OncLive Staff

The Food and Drug Administration (FDA) has approved the combination use of Venclexta (venetoclax) plus Gazyva (obinutuzumab) for the frontline treatment of patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL).

The agency’s approval is based on findings from the phase 3 CLL14 trial, in which the combination reduced the risk of disease progression or death by 67% versus Gazyva plus Leukeran (chlorambucil) in patients with treatment-naïve CLL and co-existing medical conditions.

In the trial, the combination of fixed-duration Venclexta and Gazyva was compared with Gazyva and Leukeran in 432 treatment-naïve patients with CLL and coexisting medical conditions. Patients were randomized to receive 12 months of Venclexta alongside six months of Gazyva (arm A) or six months of Gazyva followed by 6 months of Leukeran (arm B).

The overall response rate was 85% with the combination, versus 71% in the control arm. The complete response or complete response with incomplete hematologic recovery rates were 50% versus 23%, respectively.

The rate of minimal residual disease (MRD)-negativity in the bone marrow was 57% with the addition of Venclexta compared with 17% in the Gazyva plus Leukeran arm. The MRD-negativity rates in the peripheral blood were 76% versus 35%, respectively.

“Venclexta plus Gazyva is the only chemotherapy-free option of fixed duration that provides durable responses to help people live longer without progression of their disease, compared to a standard of care,” Dr. Sandra Horning, chief medical officer and head of Global Product Development at Roche (Genentech), the drugs’ manufacturer, said in a press release.

Complete results of the study are scheduled to be presented early next month at the 2019 ASCO Annual Meeting.

FDA Approves Venetoclax/Obinutuzumab Combo for Frontline CLL.”

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The Food and Drug Administration has approved the combination use of Venclexta plus Gazyva for the frontline treatment of patients with chronic lymphocytic leukemia or small lymphocytic lymphoma.

FDA Approves Venclexta-Gazyva Combo as Frontline Treatment for CLL/SLL

The Food and Drug Administration (FDA) has granted an accelerated approval to the frontline combination of Tecentriq (atezolizumab) plus Abraxane (nab-paclitaxel) for patients with unresectable locally advanced or metastatic PD-L1—positive triple-negative breast cancer (TNBC). The combination is the first cancer immunotherapy regimen approved for breast cancer.

The approval is based on the phase 3 IMpassion130 trial, in which the addition of the PD-L1 inhibitor Tecentriq to Abraxane reduced the risk of disease progression or death by 40 percent compared with Abraxane alone in this patient population.

The  study evaluated the efficacy and safety of the PD-L1 inhibitor plus chemotherapy versus Abraxane alone in treatment-naïve patients with metastatic TNBC. Patients were randomized to receive Abraxane with Tecentriq (451 patients) or with placebo (451 patients). Treatment was given until disease progression or unacceptable toxicity.

The coprimary endpoints were progression-free survival (PFS) and overall survival (OS) in both the intent-to-treat (ITT) and PD-L1—positive populations; secondary endpoints were overall response rate, duration of response and safety. Patients were stratified by prior taxane use, liver metastases and PD-L1 expression, which was defined as at least 1 percent on tumor-infiltrating immune cells to be positive.

Results of the primary PFS analysis in the PD-L1—positive population demonstrated a clinically meaningful median PFS of 7.4 months with Tecentriq/Abraxane and 5 months with chemotherapy. The one-year PFS rates were 29 percent and 16 percent with Tecentriq/Abraxane and Abraxane, respectively.

In the ITT population, the median PFS with Tecentriq/Abraxane was 7.2 months compared with 5.5 months for Abraxane. Moreover, the one-year PFS rates were 24 percent in the combination arm and 18 percent in the Abraxane arm.

At a 12.9-month follow-up, an interim OS analysis of the PD-L1—positive population showed a clinically meaningful improvement with added Tecentriq at 25 months versus Abraxane alone at 15.5 months. Two-year OS rates were 54 percent and 37 percent in the immunotherapy/chemotherapy and chemotherapy arms, respectively. 

Regarding safety, most all-grade side effects were similar between arms. The most common grade 3/4 side effects with Tecentriq/Abraxane and Abraxane were neutropenia, decreased neutrophil count, peripheral neuropathy, fatigue and anemia.

FDA Approves Atezolizumab Combo for Frontline TNBC

The Food and Drug Administration has granted an accelerated approval to the frontline combination of Tecentriq (atezolizumab) plus Abraxane (nab-paclitaxel) for patients with unresectable locally advanced or metastatic PD-L1–positive triple-negative breast cancer (TNBC).

FDA Approves Tecentriq Combo for Frontline TNBC

The Food and Drug Administration (FDA) has granted a priority review to a supplemental new drug application for Lonsurf (TAS-102; trifluridine/tipiracil) for use in previously treated patients with advanced or metastatic gastric adenocarcinoma, including cancer of the gastroesophageal junction.

