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FDA Updates Highlighting the Latest Cancer Treatments

doi: 10.1097/01.COT.0000557874.12684.64
FDA Updates
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Atezolizumab Plus Chemo Approved for Extensive-Stage Small Cell Lung Cancer

FDA; oncology

FDA; oncology

The FDA recently approved atezolizumab, in combination with carboplatin and etoposide, for the first-line treatment of adults with extensive-stage small cell lung cancer (ES-SCLC).

This approval is based on results from the phase III IMpower133 study, which showed that atezolizumab in combination with chemotherapy helped people live significantly longer compared to chemotherapy alone (median overall survival [OS]=12.3 vs. 10.3 months; HR=0.70, 95% CI: 0.54-0.91; p=0.0069) in the intention-to-treat (ITT) population.

The atezolizumab-based combination also significantly reduced the risk of disease worsening or death (progression-free survival, PFS) compared to chemotherapy alone (PFS=5.2 vs. 4.3 months; HR=0.77; 95% CI: 0.62-0.96; p=0.017). Safety for the atezolizumab and chemotherapy combination appeared consistent with the known safety profile of atezolizumab.

Atezolizumab is a monoclonal antibody designed to bind to PD-L1 expressed on tumor cells and tumor-infiltrating immune cells, blocking its interactions with both PD-1 and B7.1 receptors. By inhibiting PD-L1, atezolizumab may enable the re-activation of T cells. Atezolizumab may also affect normal cells.

“Extensive-stage small cell lung cancer is a highly aggressive form of lung cancer, which until now has seen limited treatment advances over the last 20 years,” said Andrea Ferris, President and CEO of LUNGevity Foundation. “[This] approval of atezolizumab is an important step forward in ensuring that people across the spectrum of lung cancer types have effective new therapies.”

IMpower133 is a phase III, multicenter, double-blinded, randomized, placebo-controlled study evaluating the efficacy and safety of atezolizumab in combination with carboplatin and etoposide versus carboplatin and etoposide alone in chemotherapy-naïve adults with ES-SCLC. The study enrolled 403 people who were randomized equally (1:1) to receive:

  • atezolizumab in combination with carboplatin and etoposide (Arm A), or
  • placebo in combination with carboplatin and etoposide (Arm B, control arm).

During the treatment-induction phase, people received treatment on 21-day cycles for 4 cycles, followed by maintenance with atezolizumab or placebo until progressive disease (PD) as assessed by the investigator using Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1). Treatment could be continued until persistent radiographic PD or symptomatic deterioration was observed.

The co-primary endpoints were PFS as determined by the investigator using RECIST v1.1 and OS in the ITT population.

A summary of the ITT data from the IMpower133 study that support this approval is included below:

  • Atezolizumab in combination with chemotherapy helped people live significantly longer compared to chemotherapy alone (OS=12.3 vs. 10.3 months; HR=0.70, 95% CI: 0.54-0.91; p=0.0069) in the ITT population.
  • The atezolizumab-based combination also significantly reduced the risk of disease worsening or death compared to chemotherapy alone (PFS=5.2 vs. 4.3 months; HR=0.77; 95% CI: 0.62-0.96; p=0.017).
  • Safety for the atezolizumab and chemotherapy combination appeared consistent with the known safety profile of atezolizumab. Serious adverse reactions occurred in 37 percent of people receiving atezolizumab plus chemotherapy compared with 35 percent of people receiving chemotherapy alone. The most common adverse reactions (≥20%) in people receiving atezolizumab plus chemotherapy were fatigue/asthenia (39%), nausea (38%), alopecia (37%), decreased appetite (27%), constipation (26%), and vomiting (20%).

Results from the study were simultaneously presented at the 2018 World Conference on Lung Cancer and published in The New England Journal of Medicine.

Atezolizumab is also approved in combination with bevacizumab, paclitaxel, and carboplatin for the first-line treatment of adults with metastatic non-squamous NSCLC with no EGFR or ALK genomic tumor aberrations. Additionally, atezolizumab is approved by the FDA to treat adults with metastatic NSCLC who have disease progression during or following platinum-containing chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for NSCLC harboring these aberrations prior to receiving atezolizumab.

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Trastuzumab-Qyyp Approved for Certain HER2-Overexpressing Cancers

The FDA has approved trastuzumab-qyyp, a biosimilar to trastuzumab, for the treatment of HER2-overexpressing breast cancer and HER2-overexpressing metastatic gastric or gastroesophageal junction adenocarcinoma.

