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FDA News: August 2020

August 2020, Vol 11, Special Issue: Payers' Perspectives in Oncology

In This Article


Inqovi First Oral Hypomethylating Agent Approved for Intermediate- or High-Risk Myelodysplastic Syndromes

On July 7, 2020, the FDA approved Inqovi (decitabine plus cedazuridine; Astex Pharmaceuticals/Taiho Oncology) tablets, for the treatment of adults with intermediate- or high-risk myelodysplastic syndromes (MDS), including patients with chronic myelomonocytic leukemia (CMML). Inqovi is an orally administered fixed-dose combination of the hypomethylating agent decitabine plus the cytidine deaminase inhibitor cedazuridine. The FDA granted Inqovi a priority review.

Inqovi is the first and only orally administered hypomethylating agent approved for the treatment of this patient population. The FDA approval of decitabine plus cedazuridine was based on data from the phase 3 clinical trial ASCERTAIN, as well as on supporting data from phase 1 and phase 2 clinical trials.

The ASCERTAIN study compared the efficacy and safety of 5-day administration of oral decitabine plus cedazuridine versus intravenous (IV) decitabine.

Guillermo Garcia-Manero, MD, Professor and Chief of Section of Myelodysplastic Syndromes, Department of Leukemia, M.D. Anderson Cancer Center, Houston, TX, and lead investigator of the ASCERTAIN clinical trial, said, “Intravenous or subcutaneous administered hypomethylating agents have been the cornerstone for the treatment of patients with MDS and CMML since the mid-2000s. The FDA’s approval of Inqovi builds on the proved therapeutic utility of hypomethylating agents in these diseases and offers a new orally administered option that offers patients an alternative to five consecutive days of IV infusions every month during a treatment period that can extend to several months.”

The most common adverse reactions (≥20%) with Inqovi treatment were fatigue, constipation, hemorrhage, myalgia, mucositis, arthralgia, nausea, dyspnea, diarrhea, rash, dizziness, febrile neutropenia, edema, headache, cough, decreased appetite, upper respiratory tract infection, pneumonia, and transaminase increases. The most common (≥50%) grade 3 or 4 laboratory abnormalities were decreases in leukocytes, platelet count, neutrophil count, and hemoglobin levels.

Serious adverse reactions (>5%) with Inqovi therapy included febrile neutropenia (30%), pneumonia (14%), and sepsis (13%). Adverse events leading to death included sepsis (1%), septic shock (1%), pneumonia (1%), respiratory failure (1%), and 1 case each of cerebral hemorrhage and sudden death.

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Zepzelca New Therapy Approved for Metastatic Small-Cell Lung Cancer

On June 15, 2020, the FDA accelerated the approval of lurbinectedin (Zepzelca; Jazz Pharma/Pharma Mar), an intravenous alkylating drug, for the treatment of adults with metastatic small-cell lung cancer (SCLC) that has progressed during or after platinum-based chemotherapy. Lurbinectedin represents a new mechanism of action that triggers a cascade of events involving DNA-binding proteins and DNA repair pathways that lead to the disruption of the natural cell cycle and eventual apoptosis. The FDA granted lurbinectedin an orphan drug designation and used its priority review for this indication.

“Seeing first-hand the aggressive nature of SCLC, and knowing that the large majority of those diagnosed will experience relapse, I am excited to see an effective new treatment demonstrating durable responses,” said William Jeffery Petty, MD, Professor, Hematology and Oncology, Wake Forest School of Medicine, in a Jazz Pharma press release. “For doctors, patients and their families, Zepzelca is an important and much-needed addition to the treatment landscape for relapsing SCLC.”

“The availability of Zepzelca presents new hope for patients and their loved ones, and we’re eager to see its impact on the SCLC community,” said Andrea Stern Ferris, President and CEO of LUNGevity, in the press release.

The FDA approved lurbinectedin for metastatic SCLC based on the results of the PM1183-B-005-14 clinical trial, a multicenter open-label, multicohort study of 105 patients with metastatic SCLC whose disease progressed during or after platinum-based chemotherapy.

Patients received lurbinectedin 3.2 mg/m2 by intravenous infusion every 21 days until disease progression or unacceptable toxicity.

The main end points were confirmed overall response rate (ORR) by investigator assessment using RECIST 1.1 criteria and response duration. Among the 105 patients, the ORR was 35% (95% confidence interval [CI], 26%-45%), with a median response duration of 5.3 months (95% CI, 4.1-6.4). The ORR, as determined by independent review committee, was 30% (95% CI, 22%-40%), with a median response duration of 5.1 months (95% CI, 4.9-6.4).

The most common (≥20%) adverse reactions were myelosuppression, fatigue, increased creatinine levels, increased alanine aminotransferase, increased glucose, nausea, decreased appetite, musculoskeletal pain, decreased albumin, constipation, dyspnea, decreased sodium, increased aspartate aminotransferase, vomiting, cough, decreased magnesium, and diarrhea.

