Selpercatinib Is Approved for 2 RET Fusion–Positive Solid Tumors, Non–Small Cell Lung Cancer

Selpercatinib was approved by the FDA for RET fusion–positive non–small cell lung cancer and locally advanced or metastatic RET fusion–positive solid tumors.

Selpercatinib (Retevmo) was recently approved for 2 new solid tumor indications. The kinase inhibitor was granted regular approval for locally advanced or metastatic RET fusion–positive non–small cell lung cancer (NSCLC).1 It was also granted accelerated approval for patients with solid tumor harboring a RET gene fusion mutation.2

Clinical Efficacy

Selpercatinib had previously received accelerated for RET-fused NSCLC approval based on initial findings from the phase 1/2 LIBRETTO-001 trial (NCT03157128). Confirmatory data from an additional 172 patients and 18 months of extended follow-up secured the agent’s full approval. Updated findings showed that patients with RET-positive NSCLC achieved a 61% overall response rate (ORR), a complete response rate (CR) 7.3% and a partial response (PR) rate of 54%. In addition, the median duration of response was 28.6 months (95% CI, 20–not estimable [NE]) and 63% achieved a response which lasted for 12 months or longer.

The accelerated approval was supported by findings from the phase 1/2 LIBRETTO-001 trial (NCT03157128), which showed that that the targeted therapy yielded an ORR of 44% (95% CI, 28%-60%) in patients with RET-fusion solid tumors, as well as a 4.9% complete response, and a 39% partial response rate. In this trial, the median duration of responses was 24.5 months (95% CI, 9.2-NE), and 67% of patients achieved a response that lasted for at least 6 months.

Patients who achieved responses included those with pancreatic adenocarcinoma, colorectal cancer, salivary, unknown primary, breast, soft tissue sarcoma, bronchial carcinoid, ovarian, small intestine, and cholangiocarcinoma.

In terms of testing, in the population of patients with NSCLC, 94% of RET-fusions were identified with next-generation sequencing (NGS), 84.6% were confirmed with a tumor sample, 9.3% were found with a blood or plasma sample, 4.0% were detected with FISH, and 1.6% through PCR. In addition, 0.4% had their mutation tested through another method. In solid tumors, 97.6% of RET-fusions were detected via NGS, and 2.4% of these fusions were detected through FISH.

Administration

Selpercatinib comes in 40 mg and 80 mg capsules. For patients weighing less than 50 kg, the recommended dose is 120 mg twice a day. For those who are greater than 50 kg, the recommended dose is 160 mg twice a day. If a patient has severe hepatic impairment, they should receive a reduced dose.

Providers should avoid coadministering with acid-reducing agents, strong and moderate CYP3A inhibitors or inducers, CYP2C8 and CYP3A substrates, and certain P-gp substrates. If acid-reducing agents are necessary, then selpercatinib should be taken with food and the administration time should be modified. If strong or moderate CYP3A inhibitors cannot be avoided, the selpercatinib dose should be reduced. If a patient required CYP2C8 and CYP3A substrates, or P-gp substrates, the substrate dosages should be reduced, as recommended in their product labeling.

There are no contraindications, however, the agent comes with warnings for hepatotoxicity, interstitial lung disease (ILD), hypertension, hemorrhagic events, hypersensitivity, tumor lysis syndrome, hypothyroidism, and risk of impaired wound healing. The drug also increases the risk for embryo-fetal toxicities.

For hepatotoxicity risk, the label advice monitoring alanine aminotransferase (ALT) and aspartate aminotransferase (AST), prior to initiation selpercatinib and monitoring every 2 weeks during the first 3 months, followed by monthly monitoring as necessary.

Patients with uncontrolled hypertension should not initiate selpercatinib. All patients should have their blood pressure optimized prior to starting treatment and should be monitored at their first week of treatment and monthly thereafter. Thyroid function should also be assessed at baseline and periodically throughout treatment.

Patients should be evaluated for QT interval, electrolytes and thyroid stimulating hormone at baseline, and periodically throughout treatment. If patients require concomitant treatment with strong and moderate CYP3A inhibitors, minoring should be even more frequent.

Because selpercatinib increases the risk of impaired wound healing, it should be withheld for at least 7 days prior to elective surgery. Following major surgery, patients should not receive this agent for at least 2 weeks and until their wounds have adequately healed. The safety of agent resumption following wound healing complications are not yet established.

In addition, if a patient developed hypersensitivity, the agent should be withheld, and corticosteroids should be initiated. Upon resolution, treatment should be resumed at a reduce dose and increased by 1 dose level each week until the dose is the same as it was prior to the onset of the reaction. Once the target dose has been reached, tapering can begin.

Based on the severity of possible hepatotoxicity, ILD, hypertension, or QT interval prolongation, the agent should be withheld, dose reduced, or permanently; discontinued.

The most common any-grade adverse events associated with selpercatinib include edema, diarrhea, fatigue, dry mouth, hypertension, abdominal pain, constipation, rash, nausea, and headache. The most common grade 3 or 4 laboratory abnormalities include decreased lymphocytes, increased ALT, increased AST, decreased sodium, and decreased calcium.


Reference

  1. FDA approves selpercatinib for locally advanced or metastatic RET fusion-positive non-small cell lung cancer. News release. FDA. September 21, 2022. Accessed September 21, 2022. https://bit.ly/3DFyvq0
  2. FDA approves first therapy for patients with lung and thyroid cancers with a certain genetic mutation or fusion. News release. FDA. May 8, 2020. Accessed September 21, 2022. https://bit.ly/3beo62M
  3. FDA approves selpercatinib for locally advanced or metastatic RET fusion-positive solid tumors. News release. FDA. September 21, 2022. Accessed September 21, 2022. https://bit.ly/3f8Wzr7
  4. Retevmo. Prescribing information. Eli Lilly and Company; 2022. Accessed September 21, 2022. https://bit.ly/3Sk1wvq