For the first time in patients with HER2-mutated advanced non-small cell lung cancer (NSCLC), the results of treatment with the combination of pertuzumab, trastuzumab and docetaxel, which is widely used for the management of HER2-positive breast cancer have been extrapolated in the IFCT-1703 R2D2 study. Triple therapy was associated with an objective response rate (ORR) of 29%, duration of response (DoR) of 10 months, and progression-free survival (PFS) of 6.8 months which is higher than expected with conventional treatment in pretreated patients. The study findings are reported by Prof. Julien Mazieres of the Pneumology, CHU Toulouse—Hôpital Larrey, Université Paul Sabatier in Toulouse, France and colleagues on 24 January 2022 in the Journal of Clinical Oncology.

HER2 exon 20 insertions and point mutations are oncogenic drivers identified in approximately 1-2% of patients with NSCLC. Due to their rarity and confusion with HER2 amplification and overexpression, very few prospective studies have been conducted to date. Non-specific HER2 tyrosine kinase inhibitors (TKIs), such as neratinib, afatinib, lapatinib, and dacomitinib, have been tested with disappointing response rates. Exon 20–specific TKI drugs, such as mobocertinib, poziotinib, and pyrotinib, have yielded better results, but with non-negligible side effects. Retrospective studies have suggested that HER2 antibodies might be more effective at targeting HER2-mutated NSCLC. Conjugated antibodies such as trastuzumab emtansine and trastuzumab deruxtecan have shown more favourable response rates, reaching 50%.

However, no drug has yet been approved for HER2-mutated NSCLC. Most drugs used for the treatment of HER2-mutated NSCLC have been derived from clinical research on breast cancer. One of the most validated strategies for the treatment of HER2-mutated breast cancer is the combination of two HER2 antibodies, pertuzumab and trastuzumab, with docetaxel, which is a standard treatment for both breast and lung cancer. The IFCT-1703 R2D2 study team hypothesised that this triple therapy might be effective for HER2-mutated NSCLC. They report the safety and efficacy of this combination in a prospective, open-label phase II study.

The IFCT 1703-R2D2 study is a multicentre, non-randomised phase II study performed in patients with HER2-mutated, advanced NSCLC who progressed after ≥1 platinum-based treatment. Patients received pertuzumab at a loading dose of 840 mg and 420 mg thereafter, trastuzumab at an 8 mg/kg loading dose and 6 mg/kg thereafter, and docetaxel at a dose of 75 mg/m2 every 3 weeks. The primary outcome was the ORR. Other endpoints included the DoR, PFS, and safety.

In total, 45 patients were enrolled and treated. The median age was 64.5 years (range, 31-84 years), 35% were smokers, 72% were females, 15% had an ECOG performance status of 2, and 30% had brain metastases.

The ORR was 29% (n = 13), and 58% had stable disease (n = 26).

The median DoR in patients with a confirmed response (n = 13) was 11 months (95% confidence interval [CI] 2.9 to 14.9).

The median PFS was 6.8 months (95% CI 4.0 to 8.5).

Grade 3/4 treatment-related adverse events were observed in 64% of the patients. No patient discontinued treatment because of toxicity. The most frequent grade ≥ 3 treatment-related adverse events were neutropenia (33%), diarrhoea (13%), and anaemia (9%).

The authors commented that their results highlight the effectiveness of the HER2 antibody-based strategy. HER2 mutations are treatable targets in patients with NSCLC and should be systematically screened. However, the precise status of this combination in the competitive field of HER2 inhibitors remains to be defined. Although the efficacy might appear inferior to that of trastuzumab deruxtecan, the combination of pertuzumab, trastuzumab, and docetaxel is widely used for the treatment of breast cancer, and its toxicity profiles are very well known. In particular, no cases of interstitial lung disease have been reported, while it can be a limiting side effect in patients treated with trastuzumab deruxtecan. It is important to have several options for this rare subtype. Furthermore, this triple therapy regimen can be considered a valuable option for pretreated patients because of the combination of conventional chemotherapy and dual targeted therapies.

In an accompanied editorial, drs Alissa J. Cooper and Justin F. Gainor of the Department of Medicine, Massachusetts General Hospital in Boston, MA, US wrote that it has become clear that the discovery of an oncogenic driver does not necessarily predict the straightforward development of an effective targeted therapy, as exemplified by efforts to target HER2 in NSCLC. Clinical studies investigating the use of poziotinib, a pan-HER TKI, and dual HER2 monoclonal antibody therapy in combination with chemotherapy (pertuzumab, trastuzumab and docetaxel) demonstrate moderate antitumour activity in patients with HER2-mutated NSCLC. In the absence of randomised comparisons, these studies contribute additional therapeutic options for HER2-mutated NSCLC.

Multiple HER2-targeting agents have now shown promising activity in HER2-mutated NSCLC. Future efforts will need to focus on defining optimal sequential treatment strategies, elucidating mechanisms of resistance, and better characterising CNS activity. HER2 mutations now define a distinct molecular subtype of NSCLC and screening for these alterations should be incorporated into clinical practice.

The IFCT-1703 R2D2 study was previously presented at the ASCO 2021 Congress.

It was supported by the Intergroupe Francophone de Cancérologie Thoracique (IFCT) and Roche.