The recommended dose for lurbinectedin is 3.2 mg/m2 every 21 days.

This indication is approved under accelerated approval based on ORR and duration of response. Continued approval may be contingent on clinical benefits in confirmatory clinical trials.

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Opdivo Now Approved for Advanced Esophageal Squamous-Cell Carcinoma

On June 10, 2020, the FDA accelerated the approval of a new indication for nivolumab (Opdivo; Bristol Myers Squibb), a PD-1 inhibitor, for the treatment of patients with unresectable advanced, recurrent or metastatic esophageal squamous-cell carcinoma (ESCC) after fluoropyrimidine-based and platinum-based chemotherapy. This indication was approved under the accelerated approval guidelines; final approval may be contingent on confirmatory clinical trials demonstrating clinical benefits.

Nivolumab has been previously approved by the FDA, alone or in combination with other therapies, for the treatment of many solid tumors, including lung, colorectal, liver, melanoma, urothelial, and head and neck cancers, as well as for classical Hodgkin lymphoma. This is the first indication for nivolumab for the treatment of esophageal cancer.

The FDA approved this indication based on the ATTRACTION-3 study, a multicenter, randomized, active-controlled, open-label clinical trial that included 419 patients with unresectable advanced, recurrent, or metastatic ESCC. All patients had disease refractory to or intolerant of at least 1 fluoropyrimidine- and platinum‑based regimen. Patients were randomized in a 1:1 ratio to nivolumab 240 mg by intravenous infusion over 30 minutes every 2 weeks (N = 210) or to investigator’s choice of taxane chemotherapy with docetaxel (75 mg/m2 every 3 weeks) or paclitaxel (100 mg/m2 once weekly for 6 weeks, followed by 1 week off; N = 209).

The major efficacy end point was overall survival (OS). Additional outcome measures included overall response rate (ORR), duration of response, and progression-free survival (PFS) as assessed by the investigator using RECIST 1.1 criteria.

The OS was significantly better with nivolumab than with chemotherapy. The median OS was 10.9 months (95% confidence interval [CI], 9.2-13.3) with nivolumab compared with 8.4 months (95% CI, 7.2-9.9) with chemotherapy (hazard ratio [HR], 0.77; 95% CI, 0.62-0.96; P = .0189). This OS benefit was reported regardless of consideration of tumor PD-L1 expression.

The ORR was 19.3% (95% CI, 13.7-26) in the nivolumab arm versus 21.5% (95% CI, 15.4-28.8) in the chemotherapy arm, and the median response duration was 6.9 months (95% CI, 5.4-11.1) with nivolumab versus 3.9 months (95% CI, 2.8-4.2) with chemotherapy. The results did not show an improvement in PFS (HR, 1.1; 95% CI, 0.9-1.3).

The most common (≥10%) adverse reactions in patients receiving nivolumab in this study were rash, decreased appetite, diarrhea, constipation, musculoskeletal pain, upper respiratory tract infection, cough, pyrexia, pneumonia, anemia, fatigue, pruritus, nausea, and hypothyroidism.

The recommended dose of nivolumab for ESCC is 240 mg every 2 weeks or 480 mg every 4 weeks.

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Cyramza plus Tarceva Approved for First-Line Treatment of Metastatic NSCLC with EGFR Mutation

On May 29, 2020, the FDA approved ramucirumab (Cyramza; Eli Lilly) in combination with erlotinib (Tarceva) for the first-line treatment of patients with metastatic non–small-cell lung cancer (NSCLC) and epidermal growth factor receptor (EGFR) exon 19 deletions or exon 21 (L858R) mutations. Ramucirumab was previously approved by the FDA as monotherapy and in combination with other therapies for several types of cancer, including metastatic NSCLC, in combination with docetaxel, for patients whose disease progressed after treatment with platinum-based chemotherapy.

“The approval of this new first-line metastatic EGFR-mutated non–small-cell lung cancer regimen, which inhibits the VEGFR and EGFR pathways together, is an important milestone in the treatment of this disease. It is wonderful that patients now have multiple options for initial therapy capable of delaying disease progression for considerably longer than erlotinib, which has been our traditional standard approach,” said Edward Garon, MD, David Geffen School of Medicine, University of California, and North America lead investigator of the RELAY clinical trial. “Ramucirumab, in combination with erlotinib, is a welcomed first-line option to offer our patients with metastatic EGFR-mutated non–small-cell lung cancer.”

It is estimated that approximately 15% of patients diagnosed with NSCLC have an EGFR mutation.

The efficacy of ramucirumab plus erlotinib for first-line treatment of patients with NSCLC was based on the results of the phase 3 clinical trial RELAY, a multinational, randomized, double-blind, placebo-controlled, multicenter study in treatment-naïve patients with metastatic NSCLC whose tumors have EGFR exon 19 deletion or exon 21 (L858R) substitution mutations.

