FDA Approvals, Highlights, and Summaries: Oncology

February 27, 2020

Rozlytrek (entrectinib)

Entrectinib is an inhibitor of tropomyosin receptor tyrosine kinases (TRKs) TRKA, TRKB, and TRKC (encoded by the neurotrophic tyrosine receptor kinase [NTRK] genes NTRK1, NTRK2, and NTRK3, respectively), proto-oncogene tyrosine-protein kinase ROS1 (ROS1), and anaplastic lymphoma kinase (ALK). It is indicated in adults for metastatic non–small cell lung cancer (NSCLC) with tumors that are ROS1-positive. It is also indicated for adults and children aged 12 years or older with solid tumors that have NTRK gene fusion without a known acquired resistance mutation.

Approval of entrectinib for NSCLC was based on a pooled analysis of 3 multicenter, single-arm, open-label trials (ALKA, STARTRK-1, STARTRK-2). Of the 51 patients with ROS1-positive confirmed NSCLC who were assessed, the overall response rate (ORR) was 78%, and 55% had a duration of response (DOR) that lasted at least 12 months. Favorable results were also shown in patients with CNS metastases. Rozlytrek prescribing information

Efficacy for NTRK-positive solid tumors was evaluated in a pooled subgroup of 54 patients with unresectable or metastatic solid tumors with an NTRK gene fusion enrolled in 1 of 3 multicenter, single-arm, open-label clinical trials (ALKA, STARTRK-1, STARTRK-2). Ninety-six percent of patients had metastatic disease, including 22% with CNS metastases, and 4% had locally advanced, unresectable disease. ORR was 57%, and 45% had a DOR of at least 12 months. Entrectinib penetrates the CNS. Among the 54 adult patients, 4 had measurable CNS metastases at baseline as assessed by blinded independent central review and had not received radiation therapy to the brain within 2 months of study entry. Responses in intracranial lesions were observed in 3 of these 4 patients.

Rozlytrek prescribing information

Inrebic (fedratinib)

Fedratinib is indicated for adults with intermediate-2 or high-risk primary or secondary (post polycythemia vera or post essential thrombocythemia) myelofibrosis (MF). Fedratinib inhibits Janus-associated kinase (JAK)–2, which mediates signaling of cytokines and growth factors that are important for hematopoiesis and immune function.

JAK signaling involves recruitment of STATs (signal transducers and activators of transcription) to cytokine receptors, activation, and subsequent localization of STATs to the nucleus, leading to modulation of gene expression.

Efficacy of fedratinib was investigated in JAKARTA (NCT01437787), a double-blind, randomized, placebo-controlled trial in 289 patients with intermediate-2 or high-risk MF, post–polycythemia vera MF, or post–essential thrombocythemia MF with splenomegaly. Patients were randomized to receive either fedratinib 500 mg (n=97), 400 mg (n=96), or placebo (n=96) once daily for at least 6 cycles.

The primary efficacy outcome was the proportion of patients achieving a reduction of 35% or greater from baseline in spleen volume at the end of cycle 6 measured by MRI or CT, with a follow-up scan 4 weeks later. Of the 96 patients treated with the recommended dose (400 mg) of fedratinib, 35 (37%) achieved a 35% or greater reduction in spleen volume, compared with 1 of 96 patients who received placebo (P<.0001). The median duration of spleen response was 18.2 months for the fedratinib 400-mg group. In addition, 40% of patients who received 400 mg experienced a 50% or greater reduction in myelofibrosis-related symptoms, whereas only 9% of patients receiving placebo experienced a decline in these symptoms.

JAMA Oncol. 2015 Aug;1(5):643-51

Turalio (pexidartinib)

Pexidartinib is an inhibitor of colony-stimulator factor 1 receptor (CSF1R), a tyrosine kinase receptor. Binding to CSF1R expressed on monocytes, macrophages, and osteoclasts disrupts interleukin-34 signaling for macrophages and monocytes to produce inflammatory mediators. This enhances T-cell infiltration and antitumor T-cell immune responses.

