FDA Oncology Update

June/July 2019 Vol 12, No 4 - FDA Approvals
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This section provides a brief overview of new cancer drugs or new indications approved by the FDA between April 12 and May 24, 2019.

 

Balversa First Targeted Drug FDA Approved for Metastatic Bladder Cancer with FGFR Genetic Alterations

On April 12, 2019, the FDA accelerated the approval of erdafitinib (Balversa; Janssen), a fibroblast growth factor receptor (FGFR) kinase inhibitor, for the treatment of adults with locally advanced or metastatic urothelial carcinoma and a susceptible FGFR3 or FGFR2 genetic alteration, as detected by an FDA-­approved test, whose disease progressed after platinum-containing chemotherapy, making it the first targeted drug to receive approval for this patient population.

On the same day, the FDA approved the companion diagnostic test, therascreen FGFR RGQ RT-PCR Kit, to identify patients with bladder cancer and FGFR3 alterations who are candidates for erdafitinib therapy.

“Today’s approval represents the first personalized treatment targeting susceptible FGFR genetic alterations for patients with metastatic bladder cancer,” said Richard Pazdur, MD, Director of the FDA’s Oncology Center of Excellence. “FGFRs regulate important biological processes including cell growth and division during development and tissue repair. This drug works by targeting genetic alterations in FGFRs,” Dr Pazdur added.

The FDA approved erdafitinib based on results from a phase 2, multicenter, single-arm clinical trial of 87 patients with locally advanced or metastatic urothelial cancer, with a susceptible FGFR3 or FGFR2 genetic alteration, that had progressed after chemotherapy.

In patients who received erdafitinib, the objective response rate was 32.2%, including 2.3% complete response, and the median duration of response was 5.4 months. Responses to erdafitinib were observed even among the 25% of patients who had not responded to previous anti–PD-L1/PD-1 therapy.

The most common (≥10%) adverse effects included increased phosphate level, stomatitis, fatigue, increased creatinine level, diarrhea, dry mouth, onycholysis, increased alanine aminotransferase level, increased alkaline phosphatase level, decreased sodium level, decreased appetite, decreased albumin level, altered sense of taste, decreased hemoglobin level, and dry skin.

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Keytruda plus Inlyta New First-Line Combination Approved for Advanced Renal-Cell Carcinoma

On April 19, 2019, the FDA accelerated the approval of pembro­lizumab (Keytruda; Merck) plus ­axitinib (Inlyta; Pfizer) as first-line treatment of patients with advanced renal-cell carcinoma (RCC). Keytruda was previously approved as a single agent or in combination with other agents for many other indications and types of cancers.

This latest approval was based on the phase 3, randomized, open-label KEYNOTE-426 clinical trial of 861 patients with clear-cell metastatic RCC who had not received systemic therapy for metastatic disease. The patients were randomized in a 1:1 ratio to pembrolizumab 200 mg every 21 days plus axitinib 5 mg twice daily or to monotherapy with sunitinib (Sutent) 50 mg once daily, for 28 days.

The 12-month overall survival (OS) rate was 89.9% in the combination arm versus 78.3% in the sunitinib arm. The median OS was not reached in either arm. In addition, pembrolizumab plus axitinib showed improvement in progression-free survival (PFS). The median PFS was 15.1 months with pembrolizumab plus axitinib versus 11.1 months with sunitinib monotherapy.

Grade 3 or 4 hepatotoxicity occurred in 20% of patients, leading to permanent discontinuation of pembrolizumab or axitinib in 13% of ­patients.

The most common (>20%) adverse effects with the combination regimen were diarrhea, fatigue, hypertension, hypothyroidism, decreased appetite, hepatotoxicity, palmar-plantar erythrodysesthesia, nausea, stomatitis/mucosal inflammation, dysphonia, rash, cough, and constipation.

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Tibsovo Now Indicated for First-Line Treatment of Patients with Acute Myeloid Leukemia and IDH1 Mutation

On May 2, 2019, the FDA approved ivosidenib (Tibsovo; Agios) for patients with newly diagnosed acute myeloid leukemia (AML) and a susceptible IDH1 mutation, as detected by an FDA-­approved test, in patients aged ≥75 years or those who have comorbidities that preclude the use of intensive induction chemotherapy. Ivosidenib was originally approved in 2018 for relapsed or refractory AML with IDH1 mutation.

The new indication was based on an open-label, single-­arm, multicenter clinical trial using ivosidenib monotherapy for patients with newly diagnosed AML and an IDH1 mutation, which was detected by the Abbott Real­TimeTM IDH1 Assay. All patients were aged ≥75 years or had comorbidities that precluded the use of intensive chemotherapy.

The efficacy was determined based on complete remission (CR) rate or complete remission with partial hematologic recovery (CRh), the duration of CR + CRh, and the conversion from transfusion dependence to transfusion independence. In total, 12 (42.9%) of 28 patients achieved CR + CRh, and 7 (41.2%) of the 17 transfusion-dependent patients achieved transfusion independence lasting ≥8 weeks.

The most common (≥25%) adverse reactions were diarrhea, fatigue, edema, decreased appetite, leukocytosis, nausea, arthralgia, abdominal pain, dyspnea, differentiation syndrome, and myalgia.