The study included 449 patients who were randomized in a 1:1 ratio to intravenous ramucirumab 10 mg/kg, in combination with erlotinib 150 mg orally once daily, or to placebo every 2 weeks plus erlotinib 150 mg orally once daily, until disease progression or unacceptable toxicity. The major efficacy end point was progression-free survival (PFS) as assessed by the investigator (RECIST 1.1). Additional efficacy outcome measures included overall survival (OS), overall response rate (ORR), and duration of response (DOR).

The median PFS was 19.4 months in the ramucirumab plus erlotinib arm compared with 12.4 months in the placebo plus erlotinib arm (hazard ratio [HR], 0.59; 95% confidence interval [CI], 0.46-0.76; P <.0001). The ORR was 76% in the ramucirumab plus erlotinib arm versus 75% in the placebo plus erlotinib arm, with median DOR of 18 months and 11.1 months, respectively. At the time of the final analysis, the PFS and OS data were not mature; with only 26% of the deaths required for the final analysis occurring by that time (HR, 0.83; 95% CI, 0.53-1.30).

The most common (≥20%) adverse events reported with ramucirumab plus erlotinib at a rate of ≥2% versus the placebo arm were infections, hypertension, stomatitis, proteinuria, alopecia, epistaxis, and peripheral edema. The most common (≥20%) laboratory abnormalities at a rate of ≥2% higher than in the placebo arm were increased alanine aminotransferase, increased aspartate aminotransferase, anemia, thrombocytopenia, neutropenia, increased alkaline phosphatase, and hypokalemia.

The recommended dose of ramucirumab for metastatic NSCLC in combination with erlotinib is 10 mg/kg every 2 weeks.

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Tecentriq plus Avastin Combination Approved for First-Line Treatment of Unresectable or Metastatic Hepatocellular Carcinoma

On May 29, 2020, the FDA approved the combination of 2 immunotherapies, atezolizumab (Tecentriq; Genentech), a PD-L1 inhibitor, and bevacizumab (Avastin; Genentech), a vascular endothelial growth factor inhibitor, for the treatment of patients with unresectable or metastatic hepatocellular carcinoma (HCC) who have not received systemic therapy.

Atezolizumab and bevacizumab have each previously been approved as monotherapy or in combination with other therapies for multiple indications. This is their first indication for HCC, and this is the first immunotherapy regimen approved by the FDA for first-line treatment of unresectable or metastatic HCC. Sorafenib (Nexavar), a kinase inhibitor, is currently the standard of therapy for first-line treatment of unresectable or metastatic HCC. It is estimated that more than 42,000 Americans will be diagnosed with liver cancer in 2020. HCC accounts for approximately 75% of all liver cancer cases in the United States.

“The results of the IMbrave150 study are really transformative for patients with advanced liver cancer, one of the few cancers with a rising death rate and limited options in the first-line setting,” said Richard S. Finn, MD, Professor of Medicine, David Geffen School of Medicine, UCLA, and Director, Signal Transduction and Therapeutics Program, UCLA Jonsson Comprehensive Cancer Center. “For the first time we have a regimen that markedly improves survival over sorafenib, the standard of care for first-line hepatocellular carcinoma since 2007, and offers patients the opportunity for improved disease control with a favorable tolerability profile.”

The FDA approved atezolizumab and bevacizumab for advanced HCC based on results from the phase 3 IMbrave150 clinical trial, a multicenter, open-label study that included 501 patients with unresectable or metastatic HCC who had not received systemic therapy. Patients were randomized in a 2:1 ratio to a combination of intravenous (IV) atezolizumab 1200 mg administered on day 1 of each 21-day cycle, plus IV bevacizumab 15 mg/kg administered on day 1 of each 21-day cycle (N = 336), or to monotherapy with oral sorafenib 400 mg, taken twice daily on days 1 to 21 of each 21-day cycle.

The study’s primary end points were overall survival (OS) and progression-free survival (PFS) as evaluated by an independent review facility per Response Evaluation Criteria in Solid Tumors version 1.1. Patients received the combination immunotherapy or sorafenib (N = 165) until disease progression or unacceptable toxicity.

The combination of atezolizumab and bevacizumab improved OS by 42% (hazard ratio [HR], 0.58; 95% confidence interval [CI], 0.42-0.79; P = .001). The median PFS was 6.8 months (95% CI, 5.7-8.3) versus 4.3 months (95% CI, 4.0-5.6), for a reduction in PFS or death by 41% (HR, 0.59; 95% CI, 0.47-0.76; P <.0001) compared with sorafenib. At 12 months, the OS was 67.5% (95% CI, 61.3-73.1) with atezolizumab plus bevacizumab versus 54.6% (95% CI, 45.2-64) with sorafenib.

