medwireNews: Individuals with pretreated advanced non-small-cell lung cancer (NSCLC) harboring HER2 exon 20 mutations or insertions may benefit from triple therapy with trastuzumab, pertuzumab, and docetaxel, phase 2 study findings indicate.
The triple therapy is more commonly used in people with HER2-mutated breast cancer, but Julien Mazieres (Toulouse University Hospital, France) and co-investigators hypothesized that it might also be effective in NSCLC, where there is no targeted therapy currently approved for the 1–2% of patients who have an HER2 exon 20 alteration.
They tested this hypothesis in the IFCT 1703-R2D2 trial, which enrolled 45 patients (median age 64.5 years, 72% women) with HER2-mutated, advanced nonsquamous NSCLC who had progressed after one or more previous platinum-based therapies.
The participants were given pertuzumab at a loading dose of 840 mg on day 1 of the first 3-week cycle followed by 420 mg on day 1 of each subsequent cycle; trastuzumab at a loading dose of 8 mg/kg on day 2 of cycle 1 and then 6 mg/kg on day 1 of each subsequent cycle; and docetaxel at a dose of 75 mg/m2 on day 2 of the first cycle and then on day 1 each subsequent cycle.
Mazieres et al report in the Journal of Clinical Oncology that, after a median 12 months of follow-up, 29% of participants had a confirmed objective response (all partial responses) and 58% had stable disease, which they say “is higher than expected with conventional treatment in pretreated patients.”
The objective response rate (ORR) was 14.3% in the 14 patients who had brain metastases at baseline and 35.5% in the 31 patients who did not.
Eight participants had previously received taxane treatment, of whom 25% had a confirmed response with the remainder experiencing stable disease.
The median response duration was 11.0 months, while the median progression-free and overall survival times were 6.8 and 17.6 months, respectively. At 12 months, 29% of participants were alive and progression-free.
None of the participants discontinued therapy due to toxicity, but 67% experienced a grade 3 or worse treatment-related adverse event, most commonly neutropenia (33%), diarrhea (13%), and anemia (9%).
Treatment was postponed at least once in 44% of participants, with an average postponement period of 12 days. In addition, 49% of patients required a docetaxel dose reduction.
Mazieres and co-authors believe that in the absence of a targeted therapy standard of care in patients with HER2-mutated NSCLC, the combination of pertuzumab, trastuzumab, and docetaxel “could be considered as a potential option.”
In an accompanying editorial, Alissa Cooper and Justin Gainor, both from Massachusetts General Hospital in Boston, USA, point out that treatment of HER2-mutated NSCLC is a “competitive landscape” and note that recent trials with trastuzumab deruxtecan have shown “marked antitumor activity” resulting in the FDA granting Breakthrough Therapy status for HER2-mutated NSCLC.
Mazieres and team acknowledge that trastuzumab deruxtecan may have superior efficacy but highlight the fact that interstitial lung disease can be a limiting toxicity with this drug.
They therefore conclude that “it remains important to have several options for this uncommon disease. Moreover, this triple therapy regimen can be considered a valuable option for pretreated patients because of the combination of conventional chemotherapy and dual targeted therapies.”
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J Clin Oncol 2022; doi:10.1200/JCO.21.01455
J Clin Oncol 2022; doi:10.1200/JCO.21.02550