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Kadcyla Approved for Adjuvant Treatment of HER2-Positive Early Breast Cancer with Residual Invasive Disease

On May 3, 2019, the FDA approved a new indication for ado-trastuzumab emtansine (Kadcyla; Genentech) for the adjuvant treatment of patients with HER2-positive early breast cancer who have residual invasive disease after neoadjuvant taxane- and trastuzumab (Herceptin)-based treatment. The FDA granted this application priority review. Ado­-trastuzumab emtansine was granted breakthrough therapy designation for the adjuvant treatment of patients with HER2-positive early breast cancer who have residual disease after preoperative systemic treatment. Ado-trastuzumab emtansine was initially approved in 2013 for the treatment of metastatic HER2-­positive breast cancer.

The FDA also approved the Ventana Medical Systems PATHWAY anti-­HER-2/neu Rabbit Monoclonal Primary Antibody assay and the INFORM HER2 Dual ISH DNA Probe Cocktail assay for selecting patients for this adjuvant treatment based on these companion diagnostic assays.

This new indication was based on a randomized, multicenter, open-label trial of 1486 patients with HER2-­positive early breast cancer. Tumor samples were used to demonstrate HER2 overexpression using Ventana’s PATHWAY assays. Patients had to have had neoadjuvant taxane- and trastuzumab-­based therapy with residual invasive tumor in the breast and/or the axillary lymph nodes. Patients received radiotherapy and/or hormonal therapy with the study treatment based on relevant guidelines. The patients were randomized in a 1:1 ratio to ado-trastuzumab emtansine 3.6 mg/kg or to trastuzumab 6 mg/kg on day 1 of each 21-day cycle, for a total of 14 cycles.

The primary end point was invasive disease-free survival, defined as the time from the date of randomization to first ipsilateral invasive breast tumor recurrence, ipsilateral local or regional invasive breast cancer recurrence, distant recurrence, contralateral invasive breast cancer, or death from any cause. After a median follow-up of 40 months, significant improvement was seen in invasive disease-free survival in patients who received ado-trastuzumab emtansine compared with those who received trastuzumab (hazard ratio, 0.50; P <.0001). At the time of the data analysis, the overall survival data were not mature.

The most common (≥25%) adverse events with ado-trastuzumab emtansine were fatigue, nausea, increased transaminases, musculoskeletal pain, hemorrhage, thrombocytopenia, headache, peripheral neuropathy, and arthralgia.

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Piqray First PI3K Inhibitor Approved by the FDA for Metastatic Breast Cancer and PI3KCA Mutation

On May 24, 2019, the FDA approved Piqray (alpelisib; Novartis), an oral PIK3 inhibitor, in combination with endocrine therapy with fulvestrant (Faslodex), for the treatment of postmenopausal women, as well as men, with hormone receptor (HR)-­positive, HER2-­negative advanced or metastatic breast cancer and PIK3CA mutation (as detected by an FDA-­approved test) that progressed during or after an ­endocrine-based treatment regimen. The FDA used its priority review designation to consider the application of alpelisib.

At the same time, the FDA approved the companion diagnostic test, thera­screen PIK3CA RGQ PCR Kit, to detect the PIK3CA mutation in a tissue and/or a liquid biopsy. Patients whose liquid biopsy result with thera­screen is negative should have a tissue-based biopsy for PIK3CA mutation.

“Piqray is the first PI3K inhibitor to demonstrate a clinically meaningful benefit in treating patients with this type of breast cancer. The ability to target treatment to a patient’s specific genetic mutation or biomarker is becoming increasingly common in cancer treatment, and companion diagnostic tests assist oncologists in selecting patients who may benefit from these targeted treatments,” said Richard Pazdur, MD, Director of the FDA’s Oncology Center of Excellence. “For this approval, we employed some of our newer regulatory tools to streamline reviews without compromising the quality of our assessment. This drug is the first novel drug approved under the Real-Time Oncology Review pilot program. We also used the updated Assessment Aid, a multidisciplinary review template that helps focus our written review on critical thinking and consistency and reduces time spent on administrative tasks,” Dr Pazdur added.

The efficacy of alpelisib was evaluated in SOLAR-1, a randomized clinical trial of 572 postmenopausal women, as well as in men with HR-positive, HER2-­negative, advanced or metastatic breast cancer whose cancer had progressed during or after an aromatase inhibitor therapy. The combination of alpelisib plus fulvestrant significantly prolonged progression-free survival (PFS) compared with fulvestrant alone, for a median PFS of 11 months versus 5.7 months, respectively, in patients whose tumors had a PIK3CA mutation.

The adverse reactions, including some severe reactions, reported with alpelisib are hyperglycemia (which could be severe), increased creatinine level, diarrhea, rash, decreased lymphocyte count, elevated liver enzymes, nausea, fatigue, low red blood cell count, increased lipase level, decreased appetite, stomatitis, vomiting, weight loss, low calcium levels, acquired thrombotic thrombocytopenic purpura, and hair loss. The drug must not be dispensed without a Medication Guide that describes the medication’s potential risks.

Alpelisib is the first new molecular entity for which a New Drug Application was submitted and approved by the FDA under the Real-Time Oncology Review pilot program, which allows the FDA to expedite the approval process by analyzing a drug’s key efficacy and safety data before the official submission of a drug application. The FDA also used its updated Assessment Aid, which helps to focus the FDA’s written review on critical thinking. Using these processes allowed the FDA to approve ­alpelisib approximately 3 months ahead of its Prescription Drug User Fee Act deadline.

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