Pexidartinib is indicated for adults with tenosynovial giant cell tumor (TGCT) associated with severe morbidity or functional limitations and not amenable to improvement with surgery.

Approval of pexidartinib was based on the phase 3 ENLIVEN study, the first placebo-controlled study of a systemic therapy for tenosynovial giant cell tumor. The primary endpoint, overall response rate (ORR), showed significant improvement. At week 25, patients treated with pexidartinib (n=61) had an ORR of 38% compared with 0% for placebo-treated patients (n=59) (P<.0001). The complete response rate was 15%, and the partial response rate was 23%. In responders (n=23) followed for a minimum of 6 months following the initial response, 22 maintained their response for 6 or more months. All 13 responders who had been followed for a minimum of 12 months following the initial response maintained their response for 12 or more months. Additionally, statistically significant improvements in secondary endpoints (eg, mean changes in range of motion, physical function, and worst stiffness) were observed. Liver toxicities were documented with pexidartinib that required dosage reduction or discontinuation.

Lancet. 2019 Aug 10;394(10197):478-487

Nubeqa (darolutamide)

Darolutamide, an androgen receptor (AR) inhibitor, competitively inhibits androgen binding, AR nuclear translocation, and AR-mediated transcription. It is indicated for nonmetastatic castration-resistant prostate cancer (nmCRPC). Approval was based on the phase 3 ARAMIS trial (n=1509), which evaluated metastasis-free survival, with the presence of metastasis determined by independent central review of imaging every 16 weeks. Patients received either darolutamide or placebo while continuing androgen-deprivation therapy. Median metastasis-free survival was 40.4 months with darolutamide compared with 18.4 months with placebo. Darolutamide was also associated with benefits to all secondary endpoints, including overall survival, time to pain progression, time to cytotoxic chemotherapy, and time to a symptomatic skeletal event.

N Engl J Med. 2019 Mar 28;380(13):1235-1246

Brukinsa (zanubrutinib)

Zanubrutinib is a Bruton tyrosine kinase inhibitor indicated for patients with mantle cell lymphoma (MCL) who have received at least one prior therapy. Approval was based on results from two phase 2, open-label, single-arm trials, which showed an overall response rate of 84% In one study, MCL patients (n=86) had a 59% complete response and a 24% partial response rate. In the other study, MCL patients (n=32) had a 22% complete response rate and a 62% partial response rate.

Brukinsa prescribing information

Xpovio (selinexor)

Selinexor is a first-in-class selective inhibitor of nuclear export (SINE). Selinexor acts on tumor suppressor proteins (TSPs), growth regulators, and mRNAs of oncogenic proteins by blocking exportin 1 (XPO1). Inhibition of XPO1 leads to accumulation of TSPs in the nucleus, reductions in several oncoproteins (eg, c‐myc, cyclin D1), cell-cycle arrest, and apoptosis of cancer cells. It is indicated in combination with dexamethasone for adults with relapsed or refractory multiple myeloma (RRMM) who have received at least 4 prior therapies and whose disease is refractory to at least 2 proteasome inhibitors, at least 2 immunomodulatory agents, and an anti-CD38 monoclonal antibody.

The multicenter, single-arm, open-label STORM trial analyzed selinexor plus dexamethasone. STORM part 2 included 122 patients with relapsed/refractory disease who previously had 3 or more treatments, including an alkylating agent, glucocorticoids, bortezomib, carfilzomib, lenalidomide, pomalidomide, and an anti-CD38 monoclonal antibody. Trial participants also had myeloma that was refractory to glucocorticoids, a proteasome inhibitor, an immunomodulatory agent, an anti-CD38 monoclonal antibody, and the last line of therapy that they had received. The median number of previous regimens was 7. Fifty-three percent of the patients had high-risk cytogenetic abnormalities. A partial response or better was observed in 26% of patients (95% confidence interval, 19-35), including 2 stringent complete responses; 39% of patients had a minimal response (MR) or better. Median duration of response was 4.4 months, median progression-free survival was 3.7 months, and median overall survival (OS) was 8.6 months. For the 39% of patients who had an MR or better, OS was 15.6 months, compared with 1.7 months in patients whose disease progressed or where response was not evaluable. Thrombocytopenia occurred in 73% of the patients (grade 3 in 25% and grade 4 in 33%).

