FDA Grants Regular Approval to Pralsetinib for Metastatic RET Fusion+ NSCLC

FDA

The FDA has granted regular approval to pralsetinib (Gavreto) for adult patients with metastatic RET fusion–positive non–small cell lung cancer (NSCLC), as detected by an FDA-approved test.^1,2

In September 2020, the regulatory agency had granted accelerated approval to the agent for this indication based on findings on overall response rate (ORR) and duration of response (DOR) from the phase 1/2 ARROW trial (NCT03037385).³

Pralsetinib had induced an ORR of 57% (95% CI, 46%-68%), which included a complete response (CR) rate of 5.7% in patients with NSCLC who received prior treatment with platinum-based chemotherapy (n = 87). The median DOR in this group had not yet been reached (95% CI, 15.2-not reached). In treatment-naïve patients (n = 27), the ORR with the agent was even higher, at 70% (95% CI, 50%-86%), and the CR rate was 11%.³

The conversion to regular approval was based on findings from an additional 123 patients and 25 months of additional follow-up to evaluate durability of response with the product.¹

Updated data showed that among 107 treatment-naïve patients, pralsetinib elicited an ORR of 78% (95% CI, 68%-85%), which included a CR rate of 7% and a partial response (PR) rate of 71%. In this group, the median DOR was 13.4 months (95% CI, 9.4-23.1), with 45% of patients experiencing a DOR of 12 months or longer. In 130 patients who received prior platinum-based chemotherapy, the ORR was 63% (95% CI, 54%-71%), with a CR rate of 6% and a PR rate of 57%; the median DOR of 38.8 months (95% CI, 14.8-not estimable), with 66% of patients experiencing a DOR of at least 12 months.¹

The multicenter, non-randomized, open-label, multicohort ARROW trial enrolled 2 cohorts of patients: those with metastatic RET fusion–positive NSCLC who had progressed on platinum-based chemotherapy and those with metastatic RET fusion–positive NSCLC who were treatment naïve.² Notably, those with asymptomatic central nervous system (CNS) metastases, including those with stable or decreasing steroid use within 2 weeks before study entry, were permitted.

Next-generation sequencing, fluorescence in situ hybridization, and other tests were utilized to detect RET fusions.

Study participants were given 400 mg of pralsetinib once daily. Treatment continued until progressive disease or intolerable toxicity. ORR and DOR represented the major efficacy outcomes of the trial, and both were assessed by a blinded independent central review and in accordance with RECIST v1.1 criteria.

In the group of patients who previously received platinum-based chemotherapy (n = 130), the median age was 59 years (range, 26-85). About half of patients (51%) were female, and 40% were White. Regarding ECOG performance status, 95% had a status of 0 or 1 and 3.8% had a status of 2. Almost all patients (99%) had metastatic disease, and 41% had a history of or current CNS metastases. This group had received a median of 2 prior lines of therapy, with a range of 1 to 6. In terms of prior treatment, 42% had prior PD-1/PD-L1 therapy, 27% had kinase inhibitors, and 48% had radiation.

Data from an exploratory subgroup analysis indicated that in the 54 patients who previously received an PD-1 or PD-L1 therapy, either sequentially or concurrently with platinum-based chemotherapy, the ORR with pralsetinib was 59% (95% CI, 45%-72%), with a median DOR of 22.3 months (95% CI, 8.0-NE).

Of the total cohort of 130 patients, 10 patients had measurable CNS metastases at baseline per BICR assessment . No patients received radiation therapy to the brain within 2 months before entering the study. Seven of the 10 patients experienced responses in intracranial lesions; this included 2 patients who experienced a CNS CR. Seventy-one percent of responders experienced a DOR of 6 months or longer.

In the cohort of patients with treatment-naïve RET fusion-positive NSCLC (n = 107), the median age was 62 years (range, 30-87); 53% of patients were female and 49% were White. In terms of performance status, almost all patients had a status of 0 or 1 (99%) and metastatic disease (98%). Twenty-eight percent of patients had a history of or current CNS metastases.

Regarding safety, in 281 patients who received pralsetinib, 72% were exposed to treatment for at least 6 months and 56% were exposed for more than 1 year. Sixty-five percent of patients experienced serious toxicities, which included pneumonia, anemia, pneumonitis, pyrexia, sepsis, urinary tract infection, coronavirus infection, pleural effusion, dyspnea, musculoskeletal pain, pulmonary embolism, and seizure. Additionally, 51% of patients experienced adverse effects (AEs) that required dose reductions and 73% needed interruptions. Seven percent of patients experienced fatal AEs, and they included pneumonia (n = 8), sepsis (n = 3), and COVID-19 (n = 3).

The most common AEs experienced by 15% or more of patients with RET fusion–positive NSCLC who received the agent on ARROW (n = 281) included constipation (any grade, 45%; grade 3 or 4, 0.7%), diarrhea (30%; 2.5%), nausea (19%; 0%), dry mouth (17%; 0%), edema (44%; 0%), fatigue (42%; 2.5%), pyrexia (29%; 0.7%), musculoskeletal pain (44%; 2.5%), increased blood creatinine phosphokinase (19%; 9%), hypertension (19%; 9%), cough (36%; 0.4%), dyspnea (21%; 2.1%), pneumonia (24%; 13%), urinary tract infection (16%; 3.6%), reduced appetite (18%; 1.1%), taste disorder (17%; 0%), headache (15%; 1.1%), and rash (17%; 0%).

References

1. FDA approves pralsetinib for non-small cell lung cancer with RET gene fusions. FDA. August 9, 2023. Accessed August 9, 2023. https://www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-pralsetinib-non-small-cell-lung-cancer-ret-gene-fusions
2. Pralsetinib (Gavreto) prescribing information. Genentech; August 2023. Accessed August 9, 2023. https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/213721s009lbl.pdf
3. Genentech announces FDA approval of Gavreto (pralsetinib) for the treatment of adults with metastatic RET fusion-positive non-small cell lung cancer. News release. Genentech. September 4, 2020. Accessed August 9, 2023. https://www.gene.com/media/press-releases/14875/2020-09-04/genentech-announces-fda-approval-of-gavr