The approval was based on review of a comprehensive data package, which demonstrated a high degree of similarity between trastuzumab-qyyp and the originator product. This includes results from the REFLECTIONS B327-02 clinical comparative study that was recently published in the British Journal of Cancer, which showed clinical equivalence, finding a high degree of similarity and no clinically meaningful differences between trastuzumab-qyyp and the originator product in patients with first-line HER2-overexpressing metastatic breast cancer (2019; doi:10.1038/s41416-018-0340-2).

“Approximately 15-30 percent of breast cancers and 10-30 percent of gastric cancers are HER2-positive, which is associated with aggressive disease and poor prognoses for patients,” said Mark Pegram, MD, Associate Director for Clinical Research at the Stanford Comprehensive Cancer Institute, and Director of the Breast Oncology Program at the Stanford Women's Cancer Center. “With the availability of biosimilars like trastuzumab-qyyp in the U.S., oncologists will have additional treatment options to choose from, which may help provide patients with greater access to the medicines they need.”

Trastuzumab-qyyp is a monoclonal antibody biosimilar of the originator biologic medicine, trastuzumab, which targets HER2, a protein found on the surface of some cancer cells which can stimulate the cells to divide and grow. Trastuzumab-qyyp locks on to the HER2 protein and blocks the receptors, stopping cell division and growth.

As part of the REFLECTIONS clinical trial program, trastuzumab-qyyp has been studied in nearly 500 patients and across more than 20 countries to date.

Trastuzumab-qyyp was also approved for use in the EU in July 2018 for the treatment of HER2-overexpressing breast cancer and HER2-overexpressing metastatic gastric or gastroesophageal junction adenocarcinoma.

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EC Approves Pembrolizumab Plus Chemo for Metastatic, Squamous NSCLC

The European Commission has approved pembrolizumab, an anti-PD-1 therapy, in combination with carboplatin and either paclitaxel or nab-paclitaxel, for the first-line treatment of adults with metastatic squamous non-small cell lung cancer (NSCLC).

This approval is based on data from the phase III KEYNOTE-407 trial, which demonstrated that pembrolizumab in combination with chemotherapy significantly improved overall survival (OS) in adults with metastatic squamous NSCLC regardless of PD-L1 tumor expression status, reducing the risk of death by 36 percent compared to chemotherapy alone (HR=0.64 [95% CI, 0.49-0.85]; p=0.0008).

“In KEYNOTE-407, first-line treatment with pembrolizumab in combination with chemotherapy resulted in significant improvements in overall survival for patients with metastatic squamous non-small cell lung cancer, regardless of PD-L1 expression,” said Luis Paz-Ares, MD, Chair of the Medical Oncology Department, Hospital Universitario Doce de Octubre, Madrid, Spain. “Lung cancer is the leading cause of cancer death in Europe, so this approval marks an important milestone for the patients and families facing this difficult-to-treat type of lung cancer.”

KEYNOTE-407 is a phase III, randomized, double-blind, multicenter, placebo-controlled study evaluating pembrolizumab in combination with carboplatin-paclitaxel or nab-paclitaxel compared with carboplatin-paclitaxel or nab-paclitaxel alone. The dual primary endpoints are OS and PFS; secondary endpoints include objective response rate (ORR) and duration of response (DOR). The study enrolled 559 patients who were randomized (1:1) to receive one of the following treatments via IV infusion:

  • Pembrolizumab 200 mg and carboplatin AUC 6 mg/mL/min on day 1 of each 21-day cycle for 4 cycles and paclitaxel 200 mg/m2 on day 1 of each 21-day cycle for 4 cycles or nab-paclitaxel 100 mg/m2 on days 1, 8, and 15 of each 21-day cycle for 4 cycles, followed by pembrolizumab 200 mg every 3 weeks. Pembrolizumab was administered prior to chemotherapy on day 1.
  • Placebo and carboplatin AUC 6 mg/mL/min on day 1 of each 21-day cycle for 4 cycles and paclitaxel 200 mg/m2 on day 1 of each 21-day cycle for 4 cycles or nab-paclitaxel 100 mg/m2 on days 1, 8, and 15 of each 21-day cycle for 4 cycles, followed by placebo every 3 weeks.

In KEYNOTE-407, pembrolizumab in combination with carboplatin and either paclitaxel or nab-paclitaxel significantly improved OS, reducing the risk of death by 36 percent compared to chemotherapy alone (HR=0.64 [95% CI, 0.49-0.85]; p<0.0008). The pembrolizumab combination also demonstrated improved PFS, with a reduction in the risk of progression or death of 44 percent compared to chemotherapy alone (HR=0.56 [95% CI, 0.45-0.70]; p<0.0001).

