Trastuzumab Deruxtecan Impresses With Clinical Activity in HER2-Mutant NSCLC

Fam-trastuzumab deruxtecan-nxki showcased robust and durable antitumor activity in previously treated patients with HER2-mutant non–small cell lung cancer.

Fam-trastuzumab deruxtecan-nxki (Enhertu) showcased robust and durable antitumor activity in previously treated patients with HER2-mutant non–small cell lung cancer (NSCLC), according to primary results of a fully enrolled cohort of the phase 2 DESTINY-Lung01 trial (NCT03505710) that were presented at the 2021 ESMO Congress.1

In a cohort of patients with HER2-mutant NSCLC (n = 91), the confirmed objective response rate (ORR) by independent central review (ICR) was 54.9% (95% CI, 44.2%-65.4%), which included a 1.1% (n = 1) complete response rate and a 53.8% (n = 49) partial response rate. Thirty-four patients (37.4%) achieved stable disease, 3 (3.3%) had progressive disease, and 4 (4.4%) patients were not evaluable.

At a median follow-up of 13.1 months (range, 0.7-29.1), the median progression-free survival (PFS) was 8.2 months (95% CI, 6.0-11.9), and the median overall survival (OS) was 17.8 months (95% CI, 13.8-22.1) “in this heavily pretreated population,” said lead study author Bob T. Li, MD, in a virtual presentation during the meeting. The data were simultaneously published in the New England Journal of Medicine.2

“Efficacy was consistently observed across subgroups, including in those patients with stable [central nervous system] metastases,” said Li, a physician ambassador to China and Asia-Pacific of Bobst International Center; co-director of the Thoracic Liquid Biopsy Program at Memorial Sloan Kettering Cancer Center (MSK), and chief scientific officer, of MSK Direct. “DESTINY-Lung01 provides compelling evidence of positive benefit/risk balance with [trastuzumab deruxtecan] in the second-line setting and supports its establishment as a potential new treatment standard.”

HER2 mutations comprise approximately 3% of nonsquamous NSCLC and are often seen in patients who are slightly younger, female, and never smokers. This subtype is also linked with a poor prognosis and an increased incidence of brain metastasis.

A high unmet medical need exists for patients with HER2-mutant NSCLC. HER2 mutation status is not routinely assessed, and these patients are typically treated with standard chemotherapy and/or immunotherapy.

Trastuzumab deruxtecan is a HER2 antibody-drug conjugate (ADC) that currently has a breakthrough therapy designation from the FDA for the treatment of patients with metastatic NSCLC whose tumors have a HER2 mutation and with disease progression on or after platinum-based therapy.3

In the DESTINY-Lung01 trial, investigators assessed the efficacy and safety of trastuzumab deruxtecan in patients with HER2-mutant NSCLC who had relapsed on or were refractory to standard therapy.

Earlier results from an interim analysis of DESTINY-Lung01, which had a data cutoff date of November 25, 2019, demonstrated activity with trastuzumab deruxtecan in this patient population.4 The data presented at the 2021 ESMO Congress encompassed results from the primary analysis of the fully enrolled cohort of patients with NSCLC who harbor HER2 mutations.

The multicenter, international, 2-chort DESTINY-Lung01 trial enrolled patients with unresectable or metastatic nonsquamous NSCLC that is relapsed from or is refractory to standard treatment. Patients also had to have measurable disease by RECIST v1.1 criteria, asymptomatic central nervous system (CNS) metastases at baseline, an ECOG performance status of 0 or 1, and locally reported HER2 mutation for cohort 2.

Cohort 1 of the study (n = 49) includes patients with HER2-overexpressing (immunohistochemistry [IHC] 3+ or IHC 2+); here, trastuzumab deruxtecan was given at 6.4 mg/kg every 3 weeks. In cohort 1a, the ADC was administered at 5.4 mg/kg every 3 weeks (n = 41).

Cohort 2 (n = 42) is comprised of patients with HER2-mutated NSCLC who received trastuzumab deruxtecan at 6.4 mg/kg every 3 weeks. Li noted that due to encouraging anticancer activity with the ADC, the cohort was expanded to include another 49 patients.

The primary end point was confirmed ORR by ICR; secondary outcome measures included duration of response (DOR), PFS, OS, disease control rate (DCR), and safety. Predictive biomarkers for response served an exploratory end point.

At a data cutoff date of May 3, 2021, 91 patients with HER2-mutant NSCLC were enrolled, and 15 patients (16.5%) remain on study treatment. The 76 patients (83.5%) who discontinued from the trial, did so mostly for disease progression (37.4%) and adverse events (AEs; 29.7%).

Pretreatment biopsy was performed for subsequent retrospective central confirmation in an exploratory analysis, Li explained.

The median age was 60.0 years (range, 29.0-88.0), 65.9% of patients were female, and were either Asian (34.1%), White (44.0%), Black (1.1%), or other (20.9%). Patients were also either from Asia (25.3%), Europe (36.3%), or North America (38.5%). Most patients (74.7%) had an ECOG performance status of 1 and a HER2 kinase domain mutation (93.4%). A total 36.3% of patients had baseline asymptomatic CNS metastases, more than half (57.1%) were never smokers, and 22% had a prior history of lung resection.

