Article Content

Approval of Enfortumab Vedotin-Ejfv for Locally Advanced or Metastatic Urothelial Cancer

The FDA approved enfortumab vedotin-ejfv, a Nectin-4-directed antibody and microtubule inhibitor conjugate, for adult patients with locally advanced or metastatic urothelial cancer who:

FDA; oncology resear... - Click to enlarge in new windowFDA; oncology research. FDA; oncology research

* have previously received a programmed death receptor-1 (PD-1) or programmed death-ligand (PD-L1) inhibitor and platinum-containing chemotherapy, or


* are ineligible for cisplatin-containing chemotherapy and have previously received one or more prior lines of therapy.



FDA granted accelerated approval in December 2019 to enfortumab vedotin-ejfv for patients with locally advanced or metastatic urothelial cancer who have received a PD-1 or PD-L1 inhibitor and a platinum-containing chemotherapy in the neoadjuvant/adjuvant, locally advanced, or metastatic setting.


Trial EV-301 (NCT03474107) was an open-label, randomized, multicenter trial required to confirm the clinical benefit of the 2019 accelerated approval. This trial enrolled 608 patients with locally advanced or metastatic urothelial cancer who received a prior PD-1 or PD-L1 inhibitor and platinum-based chemotherapy. Patients were randomized (1:1) to receive either enfortumab vedotin-ejfv (EV) 1.25 mg/kg on days 1, 8, and 15 of a 28-day cycle or investigator's choice of single-agent chemotherapy (docetaxel, paclitaxel, or vinflunine).


The primary efficacy endpoint was overall survival (OS) with key secondary efficacy endpoints of progression-free survival (PFS), and overall response rate (ORR) assessed by investigator using RECIST 1.1. Median OS was 12.9 months (95% CI: 10.6, 15.2) for patients on the EV arm (n=301) versus 9.0 months for those receiving chemotherapy (n=307) (95% CI: 8.1, 10.7) (HR 0.70; 95% CI: 0.56, 0.89; p=0.0014). Median PFS was 5.6 months (95% CI: 5.3, 5.8) compared with 3.7 months (95% CI: 3.5, 3.9), respectively (HR 0.62; 95% CI: 0.51, 0.75; p<0.0001). The ORR was 40.6 percent (95% CI: 34.9, 46.5) versus 17.9 percent (95% CI: 13.7, 22.8), respectively (p<0.0001).


Efficacy for patients ineligible for cisplatin-containing chemotherapy was evaluated in Cohort 2 of EV-201 (NCT03219333), a single-arm, multi-cohort, international trial in 89 patients with locally advanced or metastatic urothelial cancer who received a prior PD-1 or PD-L1 inhibitor and were ineligible for cisplatin-containing chemotherapy. The primary efficacy endpoint was confirmed ORR, assessed by blinded independent central review, and the key secondary efficacy endpoint was response duration. The confirmed ORR was 51 percent (95% CI: 39.8, 61.3), including 22 percent with complete responses, and the median response duration was 13.8 months (95% CI: 6.4, not estimable).


The most common adverse reactions, including laboratory abnormalities (>=20%), were rash, increased aspartate aminotransferase, increased glucose, increased creatinine, fatigue, peripheral neuropathy, decreased lymphocytes, alopecia, decreased appetite, decreased hemoglobin, diarrhea, decreased sodium, nausea, pruritus, decreased phosphate, dysgeusia, increased alanine aminotransferase, anemia, decreased albumin, decreased neutrophils, increased urate, increased lipase, decreased platelets, decreased weight, and dry skin.


A boxed warning for serious skin reactions, including Stevens-Johnson syndrome and toxic epidermal necrolysis, and a warning for pneumonitis were added to the USPI.


The recommended dose of enfortumab vedotin-ejfv is 1.25 mg/kg (up to a maximum dose of 125 mg) administered as an intravenous infusion over 30 minutes on days 1, 8, and 15 of a 28-day cycle until disease progression or unacceptable toxicity.


Belumosudil Approval for Chronic Graft-Versus-Host Disease

The FDA approved belumosudil, a kinase inhibitor, for adult and pediatric patients 12 years and older with chronic graft-versus-host disease (chronic GVHD) after failure of at least two prior lines of systemic therapy. Efficacy was evaluated in KD025-213 (NCT03640481), a randomized, open-label, multicenter dose-ranging trial that included 65 patients with chronic GVHD who were treated with belumosudil 200 mg taken orally once daily.


