Pralsetinib shows positive phase 1/2 results in RET fusion+ NSCLC

Pralsetinib treatment is safe and produces durable response rates in patients with RET fusion-positive non-small cell lung cancer (NSCLC), according to findings from the Phase 1/2 ARROW trial (NCT04222972). Among 75 treatment-naive patients, 54 patients had an overall response rate (ORR) of 72% (95% CI, 60%-82%), and among 130 patients who had received prior platinum-based chemotherapy, 80 patients had an ORR of 59% (95% CI, 50%-67%). Tumor shrinkage was observed in all untreated patients and in 97% of patients who had received prior platinum-based chemotherapy. In addition, the median progression-free survival (PFS) was 13.0 and 16.5 months, respectively.

In this latest analysis of patients with RET fusion-positive NSCLC in the ARROW study, platinib at a starting dose of 400 mg (daily) was generally well tolerated and showed clinical activity across all reported treatment arms, consistent with previous study results. At the data cutoff date, a total of 281 patients with RET fusion-positive NSCLC were enrolled in the multi-cohort, multi-center, open-label, Phase 1/2 ARROW trial. We aimed to evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics and efficacy of pralsetinib in patients with advanced RET-altered tumors.

Phase 1 of the trial used a dose-escalation design to evaluate platinib 30-600mg. The Phase 2 recommended dose determined by this study is 400 mg per day. In the phase 2 trial, platinib 400 mg daily was evaluated in multiple expansion groups defined by disease type and treatment history, and patients continued treatment until disease progression, intolerance, withdrawal of consent, or investigator decision. No dose reduction below 100 mg daily due to adverse events (AEs) is allowed. In addition, discontinuation of dosing for more than 28 days due to AEs was not allowed.

Patients were eligible for the study if they were 18 years of age and older, had unresectable locally advanced or metastatic solid tumors, pathologically or genetically documented RET fusions or mutations, an ECOG performance status of 0-2, and baseline measurable disease according to the RECIST version. In the phase 2 portion of the study, investigators assessed the co-primary endpoint of ORR, which included complete response (CR) or partial response (PR). Secondary endpoints were duration of response (DOR), time from first response to disease progression or death, clinical benefit rate (CBR), disease control rate (DCR), PFS, overall survival, and the correlation between RET gene alterations and efficacy.

Research results show that inIn the ITT population, treatment-naïve patients (n=75) with RET fusion-positive NSCLC had an ORR of 72% (95% CI, 60%-82%) and a median time to first response of 1.8 months (range, 0.9-6.1 months). Four patients (5%) had CR, 50 (67%) had PR, 14 (19%) had stable disease, 5 (7%) had disease progression, and 2 (3%) could not be evaluated.

For treatment-naive patients, the median DOR was not reached after a median follow-up of 7.4 months (95% CI, 6.4-9.5 months) and for patients who had received prior platinum-based chemotherapy 22.3 months. However, 84% (95% CI, 73%-95%) and 54% (95% CI, 34%-74%) of patients responded at 6 months and 12 months, respectively. The DCR was 91% (95% CI, 82%-96%), and the CBR was 80% (95% CI, 69%-88%). In addition, after a median follow-up of 9.2 months (95% CI, 8.6-11.0 months), the median PFS was 13.0 months and 16.5 months, respectively. Intracranial reactions occurred in 7 of 10 patients with measurable intracranial metastases (95% CI, 35%-93%), all of whom had received prior systemic therapy.

Regarding safety, the most common grade 3-4 treatment-related adverse events (TRAEs) in treatment-naïve patients with RET fusion-positive NSCLC who initiated platinib at the data cutoff point (n=116) were neutropenia (18%), hypertension (10%), elevated blood creatine phosphokinase (9%), and lymphopenia (9%). A total of 7% (20/281) patients discontinued treatment due to TRAEs.

Currently, the confirmatory Phase 3 AcceleRET Lung study (NCT04222972) is ongoing and examining platinib versus standard of care in the frontline setting in this patient population. In summary, the study demonstrates that once-daily oral platinib results in robust ORR, including intracranial activity and durable PFS, in patients with advanced RET fusion-positive NSCLC who are untreated or refractory to standard-of-care chemotherapy. These results demonstrate the importance of early comprehensive biomarker testing, including fusion, in all patients with metastatic NSCLC before treatment initiation to inform optimal health care decisions.

The original drug Platinib has been launched in China, but it has not yet passed the relevant policies for inclusion in medical insurance. The price of 120 pills per box may be around 60,000 yuan. The price of the European version of Platinib's original drug sold overseas may be around RMB 40,000 per box of 60 pills, and the price of the U.S. version may be around RMB 150,000 per box (the price may fluctuate due to exchange rates). There are also generic Platinib drugs available for sale overseas. The ingredients of the drug are basically the same as those of the original drug at home and abroad. The price of 120 pills per box may be more than RMB 4,000 (the price may fluctuate due to the exchange rate).