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Accelerated Approval of Sotorasib for KRAS G12C Mutated NSCLC

Sotorasib, a RAS GTPase family inhibitor, received accelerated approval for adult patients with KRAS G12C-mutated locally advanced or metastatic non-small cell lung cancer (NSCLC), as determined by an FDA-approved test, who have received at least one prior systemic therapy.

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FDA also approved the therascreen KRAS RGQ PCR kit (tissue) and the Guardant360 CDx (plasma) as companion diagnostics for sotorasib. If no mutation is detected in a plasma specimen, the tumor tissue should be tested.


Approval was based on CodeBreaK 100, a multicenter, single-arm, open-label clinical trial (NCT03600883), which included patients with locally advanced or metastatic NSCLC with KRAS G12C mutations. Efficacy was evaluated in 124 patients whose disease had progressed on or after at least one prior systemic therapy. Patients received sotorasib 960 mg orally daily until disease progression or unacceptable toxicity.


The main efficacy outcome measures were objective response rate (ORR) according to RECIST 1.1, as evaluated by blinded independent central review and response duration. The ORR was 36 percent (95% CI: 28%, 45%) with a median response duration of 10 months (range 1.3+, 11.1).


The most common adverse reactions (>= 20%) were diarrhea, musculoskeletal pain, nausea, fatigue, hepatotoxicity, and cough. The most common laboratory abnormalities (>= 25%) were decreased lymphocytes, decreased hemoglobin, increased aspartate aminotransferase, increased alanine aminotransferase, decreased calcium, increased alkaline phosphatase, increased urine protein, and decreased sodium.


The recommended sotorasib dose is 960 mg orally once daily with or without food. The approved 960 mg dose is based on available clinical data, as well as pharmacokinetic and pharmacodynamic modeling that support the approved dose. As part of the evaluation for this accelerated approval, FDA is requiring a postmarketing trial to investigate whether a lower dose will have a similar clinical effect.


Accelerated Approval of Infigratinib for Metastatic Cholangiocarcinoma

The FDA granted accelerated approval to infigratinib, a kinase inhibitor for adults with previously treated, unresectable locally advanced, or metastatic cholangiocarcinoma with a fibroblast growth factor receptor 2 (FGFR2) fusion or other rearrangement as detected by an FDA-approved test.


The FoundationOne CDx also was approved for selection of patients with FGFR2 fusion or other rearrangement as a companion diagnostic device for treatment with infigratinib.


Efficacy was demonstrated in CBGJ398X2204 (NCT02150967), a multicenter open-label, single-arm trial that enrolled 108 patients with previously treated, unresectable, locally advanced, or metastatic cholangiocarcinoma with an FGFR2 fusion or rearrangement as determined by local or central testing. Patients received infigratinib 125 mg orally once daily for 21 consecutive days followed by 7 days off therapy in 28-day cycles until disease progression or unacceptable toxicity.


The major efficacy outcome measures were overall response rate (ORR) and duration of response (DoR), as determined by blinded independent central review according to RECIST 1.1. The ORR was 23 percent (95% CI: 16, 32), with one complete response and 24 partial responses. Median DoR was 5 months (95% CI: 3.7, 9.3). Among the 23 responders, eight patients maintained the response for 6 months or more.


The most common (incidence >= 20%) adverse reactions were hyperphosphatemia, increased creatinine, nail toxicity, stomatitis, dry eye, fatigue, alopecia, palmar-plantar erythrodysesthesia syndrome, arthralgia, dysgeusia, constipation, abdominal pain, dry mouth, eyelash changes, diarrhea, dry skin, decreased appetite, blurred vision, and vomiting. The serious risks include hyperphosphatemia and retinal pigment epithelial detachment. Monitoring for these adverse reactions during treatment is recommended.


The recommended infigratinib dose is 125 mg orally once daily on an empty stomach for 21 consecutive days followed by 7 days off therapy, in 28-day cycles.


Piflufolastat F 18 Injection Approved as First & Only PSMA PET Imaging Agent for Prostate Cancer

The FDA has approved the piflufolastat F 18 injection, an F-18-labeled prostate-specific membrane antigen (PSMA)-targeted positron emission tomography (PET) imaging agent to identify suspected metastasis or recurrence of prostate cancer. Piflufolastat F 18 is the first and only commercially available approved PSMA PET imaging agent for prostate cancer. The product will be immediately available in parts of the mid-Atlantic and southern regions and availability is expected to rapidly expand over the next 6 months with broad availability across the U.S. anticipated by year end.


Piflufolastat F 18 was developed to target PSMA, a protein that is overexpressed on the surface of more than 90 percent of primary and metastatic prostate cancer cells. It binds to the target, enabling the reader of the PET scan to detect and locate the disease. Cyclotron production of F 18 offers high batch capacity and high image resolution, and the 110-minute half-life allows for wide geographic distribution.


"Conventional imaging has significant limitations in detecting prostate cancer, both in initial staging and when the cancer has recurred or spread after initial primary treatment. Specifically, standard imaging poorly detects the early spread to distant organs, such as the lymph nodes, bones, and other organs," said Michael J. Morris, MD, Prostate Cancer Section Head of Genitourinary Medical Oncology at Memorial Sloan Kettering Cancer Center, as well as lead study investigator in the CONDOR trial and study investigator in the OSPREY trial.


"Piflufolastat F 18 can detect the spread of disease well before standard imaging and can be a transformative diagnostic tool that helps clinicians develop treatment plans based on a much more accurate understanding of a patient's distribution of disease."


"We believe today's approval is a game-changer for men facing prostate cancer," said Jamie Bearse, Chief Executive Officer of ZERO - The End of Prostate Cancer, a patient advocacy group. "Having a diagnostic tool that allows doctors to see suspected metastatic or recurrent prostate cancer earlier, anywhere in the body, is a significant step forward and will have a tremendous impact on patients' lives."


The approval of piflufolastat F 18 is based on data from two studies (OSPREY and CONDOR) designed to establish the safety and diagnostic performance of piflufolastat F 18 injection across the prostate cancer disease continuum. Results from OSPREY (Cohort A) demonstrated improvement in specificity and positive predictive value of piflufolastat F 18 PET imaging over conventional imaging in men at risk for metastatic prostate cancer prior to initial therapy. CONDOR studied men with biochemical recurrent prostate cancer. In patients with biochemical recurrent prostate cancer and non-informative baseline imaging, piflufolastat F 18 injection demonstrated high correct localization and detection rates, including in patients with low PSA values (median PSA 0.8 ng/mL).


In the clinical trials, piflufolastat F 18 injection was well-tolerated. In OSPREY and CONDOR, 593 patients with various states of prostate cancer were exposed to a single dose of piflufolastat F 18 injection. Adverse reactions (headache, dysgeusia, and fatigue) were reported in <= 2 percent of patients within the studies. In addition, a delayed hypersensitivity reaction was reported in one patient (0.2%) with a history of allergic reaction.