The main efficacy outcome measure was overall response rate (ORR) through Cycle 7 Day 1 where overall response included complete response (CR) or partial response (PR) according to the 2014 criteria of the NIH Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease. The ORR was 75 percent (95% CI: 63, 85); 6 percent of patients achieved a CR, and 69 percent achieved a PR. The median time to first response was 1.8 months (95% CI: 1.0, 1.9). The median duration of response, calculated from first response to progression, death, or new systemic therapies for chronic GVHD, was 1.9 months (95% CI: 1.2, 2.9). In patients who achieved response, no death or new systemic therapy initiation occurred in 62 percent (95% CI: 46, 74) of patients for at least 12 months since response.


The most common adverse reactions (>= 20%), including laboratory abnormalities, were infections, asthenia, nausea, diarrhea, dyspnea, cough, edema, hemorrhage, abdominal pain, musculoskeletal pain, headache, decreased phosphate, increased gamma glutamyl transferase, decreased lymphocytes, and hypertension. The recommended dosage of belumosudil is 200 mg taken orally once daily with food.


Approval of Pembrolizumab & Lenvatinib for Advanced Endometrial Carcinoma

Pembrolizumab in combination with lenvatinib has been FDA-approved for patients with advanced endometrial carcinoma that is not microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR), who have disease progression following prior systemic therapy in any setting and are not candidates for curative surgery or radiation.


FDA granted accelerated approval on September 17, 2019, to pembrolizumab with lenvatinib for advanced endometrial carcinoma. Study 309/KEYNOTE-775 (NCT03517449) was a multicenter, open-label, randomized, active-controlled trial required to confirm the clinical benefit of this accelerated approval.


Study 309/KEYNOTE-775 enrolled 827 patients with advanced endometrial carcinoma previously treated with at least one prior platinum-based chemotherapy regimen in any setting, including neoadjuvant and adjuvant treatments. Patients were randomized (1:1) to either pembrolizumab 200 mg intravenously every 3 weeks with lenvatinib 20 mg orally once daily or investigator's choice of doxorubicin or paclitaxel.


The major efficacy outcome measures were progression-free survival (PFS), as assessed by blinded independent central review (BICR), and overall survival (OS). Additional efficacy outcome measures included objective response rate (ORR) and duration of response (DOR), also BICR-assessed.


For patients with advanced endometrial cancer that is not MSI-H or dMMR, the median PFS was 6.6 months (95% CI: 5.6, 7.4) for patients in the pembrolizumab and lenvatinib group and 3.8 months (95% CI: 3.6, 5.0) for those receiving investigator's choice chemotherapy (HR 0.60; 95% CI: 0.50, 0.72; p<0.0001). Median OS was 17.4 months (95% CI: 14.2, 19.9) and 12.0 months (95% CI: 10.8, 13.3), respectively (HR 0.68; 95% CI: 0.56, 0.84; p=0.0001). ORR was 30 percent (95% CI: 26, 36) and 15 percent (95% CI: 12, 19), respectively (p<0.0001). Median DOR was 9.2 months (1.6+, 23.7+) and 5.7 months (0.0+, 24.2+).


The most common adverse reactions reported in >=20 percent of patients in trials of pembrolizumab in combination with lenvatinib were hypothyroidism, hypertension, fatigue, diarrhea, musculoskeletal disorders, nausea, decreased appetite, vomiting, stomatitis, weight loss, abdominal pain, urinary tract infection, proteinuria, constipation, headache, hemorrhagic events, palmar-plantar erythrodysesthesia, dysphonia, and rash. The recommended pembrolizumab dose for endometrial carcinoma is 200 mg every 3 weeks or 400 mg every 6 weeks with lenvatinib 20 mg orally once daily.


Pembrolizumab for High-Risk Early-Stage Triple-Negative Breast Cancer

The FDA approved pembrolizumab for high-risk, early-stage, triple-negative breast cancer (TNBC) in combination with chemotherapy as neoadjuvant treatment, and then continued as a single agent as adjuvant treatment after surgery.


The organization also granted regular approval to pembrolizumab in combination with chemotherapy for patients with locally recurrent unresectable or metastatic TNBC whose tumors express PD-L1 (Combined Positive Score >=10) as determined by an FDA-approved test. FDA granted accelerated approval to pembrolizumab for this indication in November 2020.


The following trial was the basis of the neoadjuvant and adjuvant approval, as well as the confirmatory trial for the accelerated approval. The efficacy of pembrolizumab in combination with neoadjuvant chemotherapy followed by surgery and continued adjuvant treatment with pembrolizumab as a single agent was investigated in KEYNOTE-522 (NCT03036488), a randomized, multicenter, double-blind, placebo-controlled trial conducted in 1,174 patients with newly diagnosed previously untreated high-risk early-stage TNBC (tumor size >1 cm but <=2 cm in diameter with nodal involvement or tumor size >2 cm in diameter regardless of nodal involvement). Patients were enrolled regardless of tumor PD-L1 expression.