The supplemental new drug application is based on data from the phase 3 TAGS trial, in which Lonsurf reduced the risk of death by about one-third compared with placebo in patients with heavily pretreated gastric or gastroesophageal junction cancer. The TAGS trial also showed improvements in progression-free survival and disease control and demonstrated a predictable and manageable safety profile.

Under the Prescription Drug User Fee Act, the FDA is scheduled to make a decision on the supplemental new drug application by Feb. 24, 2019.

"We look forward to working with the FDA as they consider the application for Lonsurf under priority review," Martin Birkhofer, M.D., senior vice president and chief medical officer of Taiho Oncology, Inc, the manufacturer of Lonsurf, said in a press release.

TAGS was conducted to confirm findings from a phase 2 Japanese study in patients with metastatic gastric cancer in which Lonsurf was evaluated after failure of standard chemotherapies (fluoropyrimidines, platinums, and taxanes) or irinotecan and found to lead to a median overall survival of 8.7 months and a disease control rate of 65.5 percent.

The global phase 3 TAGS double-blind study enrolled 507 adults with histologically confirmed, nonresectable metastatic gastric/gastroesophageal junction cancer and an ECOG performance status of 0 or 1 who received two or more prior chemotherapy regimens. Patients were randomized 2:1 to receive Lonsurf (35 mg/m2 twice daily on days one to five and eight to 12 of each 28-day cycle) or placebo plus best supportive care, and were treated until progression, intolerability, or patient withdrawal.

The primary cancer site was gastric in 71 percent and gastroesophageal junction in 29 percent. Fifty-five percent had three or more metastatic sites. Sixty-three percent in each arm had three or more prior treatments and 44 percent in each arm had prior gastrectomy. More than 90 percent received prior platinum, fluoropyridine, and taxane treatment. About one-third in each arm had prior ramucirumab.

Median overall survival, the primary endpoint, was 5.7 months for patients assigned to Lonsurf compared with 3.6 months for patients randomized to placebo. The 2.1-month improvement in median overall survial with Lonsurf over placebo translated into a hazard ratio for death of 0.69. The 12-month overall survival rate for the Lonsurf group was 21 percent versus 13 percent for the placebo group.

Multivariate analysis the following factors to be prognostic for overall survival: ECOG performance status of 1 (vs 0), two prior regimens (vs. 33), age  less than 65 years (vs 65 years or older), one or two metastatic sites (vs. three), and negative HER2 status (vs. positive or undetermined). After adjusting for these factors, the treatment effect for Lonsurf was maintained.

Median progression-free survival, a secondary endpoint, was also significantly improved with Lonsurf compared with placebo (two vs. 1.8 months). The six-month PFS rates were 15 percent and 6 percent, respectively. The progression-free survival advantage for Lonsurf was maintained when assessed by subgroups based on age, region, ethnicity, ECOG performance status, primary site, number of metastatic sites, and prior treatment with ramucirumab, among others.

The objective response rate with Lonsurf was 4 percent compared with 2 percent for placebo. In the active treatment group, there was one complete response, 12 partial responses and 115 patients with stable disease, for a disease control rate of 44 percent. The disease control rate in the placebo group was 14 percent. The absolute difference between groups in the disease control rate was 30 percent.

Time to deterioration of ECOG performance status to 2, a secondary endpoint, was longer in the Lonsurf group compared with the placebo group (median, 4.3 vs 2.3 months).

Grade 3 or higher side effects of any cause occurred in 80 percent of patients on Lonsurf versus 58 percent of those assigned to placebo. Lonsurf was associated with more treatment-related side effects of any grade (81 percent vs 57 percent). There was one treatment-related death in each group. Grade 3 or higher febrile neutropenia of any cause was reported in 6 (2 percent) patients treated with Lonsurf.

Dosing modification (dose delay or reduction) to manage side effetcs was required in 58 percent of the Lonsurf group. Treatment had to be discontinued due to adverse events in 13 percent. G-CSF treatment to manage neutropenia was necessary in 16 percent. The most common side effects leading to dosing modification were neutropenia and/or decreased neutrophil count (37 percent), anemia and/or decreased hemoglobin level (9 percent), and leukopenia and/or decreased white blood cell count (6 percent).

Yoon-Koo Kang, M.D., Ph.D., a professor in the Department of Oncology at the Asan Medical Center of the University of Ulsan College of Medicine in Seoul, Korea, commented that although TAGS was a global trial, Asian patients were underrepresented, with Japanese patients constituting only 15% of the total patient population. Kang was not involved in the TAGS study.

The need for biomarkers to define the best third and later line of treatment for advanced gastric cancer is urgent, he said. Sequential use of these agents is possible if they are tolerated. Lonsurf in combination with immunotherapy or antiangiogenic agents should be investigated, he added.

