On December 19, Spectrum Pharmaceuticals’ shares tumbled 31% following the FDA decision to decline the company’s request of a breakthrough therapy designation (BTD) for its clinical candidate EGFR tyrosine kinase inhibitor (TKI) poziotinib for the treatment of EGFR exon 20 insertion mutation-positive non-small cell lung cancer (NSCLC).

The news was a big blow to the company’s plans to quickly bring poziotinib to the lucrative NSCLC market based on the Phase II trial conducted in collaboration with the M.D. Anderson Cancer Center. With an accelerated approval out of the picture, Spectrum will have to hold on to the original timeline based on the Phase II ZENITH20 trial, which has an estimated primary completion date of June 2022.

This is not the first bottleneck Spectrum has faced regarding poziotinib’s clinical development. Initially positioned for the treatment of patients with EGFR-mutated NSCLC who developed acquired resistance (AR) to EGFR TKIs Tarceva (erlotinib) or Iressa (gefitinib), poziotinib was unable to overcome therapy resistance in this high-unmet-need population.

The candidate was particularly ineffective in patients harbouring the EGFR T790M mutation, an alteration seen in 50% of the EGFR-mutated NSCLC cases following frontline EGFR TKI treatment, making it the most common cause of AR in these patients. Spectrum’s disappointing clinical data were soon followed by AstraZeneca’s launch of a rival EGFR TKI, Tagrisso (osimertinib), which specifically targets the EGFR T790M mutation and has been rapidly adopted for the treatment of this highly underserved patient population.

The future of poziotinib clinical development

Having lost a major proportion of the EGFR TKI-resistant patient segment to a strong competitor, combined with the lack of clinical activity for EGFR T790M mutation, necessitated repositioning of poziotinib in order to remain a viable clinical candidate for commercialisation.

EGFR exon 20 insertion mutations make up approximately 4–9% of all EGFR-mutated lung tumours. Although this would result in a relatively small patient population within NSCLC cases, it is nevertheless a very high unmet need area due to the current lack of effective treatment options.

Despite the setback for an accelerated review, poziotinib is a rare EGFR TKI that has demonstrated encouraging activity in initial clinical studies of EGFR exon 20 insertion mutation-positive NSCLC. The company will have to wait for the topline results from the ongoing confirmatory ZENITH20 trial, which is expected in H2 2019. Positive data from this study will be crucial in winning the FDA approval that the company has long been chasing.