Patients were randomized (2:1) to pembrolizumab in combination with chemotherapy or placebo in combination with chemotherapy. The main efficacy outcome measures were pathological complete response (pCR) rate and event-free survival (EFS). The pCR rate was 63 percent (95% CI: 59.5, 66.4) for patients who received pembrolizumab in combination with chemotherapy compared with 56 percent (95% CI: 50.6, 60.6) for patients who received chemotherapy alone. The number of patients who experienced an EFS event was 123 (16%) and 93 (24%), respectively (HR 0.63; 95% CI: 0.48, 0.82; p=0.00031).


The most common adverse reactions reported in >=20 percent of patients in trials of pembrolizumab in combination with chemotherapy were fatigue/asthenia, nausea, constipation, diarrhea, decreased appetite, rash, vomiting, cough, dyspnea, pyrexia, alopecia, peripheral neuropathy, mucosal inflammation, stomatitis, headache, weight loss, abdominal pain, arthralgia, myalgia, and insomnia.


The recommended dosage of pembrolizumab for TNBC is 200 mg every 3 weeks or 400 mg every 6 weeks as an intravenous infusion over 30 minutes. Pembrolizumab is administered in combination with chemotherapy for neoadjuvant treatment for 24 weeks, and then as a single agent for adjuvant treatment for up to 27 weeks.


Fast Track for Trilaciclib + Chemotherapy for Metastatic Triple-Negative Breast Cancer

The FDA has granted Fast Track designation to trilaciclib for use in combination with chemotherapy for the treatment of locally advanced or metastatic triple-negative breast cancer (TNBC). The therapy is currently being evaluated in PRESERVE 2, a pivotal Phase III, randomized, double-blind, placebo-controlled study (NCT04799249) in patients receiving first- or second-line gemcitabine and carboplatin chemotherapy for TNBC.


PRESERVE 2 has two separate cohorts (Cohort 1 and Cohort 2). Both cohorts follow the same general study conduct/design with similar primary and key secondary endpoints and identical treatment arms. The study started on April 15, 2021, and is estimated to be completed by October 25, 2024.


* Cohort 1 evaluates patients receiving first-line therapy, regardless of programmed death-ligand 1 (PD-L1) status, who are programmed cell death protein 1 (PD-1)/PD-L1 inhibitor therapy-naive.


* Cohort 2 evaluates PD-L1 positive patients receiving second-line therapy following prior PD-1/PD-L1 inhibitor therapy in the locally advanced unresectable/metastatic setting



Expanded Indication of FoundationOneLiquid CDx as Companion for Capmatinib

FoundationOne Liquid CDx has been approved to be used as a companion diagnostic to aid in identifying patients with MET exon 14 skipping (METex14) in metastatic non-small cell lung cancer (NSCLC) for whom treatment with capmatinib may be appropriate. NSCLC accounts for approximately 85 percent of lung cancer diagnoses, 3-4 percent of which are associated with METex14.


Capmatinib is the first therapy approved by the FDA for adult patients with metastatic NSCLC whose tumors have an alteration that leads to METex14. FoundationOne Liquid CDx was approved by the FDA in August 2020 to report genomic alteration results for patients with any solid tumor. FoundationOne CDx tissue test was approved as a companion diagnostic for capmatinib in May 2020.


Using a simple blood sample, the liquid test analyzes over 300 cancer-related genes for genomic alterations. It is now approved as a companion diagnostic for nine targeted therapies across four cancer types. Additionally, as a laboratory professional service which has not been reviewed or approved by the FDA, the FoundationOne Liquid CDx report delivers information about the genomic signatures microsatellite instability (MSI) and blood tumor mutational burden, as well as single-gene alterations, including NTRK fusions, to help inform the use of other therapies, including immunotherapies. Also, as a laboratory professional service, the report provides relevant clinical trial information and includes interpretive content developed in accordance with professional guidelines in oncology for patients with any solid tumor.


FoundationOne Liquid CDx is a qualitative next-generation sequencing based in vitro diagnostic test for prescription use only that uses targeted high-throughput hybridization-based capture technology to analyze 324 genes utilizing circulating cell-free DNA isolated from plasma derived from anti-coagulated peripheral whole blood of advanced cancer patients. The test is FDA-approved to report short variants in over 300 genes and is a companion diagnostic to identify patients who may benefit from treatment with specific therapies in accordance with the approved therapeutic product labeling. Additional genomic findings may be reported and are not prescriptive or conclusive for labeled use of any specific therapeutic product. Use of the test does not guarantee a patient will be matched to a treatment. A negative result does not rule out the presence of an alteration. Patients who are negative for companion diagnostic mutations should be reflexed to tumor tissue testing and genomic alteration status confirmed using an FDA-approved tumor tissue test, if feasible.