FDA Grants Priority Review to TAS-102 for Gastric/GEJ Cancer

FDA Grants Priority Review to Lonsurf for Gastric Adenocarcinoma

The Food and Drug Administration (FDA) has granted a priority review to a new drug application (NDA) for selinexor (KPT-330) for the treatment of patients with penta-refractory multiple myeloma, according to Karyopharm Therapeutics, the manufacturer of the XPO1 inhibitor.

The NDA is based on results from the phase 2b STORM trial, which examined the combination of selinexor and dexamethasone in patients with penta-refractory multiple myeloma. Updated data from the study presented at the 2018 Society of Hematologic Oncology (SOHO) Annual Meeting showed that the doublet regimen was associated with an overall response rate of 26.2 percent and a median overall survival of 8.6 months in patients with penta-refractory disease.

Sundar Jagannath, M.D., director of the Multiple Myeloma Program and professor of medicine at The Tisch Cancer Institute, Mount Sinai Health System, delivered the STORM findings at SOHO. He explained that patients who had a response to treatment, even a minor response, did significantly better, with a median overall survival of 15.6 months. Historically, the median overall survival in this patient population is an estimated 3.6 months.

According to Karyopharm, the study defined penta-refractory as “patients who have previously received at least one alkylating agent, glucocorticoids, two immunomodulatory drugs (lenalidomide [Revlimid] and pomalidomide [Pomalyst]), two proteasome inhibitors (bortezomib [Velcade] and carfilzomib [Kyprolis]), and daratumumab (Darzalex), and whose disease is refractory to glucocorticoids, at least one proteasome inhibitor, at least one immunomodulatory drug, and daratumumab, and whose disease has progressed following their most recent therapy.”

Under the Prescription Drug User-Fee Act, the FDA is scheduled to make a decision on the NDA by April 6, 2019.

"As a potential new therapy with a novel mechanism and compelling clinical profile, we believe oral selinexor, if approved, will provide a meaningful therapeutic option for patients battling highly resistant, penta-refractory myeloma," Sharon Shacham, Ph.D., MBA, founder, president and chief scientific officer of Karyopharm, said in a statement. "The acceptance of this NDA for review and grant of priority review mark significant milestones for the selinexor program, and further underscores the high level of unmet need in this patient population.  We look forward to working with the FDA during the review process."

The STORM trial included 122 patients with penta-refractory multiple myeloma at 38 sites in the United States; 85 patients were treated per-protocol. The median patient age was 65 years. Eligible patients had to have received prior treatment with bortezomib, carfilzomib, lenalidomide, pomalidomide, daratumumab, an alkylator, and glucocorticoids.

Patients had undergone a median of seven prior treatments, and all were refractory to proteasome inhibitor/immunomodulatory drugs/ daratumumab/glucocorticoid. Ninety-six percent were refractory to carfilzomib/pomalidomide/daratumumab. Eighty-four percent had undergone stem cell transplant, and 28 percent had undergone two or more transplants.

Patients received 80 mg of oral selinexor plus 20 mg of oral dexamethasone twice weekly until progression. The primary endpoint was overall response rate.

Two patients, both of whom were negative for minimal residual disease, achieved stringent complete response. Two patients who relapsed following chimeric antigen receptor T-cell therapy achieved a partial response.

The median progression-free survival was 3.7 months for the entire cohort. For partial responders, the median progression-free survival was 5.3 months, and 4.6 months for those who had at least minimal response.

Duration of response was 4.4 months. Jagannath said responses typically occurred in the first four weeks of treatment. The clinical benefit rate was 39.3 percent and the disease control rate was 78.7 percent.

“If you’re able to arrest the growth of the tumor, you’re able to get a survival benefit for these patients,” Jagannath said.

The most common grade 3/4 treatment-related hematological side effect was thrombocytopenia (53.7 percent), followed by anemia (29.3 percent), neutropenia (17.9 percent), leukopenia (13.8 percent), and lymphopenia (8.9 percent). There was only one instance of grade 4 anemia and no grade 4 leukopenias recorded.

There were no grade 4 non-hematological side effects observed. The most common grade 3 non-hematological side effects were fatigue/asthenia (22.8 percent), hyponatremia (16.3 percent), and nausea (9.8 percent).

Selinexor links to and inhibits XPO1 (CRM1), a nuclear export protein. There is an accumulation of tumor suppressor proteins in the cell nucleus as a result of this activity, and, subsequently, the cell’s tumor suppressor function is regained and amplified, which investigators hypothesize induces apoptosis.

FDA Grants Selinexor Priority Review for Multiple Myeloma

The Food and Drug Administration has granted a priority review to a new drug application for selinexor (KPT-330) for the treatment of patients with penta-refractory multiple myeloma.

OncLive Staff

FDA Approves Venclexta-Gazyva Combo as Frontline Treatment for CLL/SLL

FDA Approves Tecentriq Combo for Frontline TNBC

FDA Grants Priority Review to Lonsurf for Gastric Adenocarcinoma

FDA Grants Priority Review to Selinexor for Multiple Myeloma

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