Hypomagnesaemia and its management following treatment with anti-epidermal growth factor receptor (EGFR) monoclonal antibodies (mAbs): Results from 3 randomized studies of necitumumab (NECI) plus chemotherapy in first-line treatment of patients with stage IV non-small cell lung cancer (NSCLC)

Background

Hypomagnesaemia is a known side effect of certain chemotherapies and an established class effect of EGFR mAbs. We present analyses of hypomagnesaemia and its management from 3 clinical trials of NECI, a human IgG1 anti-EGFR mAb recently approved in the US and the EU for the treatment of advanced squamous NSCLC.

Methods

Three randomized global trials of 1st-line treatment for stage IV NSCLC were included in this analysis. SQUIRE (N=1079) and INSPIRE (N=616) were phase 3 trials of gemcitabine (Gem)-cisplatin (Cis) +/- NECI in squamous NSCLC and pemetrexed (Pem)-Cis +/- NECI in non-squamous NSCLC, respectively. JFCL (N=161) was a phase 2 trial of paclitaxel (Pac)-carboplatin (Carbo) +/- NECI in squamous NSCLC. Per protocols, hypomagnesaemia was managed by investigators based on local guidelines. Hypomagnesaemia frequency was assessed based on reported adverse events (AEs) and lab data.

Results

Hypomagnesaemia was reported as an AE more frequently in the NECI arms as compared to the control arms. SQUIRE: NECI + Gem-Cis 31.2% (9.3% grade ≥3) vs. Gem-Cis 15.7% (1.1%); INSPIRE: NECI + Pem-Cis 26.6% (7.6%) vs. Pem-Cis 12.8% (2.2%); JFCL: NECI + Pac-Carbo 24.5% (5.7%) vs. Pac-Carbo 12.7% (0%). Hypomagnesaemia rates based on lab values were higher as compared to reported AEs across trials and in both arms. A small number of patients discontinued treatment due to hypomagnesaemia (0.6% SQUIRE, 0% INSPIRE and JFCL). In SQUIRE, no clear association was seen between hypomagnesaemia and hypokalemia or cardiac events. Magnesium levels gradually reduced over time and stabilized. Magnesium supplementation was given to 31% and 16.7% of patients with hypomagnesaemia based on lab data for NECI + Gem-Cis and Gem-Cis, respectively.

Conclusions

Hypomagnesaemia is a common side effect of the combinations of chemotherapy with NECI, especially Cis-containing regimens. Our data suggest that hypomagnesaemia may be underreported and perhaps undertreated. Close monitoring of magnesium levels and prompt repletion is recommended.

Clinical trial identification

NCT00981058

NCT00982111

NCT01769391

Legal entity responsible for the study

Eli Lilly and Company

Funding

Eli Lilly and Company

Disclosure

E. Vokes: Eli Lilly and Company – Consultant. M. Socinski: Eli Lilly and Company - Steering Committee Member. L. Paz-Ares: Scientific advice (Roche, Eli Lilly and Company, Astra Zeneca, Merck Sharp, Boehringer Ing., Bristol Meyers Squibb, Pfizer, Clovis Oncology, Novartis, Bayer, Amgen). R. Kurek, S. Nanda, G. Grau, J. Shahidi: Eli Lilly and Company – Employee. N. Thatcher: Advisory Speaker - Eli Lilly and Company, Genentech, and AstraZeneca. D. Gandara: Eli Lilly and Company - Consultant and/or Advisor. All other authors have declared no conflicts of interest.