Among patients who received the pembrolizumab combination, the ORR was 58 percent (95% CI, 52-64) compared to 38 percent (95% CI, 33-44) for patients who received chemotherapy alone (p<0.0001). The median DOR was 7.7 months (range, 1.1+ to 14.7+ months) for patients who received the pembrolizumab combination compared to 4.8 months (range, 1.3+ to 15.8+ months) for patients who received chemotherapy alone.

The safety of pembrolizumab in combination with chemotherapy has been evaluated in 791 patients with NSCLC receiving 200 mg, 2 mg/kg, or 10 mg/kg pembrolizumab every 3 weeks in clinical studies. In this patient population, the most frequent adverse reactions were nausea (49%), anemia (48%), fatigue (38%), constipation (34%), diarrhea (31%), neutropenia (29%), and decreased appetite (28%). Incidences of grade 3-5 adverse reactions were 67 percent for the pembrolizumab combination and 66 percent for chemotherapy alone.

The approval allows marketing of the pembrolizumab combination in all 28 EU member states plus Iceland, Lichtenstein, and Norway, at the approved dose of 200 mg every 3 weeks until disease progression or unacceptable toxicity. In NSCLC, pembrolizumab is also approved in Europe for the following:

  • first-line treatment of metastatic nonsquamous NSCLC in combination with pemetrexed and platinum chemotherapy in adults whose tumors have no EGFR- or ALK-positive mutations (KEYNOTE-189);
  • first-line treatment of metastatic squamous or nonsquamous NSCLC as monotherapy in adults whose tumors have high PD-L1 expression (tumor proportion score [TPS] ≥50%) with no EGFR- or ALK-positive tumor mutations (KEYNOTE-024); and
  • treatment of locally advanced or metastatic NSCLC in adults whose tumors express PD-L1 (TPS ≥1%) and who have received at least one prior chemotherapy regimen (KEYNOTE-010).
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First Therapy Approved for Adult Patients With a Rare Blood Clotting Disorder

The FDA approved caplacizumab-yhdp injection, the first therapy specifically indicated in combination with plasma exchange and immunosuppressive therapy for the treatment of adult patients with acquired thrombotic thrombocytopenic purpura (aTTP), a rare and life-threatening disorder that causes blood clotting.

“Patients with aTTP endure hours of treatment with daily plasma exchange, which requires being attached to a machine that takes blood out of the body and mixes it with donated plasma and then returns it to the body. Even after days or weeks of this treatment, as well as taking drugs that suppress the immune system, many patients will have a recurrence of aTTP,” said Richard Pazdur, MD, Director of the FDA's Oncology Center of Excellence and Acting Director of the Office of Hematology and Oncology Products in the FDA's Center for Drug Evaluation and Research. “[Caplacizumab-yhdp] is the first targeted treatment that inhibits the formation of blood clots. It provides a new treatment option for patients that may reduce recurrences.”

Patients with aTTP develop extensive blood clots in the small blood vessels throughout the body. These clots can cut off oxygen and blood supply to the major organs and cause strokes and heart attacks that may lead to brain damage or death. Patients can develop aTTP because of conditions such as cancer, HIV, pregnancy, lupus, or infections, or after having surgery, bone marrow transplantation, or chemotherapy.

The efficacy of caplacizumab-yhdp was studied in a clinical trial of 145 patients who were randomized to receive either caplacizumab-yhdp or a placebo. Patients in both groups received the current standard of care of plasma exchange and immunosuppressive therapy. The results of the trial demonstrated that platelet counts improved faster among patients treated with caplacizumab-yhdp compared to placebo.

Treatment with caplacizumab-yhdp also resulted in a lower total number of patients with either aTTP-related death and recurrence of aTTP during the treatment period, or at least one treatment-emergent major thrombotic event. The proportion of patients with a recurrence of aTTP in the overall study period (the drug treatment period plus a 28-day follow-up period after discontinuation of drug treatment) was lower in the caplacizumab-yhdp group (13%) compared to the placebo group (38%), a finding that was statistically significant.

Common side effects of caplacizumab-yhdp reported by patients in clinical trials were bleeding of the nose or gums and headache. The prescribing information for caplacizumab-yhdp includes a warning to advise health care providers and patients about the risk of severe bleeding. Health care providers are advised to monitor patients closely for bleeding when administering caplacizumab-yhdp to patients who currently take anticoagulants.

The FDA granted this application Priority Review designation. Caplacizumab-yhdp also received Orphan Drug designation.

Wolters Kluwer Health, Inc. All rights reserved.
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