IMbrave150 is the first phase 3 immunotherapy study to show an improvement in OS and PFS in patients with unresectable or metastatic HCC compared with sorafenib.

The most common (≥2%) serious adverse reactions with the immunotherapy combination were gastrointestinal bleeding, infections, and fever.

Grade 3 or 4 adverse events occurred in 56.5% of those who received the immunotherapy combination and in 55.1% of the patients who received sorafenib. The rate of grade 3 or 4 hypertension was 15.2% with the immunotherapy combination.

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Opdivo plus Yervoy and Limited Chemotherapy Approved as First-Line Therapy for Metastatic NSCLC, Regardless of PD-L1 Expression

On May 26, 2020, the FDA approved a new indication for the combination of the PD-1 inhibitor nivolumab (Opdivo; Bristol Myers Squibb) and the CTLA-4 inhibitor ipilimumab (Yervoy; Bristol Myers Squibb) plus 2 chemotherapy cycles for the first-line treatment of patients with recurrent or metastatic non–small-cell lung cancer (NSCLC), including patients with squamous or nonsquamous NSCLC, regardless of PD-L1 expression, and no EGFR or ALK genomic aberrations. Nivolumab plus ipilimumab may offer a synergistic mechanism of action of 2 types of immune checkpoint inhibitors—PD-1 and CTLA-4 inhibitors.

This new approval comes on the heels of the May 15, 2020, approval of nivolumab plus ipilimumab for the first-line treatment of patients with metastatic NSCLC whose tumors express PD-L1 ≥1% and have no EGFR or ALK genomic aberrations. The new approval represents the sixth indication for the combination of nivolumab plus ipilimumab across 5 types of cancer.

“We have come a long way in understanding the role of dual immunotherapy-based approaches in cancer and the potential impact on patients’ long-term outcomes,” said David P. Carbone, MD, PhD, study investigator and Director of the James Thoracic Oncology Center, Ohio State University. “The positive findings from CheckMate-9LA demonstrate the benefit of combining dual immunotherapy with limited chemotherapy for NSCLC patients regardless of PD-L1 status.”

“Receiving a diagnosis of advanced lung cancer is devastating,” said Andrea Ferris, President and Chief Executive Officer of LUNGevity. “Today’s announcement is welcome news as it provides a new dual immunotherapy-based option for previously untreated patients searching for a treatment that may help extend their lives.”

The FDA approved this new indication for nivolumab plus ipilimumab and limited chemotherapy based on the results of the CheckMate-9LA phase 3 clinical trial, a randomized, open-label, multicenter study. The study included patients with metastatic or recurrent NSCLC regardless of PD-L1 expression who received either nivolumab plus ipilimumab and 2 cycles of platinum-doublet chemotherapy (N = 361) or 4 cycles of platinum-doublet chemotherapy followed by optional pemetrexed maintenance therapy if eligible (N = 358), for up to 2 years, or until disease progression or unacceptable toxicity.

The primary end point was overall survival (OS). The secondary efficacy outcomes included progression-free survival, overall response rate (ORR), and duration of response, as assessed by blinded independent central review.

The approval of 360 mg of nivolumab plus 1 mg/kg of ipilimumab with limited chemotherapy for this indication was based on the results of the prespecified interim analysis from the CheckMate-9LA study, which showed that nivolumab plus ipilimumab and 2 cycles of platinum-doublet chemotherapy had superior OS versus chemotherapy (P = .0006), regardless of PD-L1 expression or tumor histology. The median OS was 14.1 months (95% confidence interval [CI], 13.2-16.2) versus 10.7 months (95% CI, 9.5-12.5), respectively.

The ORR was 38% (95% CI, 33-43) with nivolumab plus ipilimumab and limited chemotherapy versus 25% (95% CI, 21-30) with chemotherapy alone. At 12.7 months, the median OS was 15.6 months (95% CI, 13.9-20.0) versus 10.9 months (95% CI, 9.5-12.5), respectively. Furthermore, at 1 year, 63% of patients who received the combination therapy plus limited chemotherapy versus 47% of those who received chemotherapy alone were still alive.

As with all immunotherapies, nivolumab and ipilimumab are associated with immune-mediated adverse events. The most common (>2%) serious adverse events with nivolumab and ipilimumab in combination with platinum-doublet chemotherapy were pneumonia, diarrhea, febrile neutropenia, anemia, acute kidney injury, musculoskeletal pain, dyspnea, pneumonitis, and respiratory failure.

Serious adverse reactions were reported in 57% of the patients who received the immunotherapy combination with limited chemotherapy; 24% of patients discontinued treatment because of adverse events, and 56% of patients had at least 1 treatment withheld because of side effects. Fatal adverse reactions occurred in 7 (2%) patients.

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