All but 1 patient (98.9%) had received any prior systemic cancer therapy, and the median prior lines of treatment was 2 (range, 0-7), which included platinum-based therapy (94.5%), anti–PD-1/PD-L1 therapy (65.9%), platinum-based and PD-1/PD-L1 inhibition (62.6%), docetaxel (19.8%), and a HER2 TKI (14.3%).

Further findings showed that for the 85 patients with centrally confirmed RECIST measurable disease, responses were observed across HER2 mutation subtypes, including in exon 20, exon 19, and exon 8, as well as in those with no detectable HER2 expression or HER2 gene amplification. Responses were also reported in those who previously received a HER2 TKI, Li noted.

The anticancer activity with trastuzumab deruxtecan was seen across subgroups, including those with HER2 kinase domain mutation (57.6%; 95% CI, 46.5%-68.3%), prior platinum-based therapy (53.5%; 95% CI, 42.4%-64.3%), platinum-based therapy plus PD-1/PD-L1 inhibition (64.9%; 95% CI, 51.1%-77.1%), and those with asymptomatic CNS metastasis at baseline (54.5%; 95% CI, 36.4%-71.9%) and without (55.2%; 95% CI, 41.5%-68.3%).

Additional data showed that, at the median follow-up of 13.1 months, the DCR was 92.3% (95% CI, 84.8%-96.9%) and the median DOR was 9.3 months (95% CI, 5.7-14.7).

The safety findings in this study were consistent with prior data of trastuzumab deruxtecan. The median treatment duration was 6.9 months (range, 0.7-26.4), and 96.7% of patients experienced any drug-related treatment-related, treatment-emergent AE (TEAE); the rate of grade 3 or higher TEAEs was 46.2%. A total 19.8% of patients had serious treatment-related TEAEs.

The most common treatment-related TEAEs linked with dose reduction (34.1%) were nausea (11.1%) and fatigue (8.8%). Moreover, the most common treatment-related, TEAEs linked with drug discontinuation (25.3%) was investigation-reported pneumonitis (13.2%) and interstitial lung disease (ILD; 5.5%). Two patients had died as a result of their TEAEs.

All-grade and grade 3 or higher treatment-related AEs with a 20% or higher incidence in all patients mirrored those of chemotherapy, Li said, and included nausea (72.5% and 8.8%, respectively), fatigue (52.7% and 6.6%), alopecia (46.2% and 0%), vomiting (39.6% and 3.3%), neutropenia (35.2% and 18.7%), anemia (33.0% and 9.9%), diarrhea (31.9% and 3.3%), decreased appetite (29.7% and 0%), leukopenia (23.1% and 4.4%), and constipation (22.0% and 0%).

“Most were well managed with supportive care; this is very reflective of chemotherapy toxicity profile, suggestive of the effects of the cytotoxic payload of [trastuzumab deruxtecan],” Li added.

Adjudicated treatment-related ILD and pneumonitis were closely analyzed in the trial, which occurred in 26.4% (n = 24) of patients and were the cause of the 2 patient deaths. Both patients who died had a history of lobectomy or partial lobectomy, and both had received prior treatment with a PD-1/PD-L1 inhibitor.

The median time to onset of first reported treatment-related ILD/pneumonitis was 141 days (range, 14-462 days), and the median duration of this AE was 43 days (95% CI, 24-94). Three-fourths of adjudicated drug-related ILD/pneumonitis events were of grades 1/2.

Although 21 of 24 patients with ILD/pneumonitis recevied at least 1 dose of glucocorticoids, not all glucocorticoid treatment was administered per ILD/pneumonitis management guidelines. Thirteen (54%) investigator-reported cases had fully resolved at the time of data cutoff.

“[ILD and pneumonitis] remains an important identified risk,” Li said. “Effective early detection and management are critical in preventing high-grade ILD and pneumonitis as seen in this study.”

To further optimize the dosing regimen of trastuzumab deruxtecan in this patient population, the 5.4-kg/mg dose is being evaluated in the phase 2 DESTINY-Lung02 trial (NCT04644237).

References

  1. Li B, Smit EF, Goto Y, et al. Primary data from DESTINY-Lung01: a phase 2 trial of trastuzumab deruxtecan (T-DXd) in patients (Pts) with HER2-mutated (HER2m) metastatic non–small cell lung cancer (NSCLC). Presented at: 2021 ESMO Congress; September 16-21, 2021; virtual. Abstract LBA45.
  2. Li B, Smit EF, Goto Y, et al. Trastuzumab deruxtecan in HER2-mutant non–small cell lung cancer. N Eng J Med. Published online September 18, 2021. doi:10.1056/NEJMoa2112431
  3. Enhertu granted breakthrough therapy designation in the US for HER2 mutant metastatic non-small cell lung cancer. News release. Daiichi Sankyo. May 18, 2020. Accessed September 17, 2021. https://bit.ly/39j3PdE
  4. Smit EF, Nakagawa K, Nagasaka M, et al. Trastuzumab deruxtecan (T-DXd; DS-8201) in patients with HER2-mutated metastatic non-small cell lung cancer: Interim results of DESTINY-Lung01. J Clin Oncol. 2020;38(suppl 15):9504. doi:10.1200/JCO.2020.38.15_suppl.9504