FDA Schedules ODAC Meeting for Necitumumab in NSCLC

Martin Reck, MD, PhD

The FDA has scheduled an ODAC advisory hearing to discuss the biologics license application (BLA) for necitumumab in combination with gemcitabine and cisplatin as a first-line treatment for patients with locally advanced or metastatic squamous non-small cell lung cancer (NSCLC). The meeting is scheduled for July 9, 2015.

Eli Lilly and Company, the developer of necitumumab, completed a rolling submission to the FDA for the anti-EGFR antibody in combination with chemotherapy in the fourth quarter of 2014. This submission was based on findings from the phase III SQUIRE trial, which demonstrated an 18% improvement in overall survival (OS) with the necitumumab combination versus chemotherapy alone in patients with metastatic squamous NSCLC.¹

"The SQUIRE trial is the largest trial reported for patients with advanced squamous cell carcinoma, and the therapeutic options that we do have are very limited," study author Martin Reck, MD, PhD, Head of Thoracic Oncology, Hospital Grosshansdorf, said at the 2015 ASCO Annual Meeting. "We observed a significant improvement in overall survival and progression-free survival in favor of the combination with necitumumab."

In the study, 1093 patients were randomized to received gemcitabine plus cisplatin plus necitumumab (n = 545) or gemcitabine plus cisplatin (n = 548). Necitumumab was administered at 800 mg on day 1 and 8 every 3 weeks. In both arms, gemcitabine was administered at 1250 mg/m² on days 1 and 8 and cisplatin was administered at 75 mg/m² on day 1. Those who responded in the investigational arm went on to receive single-agent necitumumab.

Baseline characteristics were balanced between the two arms. The median age of patients was 62 years, the majority of patients were white (84%), and most had smoked (91%). The most frequent metastatic site was the lung (83%).

The primary endpoint of the study was OS, with secondary outcome measures focused on progression-free survival (PFS) and objective response rate (ORR). The study was designed to detect a hazard ratio (HR) for OS of 0.80 with a P value of 0.5.

After a follow-up of approximately 25 months, the median OS was 11.5 months in the necitumumab arm versus 9.9 months with the chemotherapy alone (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 median PFS with necitumumab was 5.7 versus 5.5 months for chemotherapy alone (HR = 0.85; 95% CI, 0.74-0.98; P = .02). The ORR was 31.2% in the necitumumab arm and 28.8% with the chemotherapy alone (P = .4). The disease control rate (ORR plus stable disease) was 81.8% in the necitumumab group compared with 77% in the chemotherapy arm (P = .043).

Outcomes were similar in an exploratory analysis by EGFR H-score. In those with an H score ≥200 (n = 374) there was a 25% improvement in OS with necitumumab. In those with a score less than 200 (n = 608), the benefit was 10%. For PFS, the HR score was not predictive, with 12% to 17% improvement across all scores.

Grade ≥3 adverse events were apparent in 72.1% of patients treated with necitumumab versus 61.6% with chemotherapy alone. Adverse events leading to discontinuation of treatment occurred at a rate of 31.2% in the necitumumab/chemotherapy arm and 24.6% in the chemotherapy alone arm. The incidences of adverse events with an outcome of death were 12.3% and 10.5%, respectively.

Grade ≥3 adverse events that occurred significantly more often in the necitumumab/chemotherapy arm were hypomagnesemia (9.3% vs 1.1%), skin rash (7.1% vs 0.4%), and venous thromboembolic events (5.0% vs 2.6%).

"We do know that squamous cell patients are different than other lung cancer patients," Reck said. "They do have more comorbidities, they do have more symptoms, and treatment is a little more difficult in these patients."

A post-hoc analysis was conducted on data from the SQUIRE trial, in attempt to find prognostic or predictive factors for survival. This analysis explored maximum severity score (MMS) and Lung Cancer Symptom Scale (LCSS), as a potential marker. Overall, the analysis found that patients with the highest symptomatic burden, represented by a high MSS, experienced the greatest benefit with necitumumab.

In 172 patients with the highest MMS (≥75) the median OS was 10.1 versus a 6.9 months, for the necitumumab group and chemotherapy, respectively (HR = 0.70, P = .004), according to the post-hoc analysis that was presented at the ASCO 2015 Annual Meeting.² In MMS ≥60 (n = 263), the median OS was 10.7 months with necitumumab and 7.3 months with chemotherapy (HR = 0.67; P <.001). In the groups with an MSS lower than 15 the HR was above 1.00 and the P value was not significant.

"What was quite interesting is that in the group with the worse symptomatic presentation, with the highest severity score at baseline, we did see the best therapeutic impact. This was true for overall survival and progression-free survival," Reck explained. "Symptomatic patients did benefit the most from necitumumab, cisplatin, and gemcitabine. This was an interesting finding, and has never been investigated before in any other lung cancer trial."

Despite this slow progress over the past 20 to 25 years, the past year has demonstrated substantial advancements for patients with squamous NSCLC. In March 2015, the PD-1 inhibitor nivolumab (Opdivo) received FDA approval as a treatment for patients with squamous NSCLC who had progressed on or after platinum-based chemotherapy. This decision was based on a 3.2-month improvement in OS with nivolumab versus docetaxel in the phase III CheckMate-017 study.

In this open-label phase III study, 272 previously treated patients with advanced or metastatic squamous cell NSCLC were treated with nivolumab at 3 mg/kg IV every 2 weeks (n = 135) or docetaxel at 75 mg/m2 IV (n = 137) every 3 weeks. The primary outcome measure of the trial was OS, with secondary endpoints focused on ORR and PFS.

In findings presented at the 2015 ASCO Annual Meeting, the median OS was 9.2 months with nivolumab versus 6.0 months with chemotherapy (HR = 0.59; 95% CI, 0.44-0.79; P = .00025). The 1-year OS was 42% versus 24%, respectively.

The median PFS was 3.5 versus 2.8 months, for nivolumab and docetaxel, respectively (HR = 0.62; 95% CI, 0.47-0.81; P = .0004). The one-year PFS rate was 21% versus 6% in the nivolumab and control arm, respectively. The ORR with nivolumab was 20% compared with 9% for chemotherapy (P = .0083).

References:

1. Thatcher N, Hirsch FR, Szczesna A, et al. A randomized, multicenter, open-label, phase III study of gemcitabine-cisplatin (GC) chemotherapy plus necitumumab (IMC-11F8/LY3012211) versus GC alone in the first-line treatment of patients (pts) with stage IV squamous non-small cell lung cancer (sq-NSCLC). J Clin Oncol. 2014;32:5s (suppl; abstr 8008).
2. Reck M, Gralla RJ, Bonomi P, et al. Maximum severity score (MSS) of baseline patient-reported Lung Cancer Symptom Scale (LCSS) as a prognostic and predictive factor for overall survival (OS) in the Phase III SQUIRE study. J Clin Oncol. 2015;33 (suppl; abstr 8099).