November's CHMP meeting sets up a GSK-Novartis battle

In addition to making a rare U-turn on the approvability of Mirati's KRAS G12C inhibitor Krazati, the EU CHMP on Friday issued verdicts on several other drugs that, like Krazati, will be eyed carefully by competitors.

GSK's JAK inhibitor Omjjara (momelotinib), acquired via Sierra Oncology, has been recommended for disease-related splenomegaly or symptoms in adults with moderate-to-severe anaemia who have primary myelofibrosis, post polycythaemia vera myelofibrosis or post essential thrombocythaemia myelofibrosis and who are JAK inhibitor naive or have been treated with Novartis/Incyte's Jakafi.

The positive opinion is based on the phase 3 Momentum (post-JAK inhibitor) and Simplify-1 (JAK inhibitor-naive) trials. Primary analysis results from Momentum were presented at ASCO and EHA 2022 and published in The Lancet. The primary endpoint of total symptom score of ≥50% was 25% in the momelotinib arm versus 9% in the danazol cohort (p=0.0095). 

In Simplify-1 momelotinib achieved the primary endpoint of non-inferiority versus Jakafi for spleen response rate at week 24. 27% of patients treated with momelotinib achieved a ≥35% reduction in spleen volume versus 29% of those on Jakafi (p=0.011). The threat to Jakafi is clear.

The positive opinion for Pfizer's PARP inhibitor Talzenna (talazoparib) in combination with Xtandi, in patients with metastatic castration-resistant prostate cancer (mCRPC) in whom chemotherapy is not clinically indicated, is based on the phase 3 Talapro-2 trial. Results were presented at ASCO-GU 2023 and published in The Lancet.

In the primary analysis, the median rPFS in the overall population was not reached in the Talzenna arm versus 21.9 months for Xtandi alone (HR=0.63; p<0.001). In the HRR-deficient subgroup, the rPFS HR was 0.46 (p<0.001) and in the HRR-non-deficient or unknown subgroup the rPFS HR was 0.70 (p=0.004). 

Of note, the US FDA approved the combination of Talzenna and Xtandi only in HRR-mutated mCRPC patients. A trend in OS favouring the Talzenna group was also said to have been observed, although these data are immature, and final OS results are expected in 2024.

The CHMP's positive opinion for Merck & Co's Keytruda plus chemo for first-line biliary tract carcinoma is another challenge to AstraZeneca's Imfinzi, available as a chemo combo in this setting based on the Topaz-1 study since late 2022.

The positive opinion was based on the phase 3 Keynote-966 trial whose results were presented at AACR 2023 and published in The Lancet. At final analysis the median OS was 12.7 months in the Keytruda arm versus 10.9 months for gemcitabine and cisplatin alone (HR=0.83; p=0.0034). At the first interim analysis, the median PFS was 6.5 months versus 5.6 months (HR=0.86; p=0.0225).

The PFS benefit failed to clear the bar for statistical significance, and ORR was virtually identical in the two cohorts (28.7% versus 28.5%). 

Although not mentioned in the CHMP highlights document, Roche's subcutaneous (SC) Tecentriq (atezolizumab) was also recommended for EU approval, according to the Swiss company, for all indications in which IV Tecentriq has been approved. 

The positive opinion was based on the Imscin-001 trial. Results were presented at ESMO-IO 2022 and published in Annals of Oncology showing comparable exposure and similar safety and efficacy versus standard IV Tecentriq in previously treated NSCLC. 

Tecentriq is the first PD-(L)1 antibody to be commercially available with a SC administration in Europe, by virtue of its earlier approval in Great Britain. The situation in the US is less clear after the FDA requested an update on the CMC processes, delaying US launch to 2024 versus the original September 15th PDUFA date. The BLA resubmission is expected to be completed by the end of the year.

Blueprint Medicines' Ayvakyt (avapritinib) has been recommended for adults with indolent systemic mastocytosis with inadequately controlled moderate-to-severe symptoms.

The positive opinion was based on the phase 2 Pioneer trial, which already backs Ayvakit's US approval in this setting, and whose results were presented at AAAI 2023 and published in NEJM Evidence. At week 24 patients treated with Ayvakyt had a decrease of 15.6 points in total symptom score versus a decrease of 9.2 points in the placebo group (p<0.003). 

Finally, Novartis' Spexotras (trametinib) plus Finlee (dabrafenib) was recommended for paediatric patients aged 1 year and older with low-grade glioma (LGG) with a BRAF V600E mutation who require systemic therapy and with high-grade glioma (HGG) with a BRAF V600E mutation who have received at least one prior radiation and/or chemotherapy treatment, backed by the phase 2/3 Tadpole trial. 

Results in paediatric LGG were presented at ASCO 2022 and published in the NEJM, showing ORR of 47% versus 11% for chemo (p<0.001), and median PFS of 20.1 months versus 7.4 months (HR=0.31; p<0.001). Results in paediatric HGG were presented at ASCO 2022 and published in JCO. Here ORR was 56% and median DOR was 22.2 months, while median PFS and OS were 9.0 and 32.8 months respectively.

This is an updated version of a story published earlier.