Spectrum Pharmaceutecals Inc (SPPI)

[antihama]

Non-Pozi Combo trial This Year Silver Lining Conjecture. Note that the references I quote below are for HER2 exon 20 mutations but I don’t think it’s a reach in surmising similar effects for EGFR ex20 mutations.

It was news to me when Spectrum semi-recently indicated they weren't starting a pozi combo trial this year after indicating for the last year plus that they were going to start one. And it's also a palpable feeling that one gets in reading several of MDACC's journal articles they are eager for a trial to start since in reading them they are strongly pointing out based on their pre-clinical work that a TDM1 combo w pozi would be very effective. In the recent Cancer Cell paper they state

We find that poziotinib upregulates mutant, but not WT, HER2 on the cell surface and that combination of poziotinib with T-DM1 decreases cell viability in vitro and causes complete regression of HER2 exon 20 mutant NSCLC tumors in mice. Together, these data suggest that the high affinity and specificity of poziotinib for HER2 mutants make poziotinib a good candidate for combination with T-DM1 by enhancing mutant, but not WT, HER2 on the cell surface for targeting with T-DM1. Furthermore, these data highlight the need for clinical trials testing the efficacy of poziotinib and T-DM1 combination therapy in ERBB2 mutant malignancies

And more details are provided in AACR 2019 Abstract 347: Identification of poziotinib alone or in combination with TDM1 as a pan-HER2 inhibitor

Lastly, in a HER2 mutant NSCLC PDX model (HER2 Y772dupYVMA), the combination of low dose poziotinib (2.5mpk) & a single dose of TDM1 (10mpk) resulted in complete tumor regression in 9/9 mice, compared to 2/9 mice receiving TDM1 alone or 0/9 mice receiving low dose poziotinib (p<0.0001). In conclusion, HER2 exon 20 insertions & L755P mutations are resistant to the majority of HER2 TKIs, but remain sensitive to poziotinib. Combination of low dose poziotinib & TDM1 caused complete tumor regression in a HER2 exon 20 mutant PDX model. These data suggest that poziotinib alone & in combination with TDM1 has activity against the most common HER2 variants across diverse malignancies & that clinical studies testing these agents in HER2 mutant cancers are warranted.

So when they indicated the combo trial won’t be run this year, the 1st thing that came to mind was that they didn’t want to burn through their cash hoard before BLA approvals are closer at hand. But thinking about it further, assuming they get Accelerated Approval (AA) for 2nd /1st-line patients, they would need to do a P3 trial to get full Regulatory Approval (RA) and doing a combo trial would be a great way to get RA; two birds w one stone if you think about it. Interesting to see what new trials transpire next year.