N Engl J Med. 2019 Aug 22;381(3):727-728

Balversa (erdafitinib)

Erdafitinib is a first-in-class fibroblast growth factor receptor (FGFR) inhibitor. Erdafitinib inhibits FGFR phosphorylation and signaling, and thereby decreases cell viability in cell lines expressing FGFR genetic alterations, including point mutations, amplifications, and fusions. FGFRs regulate important biological processes, including cell proliferation and differentiation, which are part of a complex signaling pathway in tumorigenesis.

The FDA granted erdafitinib accelerated approval for locally advanced or metastatic urothelial carcinoma that has FGFR2 or FGFR3 genetic alterations and progressed during or following at least one line of prior platinum-containing chemotherapy, including within 12 months of neoadjuvant or adjuvant platinum-containing chemotherapy. Approval was based on a multicenter, open-label, single-arm study (n=87) of patients with urothelial carcinoma with disease that had progressed on or after at least one prior chemotherapy, with FGFR3 or FGFR2 genetic alterations. Results demonstrated a 32.2% overall response rate, with 2.3% having a complete response and almost 30% having a partial response.

BLC2001 study

Padcev (enfortumab vedotin)

Enfortumab vedotin is an antibody-drug conjugate (ADC) composed of an anti–nectin-4 monoclonal antibody attached to the cell-killing agent, monomethylauristatin E (MMAE). It is indicated for locally advanced or metastatic urothelial cancer in patients who have received a programmed cell death 1 (PD-1)/PD ligand (L1) inhibitor and platinum-containing chemotherapy in the neoadjuvant/adjuvant, locally advanced, or metastatic setting.

Approval was based on the EV-201 global trial. The trial was a single-arm, phase 2 multicenter trial that enrolled 125 patients with locally advanced or metastatic urothelial cancer who received prior treatment with a PD-1 or PD-L1 inhibitor and a platinum-based chemotherapy. The primary endpoint of confirmed overall response rate was 44% per blinded independent central review (55 of 125; 95% confidence interval, 35.1, 53.2). Among patients treated with the single agent enfortumab vedotin, 12% (15 of 125) experienced a complete response and 32% (40 of 125) experienced a partial response.

J Clin Oncol. 2019 Oct 10;37(29):2592-2600

Enhertu (trastuzumab deruxtecan)

Trastuzumab deruxtecan is a human epidermal growth factor receptor 2 (HER2)–targeted antibody-drug conjugate (ADC) that contains the humanized anti-HER2 IgG1, trastuzumab, covalently linked to the topoisomerase I inhibitor, deruxtecan. It gained FDA approval for unresectable or metastatic HER2-positive breast cancer in adults who have received 2 or more prior anti-HER2–based regimens in the metastatic setting.

In the open-label, phase 2 DESTINY-Breast01 study (n=184), patients who had received a median of 6 previous treatments were given trastuzumab deruxtecan every 3 weeks. The overall response rate was 60.3%; complete responses were observed in 4.3%; and partial responses were seen in 56%. Median duration of response was 14.8 months. Median progression-free survival was 16 months.

N Engl J Med. 2019 Dec 11

Enhertu Prescribing Information

Piqray (alpelisib)

Alpelisib is a phosphatidylinositol-3-kinase (PI3K) inhibitor. It is indicated in combination with fulvestrant for treatment of men and postmenopausal women with hormone receptor (HR)–positive, human epidermal growth factor receptor 2 (HER2)–negative, PIK3CA-mutated, advanced or metastatic breast cancer following progression on or after an endocrine-based regimen.

