Update Identifies Best Responders to Necitumumab in NSCLC

Luis Paz-Ares, MD

Adding necitumumab to conventional chemotherapy improved outcomes in patients with metastatic squamous non—small cell lung cancer (NSCLC) in the phase III SQUIRE trial, but the greatest benefit was derived by patients with EGFR-expressing tumors, according to a subgroup analysis presented at the 2016 European Lung Cancer Conference (ELCC).

Necitumumab (Portrazza) is a novel anti-EGFR monoclonal antibody that received different approvals from the FDA and European Commission as a first-line treatment in combination with gemcitabine and cisplatin for patients with advanced squamous NSCLC based upon SQUIRE results.

“Based on this analysis, the European Medicines Agency has decided that necitumumab is approved only for patients with EGFR expressing tumors,” said lead author Luis Paz-Ares, MD, chief of Medical Oncology at the Hospital Universitario Doce de Octubre, Madrid, Spain.

“On the other hand the US Food and Drug Administration has taken the more conservative approach, which recognizes that SQUIRE was designed for all-comers without prior selection, and this subgroup analysis is insufficient evidence to conclude that patients with EGFR-negative tumors are not candidates.”

The overall patient cohort receiving necitumumab plus chemotherapy demonstrated median overall survival (OS) of 11.5 months compared with 9.9 months for patients receiving the gemcitabine-cisplatin regimen only (HR, 0.84; 95% CI, 0.74-0.96; P = .012). The 1-year OS rate was 47.7% versus 42.8%, and the 2-year OS rate was 19.9% compared with 16.5%, for the necitumumab and chemotherapy arms, respectively.

The analysis revealed that the subgroup of patients with EGFR expression >0 demonstrated median OS with chemotherapy plus necitumumab of 11.7 months compared with 10.0 months in patients receiving just gemcitabine plus cisplatin (HR 0.79; 95% CI 0.69-0.92; P = .002).

Median progression-free survival (PFS) in the EGFR >0 cohort was 5.7 months with necitumumab plus chemotherapy versus 5.5 months with chemotherapy alone (HR, 0.84; 95% CI, 0.72-0.97; P = .018).

Paz-Ares presented results at ELCC on behalf of colleagues from a prespecified analysis of data from 982 patients with evaluable IHC assay results of EGFR protein expression. Patients were characterised as having tumors that were EGFR-expressing (EGFR >0) or non-expressing (EGFR = 0).

In SQUIRE, patients with pathologically confirmed stage IV squamous NSCLC were randomized equally to first-line treatment with gemcitabine at 1250 mg/m2 on days 1 and 8 plus cisplatin at 75 mg/m2 on day 1, with or without necitumumab at 800 mg IV on days 1 and 8. The treatment cycle was 21 days for a maximum of 6 cycles, after which patients showing no progression were continued on necitumumab monotherapy until progressive disease or intolerable toxicity.

EGFR protein was expressed in the tumors of 935 (95.2%) patients with just 47 (4.8%) patients having tumors without detectable EGFR protein. Baseline characteristics for EGFR >0 patients were well-balanced between the arms, including expression levels of EGFR detected by IHC. The OS benefit was observed across all prespecified subgroups in EGFR >0 patients; however, little benefit with necitumumab was seen in the EGFR = 0 cohort.

“Benefit from addition of necitumumab to chemotherapy was not apparent in the analysis for the small subgroup of 47 patients with EGFR non-expressing tumors,” said Paz-Ares. “Necitumumab is targeted at EGFR so it makes sense that the drug is active in patients with the receptor. Our analysis showed that the drug had no effect when the receptor was absent, presumably because there was no target to bind to.”

Similar benefit between the 2 treatments was observed when OS and PFS in the chemotherapy plus necitumumab arm was compared with the chemotherapy arm in patients with EGFR-negative tumors (HR for OS, 1.52; 95% CI, 0.74-3.12; P = .253; and HR for PFS, 1.33; 95% CI, 0.65-2.70; P = .428).

At the meeting, Tony Mok, MD, Department of Clinical Oncology at the Chinese University of Hong Kong, asked whether Paz-Ares thought EGFR testing should be done prior to advising necitumumab and if it should not be given to patients with EGFR non-expressing tumors.

Paz-Ares replied, “I would not make a recommendation based on 47 patients; we cannot make robust conclusions because the subgroup of patients with negative EGFR was very small, but the hypothesis generated here is that those tumors do not respond well to necitumumab.”

The administration of post-progression anticancer therapy was similar between arms at 49% versus 47% of EGFR-positive versus EGFR-negative patients, respectively.

Adverse events (AEs) in EGFR-positive patients were similar between treatment arms; differences were only noted for hypomagnesemia occurring in 9.6% versus 0.9%, and skin rash in 6.4% versus 0.4% of EGFR-positive and -negative patients, respectively.

AEs of grade ≥3 in patients receiving chemotherapy plus necitumumab compared with chemotherapy alone included neutropenia at 25% versus 27%, anemia at 10% versus 11%, thrombocytopenia at 11% versus 11%, and hypomagnesemia (with lab data) in 21% versus 6%, respectively.

Paz-Ares concluded, “Our results need to be interpreted with caution. A confirmatory study in patients with EGFR-negative tumors is needed to assess whether they are good candidates for necitumumab or not. In addition, so far, our analysis has not provided a breakpoint of the level of EGFR expression to determine whether to advise prescribing necitumumab.”

Paz-Ares L, Socinski MA, Shahidi J, et al. Subgroup analyses of patients with epidermal growth factor receptor (EGFR)-expressing tumors in SQUIRE: a randomized, multicenter, open-label, phase III study of gemcitabine-cisplatin (GC) plus necitumumab (N) versus GC alone in the first-line treatment of patients (pts) with stage IV squamous non-small cell lung cancer (sq-NSCLC). Presented at: 2016 European Lung Cancer Conference; April 13-16, 2016; Geneva, Switzerland. Abstract 1320.

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