SUMMARY: The FDA on August 9, 2023, granted regular approval to Pralsetinib (GAVRETO®) for adult patients with metastatic Rearranged during Transfection (RET) fusion-positive Non-Small Cell Lung Cancer (NSCLC) as detected by an FDA approved test. Pralsetinib was previously granted accelerated approval for the NSCLC indication in Sept. 2020, based on initial Overall Response Rate (ORR) and Duration of Response (DOR) in 114 patients enrolled in the ARROW trial. The conversion to regular approval was based on data from an additional 123 patients and 25 months of additional follow up, to assess Durability of Response.
Lung cancer is the second most common cancer in both men and women and accounts for about 13% of all new cancers and 21% of all cancer deaths. The American Cancer Society estimates that for 2023, about 238,340 new cases of lung cancer will be diagnosed and 127,070 patients will die of the disease. Lung cancer is the leading cause of cancer-related mortality in the United States. Non-Small Cell Lung Cancer accounts for approximately 85% of all lung cancers.
In addition to the well characterized gene fusions involving ALK and ROS1 in NSCLC, genetic alterations involving other kinases including EGFR, BRAF, RET, MET, KRAS, NTRK, are all additional established targetable drivers. These genetic alterations are generally mutually exclusive, with no more than one predominant driver in any given cancer. The hallmark of all of these genetic alterations is oncogene addiction, in which cancers are driven primarily, or even exclusively, by aberrant oncogene signaling, and are highly susceptible to small molecule inhibitors.
RET kinase is a transmembrane Receptor Tyrosine Kinase and plays an important role during the development and maintenance of a variety of tissues, including neural and genitourinary tissues. RET signaling activates downstream pathways such as JAK/STAT3 and RAS/RAF/MEK/ERK and leads to cellular proliferation, survival, invasion, and metastasis. Oncogenic alterations to the RET proto-oncogene results in uncontrolled cell growth and enhanced tumor invasiveness. RET alterations include RET rearrangements, leading to RET fusions, and activating point mutations occurring across multiple tumor types. RET fusions have been identified in approximately 2% of NSCLCs, 10-20% of non-medullary thyroid cancers. Activating RET point mutations account for approximately 60% of sporadic Medullary Thyroid Cancers (MTC) and more than 90% of inherited MTCs. Other cancers with documented RET alterations include colorectal, breast, and several hematologic malignancies.
Patients without a driver mutation are often treated with a platinum-doublet cytotoxic chemotherapy with/without Immune checkpoint inhibitors, or with Immune checkpoint inhibitor monotherapy. However, outcomes with immune checkpoint inhibitors remain poor in patients with RET fusion–positive NSCLC, regardless of PD-L1 expression.
Pralsetinib (GAVRETO®) is an oral, highly potent, selective RET kinase inhibitor targeting oncogenic RET alterations, including fusions and mutations, regardless of the tissue of origin. The efficacy of Pralsetinib was investigated in a multicenter, open-label, multi-cohort, Phase I/II basket clinical trial (ARROW), in patients with tumors showing RET alterations. Identification of RET gene alterations was prospectively determined in local laboratories using either, Next Generation Sequencing (NGS), Fluorescence In Situ Hybridization (FISH), or other tests. (In a basket trial, tumors with different histologies and single biomarker are placed in different baskets and receive a single treatment). Phase I Pralsetinib dose escalation study determined 400 mg QD as the recommended Phase II trial dose. Phase II trial evaluated Pralsetinib in multiple expansion groups, defined by disease type and treatment history.
The FDA regular approval was based on the efficacy of Pralsetinib in a total of 237 patients (N=237) with locally advanced or metastatic RET fusion-positive NSCLC. Patients received Pralsetinib 400 mg once daily until disease progression or unacceptable toxicity. Among the patients studied, 107 (N=107) were treatment-naïve and 130 patients (N=130) were previously treated with platinum-based chemotherapy. The main efficacy outcome measures were Overall Response Rate (ORR) and Duration of Response, as determined by a Blinded Independent Review Committee, using RECIST criteria.
The median age of the 107 patients in the treatment-naïve group was 63 years and 28% of patients had a history of or active CNS/brain metastases. The ORR in this group was 78%, with a Complete Response (CR) rate of 7%. The median Duration of Response was 13.4 months and 45% of patients experienced a Duration of Response of 12 months or longer.
The median age of the 130 patients in the group that was previously treated with platinum-based chemotherapy, was 59 years and 41% had a history of or active CNS/brain metastases. The ORR in this group was 63% with a CR rate of 6%. The median Duration of Response of 38.8 months and 66% of patients experienced a Duration of Response of at least 12 months.
In patients with measurable intracranial metastases, the intracranial response rate was 70%.
The most common adverse reactions were fever, fatigue, cough, constipation, diarrhea, musculoskeletal pain, hypertension and edema.
It was concluded from this study that treatment with Pralsetinib produced robust efficacy including intracranial activity, in patients with advanced RET fusion–positive NSCLC who are treatment-naive or are refractory to standard-of-care chemotherapy. Results from the confirmatory Phase III AcceleRET Lung study of Pralsetinib versus standard of care in the first-line setting are eagerly awaited and may further support the use of Pralsetinib for RET fusion-positive NSCLC in the first-line setting.
https://www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-pralsetinib-non-small-cell-lung-cancer-ret-gene-fusions