Approval for alpelisib was supported by the SOLAR-1 trial (n=572). Results demonstrated that adding alpelisib to fulvestrant significantly prolonged median progression-free survival (11 months) compared with fulvestrant alone (5.7 months) in patients whose tumors had a PIK3CA mutation.

N Engl J Med. 2019 May 16;380(20):1929-1940

Polivy (polatuzumab vedotin)

Polatuzumab vedotin is an antibody-drug conjugate that targets CD79b. The small molecule antimitotic agent monomethyl auristatin E (MMAE) portion of the conjugate binds to microtubules in B cells, which results in apoptosis. Polatuzumab vedotin is indicated for adults with relapsed or recurrent diffuse large B-cell lymphoma in combination with bendamustine and a rituximab product after at least 2 prior therapies.

Approval was based on a study that showed 40% of people treated with polatuzumab vedotin plus bendamustine and rituximab (BR) achieved a complete response (n=16/40; 95% confidence interval [CI], 25-57) compared with 18% in those receiving BR alone (n=7/40; 95% CI, 7-33). The study also showed an overall response of 45% with polatuzumab plus BR at the end of treatment (n=18/40; 95% CI, 29-62) compared with 18% in BR alone (n=7/40; 95% CI, 7-33). Of patients receiving polatuzumab plus BR who achieved a complete or partial response, 64% (n=16/25) had a duration of response (DOR) lasting at least 6 months compared with 30% (n=3/10) for BR alone. Additionally, a DOR of at least 1 year was observed in 48% (n=12/25) for polatuzumab plus BR compared with 20% (n=2/10) for BR alone.

Polivy prescribing information

Additional 2019 Oncology approvals

Darzalex (daratumumab) use for multiple myeloma includes new combination regimens for newly diagnosed patients who are either ineligible or eligible for autologous stem cell transplantation.

Keytruda (pembrolizumab) is now indicated for recurrent locally advanced or metastatic squamous cell esophageal carcinoma in patients with tumors that express programmed cell death ligand 1 (PD-L1) (combined positive score ≥10).

Tecentriq (atezolizumab) indication was expanded for first-line, metastatic, nonsquamous, epidermal growth factor receptor/anaplastic large-cell lymphoma kinase (EGFR/ALK)–negative non–small cell lung cancer to use in combination with paclitaxel protein-bound and carboplatin.

Calquence (acalabrutinib) is now indicated for treatment of adults with chronic lymphocytic leukemia or small lymphocytic lymphoma.

Xtandi (enzalutamide) indication for prostate cancer is expanded to include metastatic castration-sensitive prostate cancer.

Lynparza (olaparib) is indicated for first-line maintenance treatment of adults with deleterious or suspected deleterious gBRCAm metastatic pancreatic adenocarcinoma whose disease has not progressed on at least 16 weeks of a first-line platinum-based chemotherapy regimen.

Jakafi (ruxolitinib) gained a new indication for acute steroid-refractory graft versus host disease in patients aged 12 years or older.

Cyramza (ramucirumab) was approved for hepatocellular carcinoma.

Revlimid (lenalidomide) in combination with a rituximab product was approved for previously treated follicular lymphoma or marginal zone lymphoma.

Keytruda (pembrolizumab) continues to gain new indications, including first-line treatment for head and neck squamous cell carcinoma and second-line treatment of metastatic small-cell lung cancer.

Venclexta (venetoclax) was approved as initial treatment for chronic lymphocytic leukemia/small lymphocytic lymphoma in combination with obinutuzumab.

Bavencio (avelumab) is now indicated for first-line treatment of advanced renal cell carcinoma in combination with axitinib.

Tecentriq (atezolizumab) gained approval for first-line treatment of unresectable locally advanced or metastatic triple-negative breast cancer.

Cabometyx (cabozantinib) was approved for hepatocellular carcinoma in patients previously treated with sorafenib.

Herceptin Hylecta (trastuzumab/hyaluronidase) was approved for adjuvant or metastatic breast cancer.


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