High Response Rate in Non-Small Cell Lung Cancer With RET Inhibitor

About three-fourths of patients with advanced RET-fusion-positive non-small cell lung cancer (NSCLC) responded to the RET inhibitor pralsetinib (Gavreto), a prospective study of patients from China showed.

Two-thirds of patients with previously treated disease responded, as did 80% of patients with no prior systemic therapy. The treatment resulted in a disease control rate (DCR) of about 90%.

Pralsetinib was generally well tolerated and associated with a 10% discontinuation rate, reported Qing Zhou, MD, of Guangdong Lung Cancer Institute in Guangzhou, during the virtual World Conference on Lung Cancer (WCLC).

“Pralsetinib is a promising targeted therapy with rapid and durable clinical activity in Chinese patients with RET-fusion-positive non-small cell lung cancer, regardless of prior therapies,” Zhou concluded.

“The efficacy results in this Chinese population are consistent with those previously reported from the global population in the ARROW trial,” he continued. “With a favorable benefit-risk profile, pralsetinib represents an efficacious treatment option and demonstrates the potential of being a new standard of care for Chinese patients with RET-fusion-driven advanced non-small cell lung cancer.”

In NSCLC, RET fusions occur as driver mutations in 1-2% of tumors. Until recently, the efficacy of RET inhibitors in RET-fusion-positive NSCLC remained unproven. A phase I/II trial of RET inhibitor selpercatinib (Retevmo) showed an overall response rate of almost 70% in RET-fusion-positive NSCLC, providing support for subsequent FDA approval.

Pralsetinib is a selective RET kinase inhibitor that targets RET alterations, including fusions. The drug has FDA approved indications for NSCLC and thyroid cancer associated with RET alterations. Support for the approvals included the phase I/II ARROW trial, which included multiple cohorts of patients with RET-altered solid tumors. Investigators at 71 sites in Europe, Asia, and the U.S. enrolled patients for the trial, and Gong reported findings for 68 Chinese patients with RET-fusion-positive NSCLC.

The analysis included 37 patients previously treated with platinum-based chemotherapy and 31 who received pralsetinib as initial systemic therapy. Baseline characteristics showed that 29 (78.4%) of the previously treated patients had stage IVb disease, and the remaining eight patients had stage IVa NSCLC. A majority (17, 54.8%) of the untreated patients had stave IVb disease and 12 (38.7%) had stage IVa disease. Brain metastases were present in 15 (40.5%) previously treated patients and eight (25.8%) untreated patients. Almost half of the previously treated patients had received at least three prior systemic regimens.

Efficacy results were based on 63 patients with measurable disease at enrollment (33 previously treated, 30 untreated). Overall, 22 (66.7%) previously treated patients had objective responses with pralsetinib (one complete response) and nine patients had stable disease. One patient had progressive disease and one was not evaluable for response. In the untreated group, 24 (80.0%) had objective responses (two complete responses), and two had stable disease. Two patients had progressive disease, and two others had not been evaluated for response.

Among 60 patients who could be evaluated for tumor shrinkage, all but one had some degree of reduction in tumor size. The vast majority of tumors shrank by 30% or more, including seven patients who had 100% tumor shrinkage from baseline (including confirmed and unconfirmed complete responses).

Median treatment duration was 14.65 months among previously treated patients, and 15 of 22 (68.2%) responding patients remained on treatment. The previously untreated patients had a median treatment duration of 7.1 months, and 19 of 24 (79.2%) remained on treatment.

The most common grade 3/4 treatment-related adverse events were decreased neutrophil count (33.8%), anemia (32.4%), increased serum creatine phosphokinase (17.6%), decreased white cell count (13.2%), and hypertension (11.8%).

Both pralsetinib and selpercatinib have demonstrated durable efficacy in RET-fusion-positive NSCLC, said WCLC invited discussant Shengxiang Ren, MD, PhD, of Shanghai Pulmonary Hospital. The drugs have shown similar efficacy in global and Chinese populations.

Two phase III trials are evaluating the RET inhibitors as first-line treatment for RET-fusion-positive NSCLC, Ren continued. The AcceleRET trial is comparing pralsetinib with investigator’s choice of platinum-based chemotherapy plus or minus pembrolizumab (Keytruda). LIBRETTO-431 will compare selpercatinib with carboplatin- or cisplatin-based chemotherapy plus or minus pembrolizumab.