemia (10.9%). Moreover, 12.9% of patients in this group experienced ILD or pneumonitis determined to be related to treatment by an independent adjudication committee. Most effects were grade 1 or 2 (10.9%), with 1 grade 3 event and 1 grade 5 event.

The European Commission will now review the recommendation to determine whether the agent will receive marketing authorization in the European Union for this indication.

In August 2022, the FDA granted an accelerated approval to trastuzumab deruxtecan for patients with unresectable or metastatic NSCLC whose tumors have activating HER2 mutations and who have previously received systemic therapy.³ More recently, in August 2023, Japan’s Ministry of Health, Labour, and Welfare approved trastuzumab deruxtecanfor patients with unresectable advanced or recurrent, HER2-mutant NSCLC that has progressed after chemotherapy.⁴

References

1. Enhertu recommended for approval in the EU by CHMP for patients with HER2 mutant advanced non-small cell lung cancer. News release. Daiichi Sankyo. September 15, 2023. Accessed September 15, 2023. https://www.daiichisankyo.com/files/news/pressrelease/pdf/202309/20230915_E.pdf
2. Goto K, Goto Y, Kubo T, et al. Trastuzumab deruxtecan in patients with HER2-mutant metastatic non-small-cell lung cancer: primary results from the randomized, phase II DESTINY-Lung02 trial. J Clin Oncol. Published online September 11, 2023. doi:10.1200/JCO.23.01361
3. FDA grants accelerated approval to fam-trastuzumab deruxtecan-nxki for HER2-mutant non-small cell lung cancer. FDA. August 11, 2022. Accessed September 15, 2023. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-fam-trastuzumab-deruxtecan-nxki-her2-mutant-non-small-cell-lung
4. Enhertu approved in Japan as first HER2 directed therapy for patients with HER2 mutant metastatic non-small cell lung cancer. News release. Daiichi Sankyo. August 23, 2023. Accessed September 15, 2023. https://www.daiichisankyo.com/files/news/pressrelease/pdf/202308/20230823_E.pdf