Jason M Broderick

The U.S. Food and Drug Administration (FDA) has granted an accelerated approval to Polivy (polatuzumab vedotin) for use in combination with bendamustine and Rituxan (rituximab) for the treatment of patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL) who have received at least two prior therapies.

"Antibody-drug conjugates are an emerging class of targeted immunotherapies for cancer. This type of therapy, unlike traditional chemotherapy, is intended to target specific cells," Richard Pazdur, M.D., 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, said in a statement. "Today's approval of Polivy provides an alternative option for patients in whom multiple treatments have not worked.

Patients with relapsed/refractory DLBCL and those who are ineligible for transplant have limited treatment options and a poor prognosis. CD79b is a component of the B-cell receptor and is expressed ubiquitously in DLBCL. Polivy is an anti-CD79b antibody linked to microtubule-disrupting monomethyl auristatin E.

Preliminary results from the phase 1b part of the trial provided evidence of the drug’s safety and efficacy in safety run-in, expansion and randomized cohorts, which were reported prior to the 2018 ASH meeting. The data presented at ASH included six patients from the safety cohort, 27 from the expansion phase and 80 from the randomized comparison of bendamustine/Rituxan with or without Polivy.

The median age across the cohorts ranged from 65 to 71, and from two-thirds to three-fourths of the patients in each cohort had received two or more prior lines of therapy. Additionally, 20% of the patients in the randomized study had undergone a transplant.

The primary endpoint of complete response was determined by independent review of PET—CT imaging at the end of treatment. Secondary endpoints included duration of response and progression-free survival (PFS) by independent review. Exploratory endpoints included duration of response and progression-free survival by investigator review, overall survival and efficacy by cell of origin and MYC/BCL2 double-expression (DE) status.

Median follow-up was 37.6 months for the safety cohort, 27.0 months for the expansion cohort and 22.3 months for the randomized comparison.

Three of six patients in the safety cohort attained complete response with the Polivy-bendamustine-Rituxan regimen. Duration of response, progression-free survival and overall survival could not be determined.

In the expansion cohort, 11 patients (41%) had objective responses by independent review. Median duration of response, median progression-free survivaPFSl and overall survivalOS were 28.4 months, 5.4 months and 10.8 months, respectively.

In the randomized, phase 2 component of the evaluation, 16 (40%) patients had complete responses in the Polivy arm as compared with seven (18%) patients who received bendamustine-Rituxan without the ADC. Median duration of response by independent review had yet to be reached in the Polivy arm as compared with 7.7 months in the control arm. By investigator assessment, median duration of response was 10.3 months with Polivy versus 4.1 months without.

Median progression-free survivalPFS by independent review was 11.1 months with Polivy and 3.7 months without. By investigator assessment, the median values were 7.6 versus 2.0 months without.

Analyses by cell of origin — activated B-cell like (ABC) or germinal B-cell like (GCB) &mdash; showed consistent advantages for the addition of Polivy. Median progression-free survivalPFS by investigator assessment and OS in the ABC subgroup were 10.8 months and 15.4 months, respectively, versus 2.0 and 4.7 months without Polivy. The GBC subgroup had inferior outcomes but still favored the ADC: 2.5 versus 1.9 months for median progression-free survival and 7.2 versus 3.8 months for overall survival.

Analysis by DE status showed median progression-free survival of 7.0 versus 1.4 months for the Polivy group among patients with DE and 6.2 versus 3.1 months for those without. Overall survival was 8.9 versus 4.6 months for the DE subgroup and 10.0 versus 4.5 months for patients without DE.

With continued follow-up, no new safety signals emerged, and the safety data remained consistent with initial reports from the study. The most common grade 3/4 side effect overall were infections and cytopenias. While infection and transfusion rates were similar with BR alone or the addition of Polivy, the rates of grade 3/4 cytopenias were higher in the ADC arm.

The accelerated approval of Polivy is contingent on a confirmatory trial.

FDA Approves Polatuzumab Vedotin for DLBCL."

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The FDA has granted an accelerated approval to Polivy for use in combination with bendamustine and Rituxan for the treatment of patients with relapsed/refractory diffuse large B-cell lymphoma who have received at least two prior therapies.

FDA Grants Polivy Accelerated Approval for DLBCL

The Food and Drug Administration (FDA) has approved the combination regimen of Revlimid (lenalidomide) plus Rituxan (rituximab), also known as the R

regimen, for use in patients with previously-treated follicular lymphoma and marginal zone 

“Nearly 15 years following the initial FDA approval, Revlimid continues to demonstrate benefits for new patient populations,” Dr. Jay Backstrom, chief medical officer and head of Global Regulatory Affairs for Celgene, the manufacturer of Revlimid, said in a statement. “Revlimid in combination with rituximab leads to immune-mediated treatment effects and represents a chemotherapy-free treatment option that can help patients with previously treated follicular lymphoma and marginal zone lymphoma delay disease progression.”

The agency based its decision on results from the double-blind, phase 3 AUGMENT trial, which included 358 patients with relapsed/refractory follicular lymphoma (295 patients) or marginal zone lymphoma (63 patients) in need of treatment. Patients had to have received at least one prior chemotherapy, immunotherapy or chemoimmunotherapy regimen and could not be refractory to treatment with Rituxan.

Patient characteristics at baseline were well balanced overall between the two arms: about 60% of patients were aged 60 or older; over 70% of patients had advanced-stage disease at study entry; about 50% of patients had high tumor burden; and around 83% of patients in each arm had follicular lymphoma, with the remaining 17% having marginal zone lymphoma.

In the trial, the combination regimen reduced the risk of disease progression or death by 54% compared with Rituxan alone. At a median follow-up of 28.3 months, the median progression-free survival (or time from treatment to disease worsening) was 39.4 months with the combination regimen versus 14.1 months with Rituxan alone.

By investigator assessment, the median progression-free survival was 25.3 months versus 14.3 months, respectively. Overall response rate was also significantly improved with the combination: 78% versus 53%, respectively. Of note, the 78% overall response rate included a 44% complete response rate and a 34% partial response rate.

In addition, the progression-free survival benefit with Revlimid and Rituxan was sustained across almost all prespecified subgroups, regardless of age, disease histology, whether or not they had prior Rituxan, number of prior regimens, time since last anti-lymphoma therapy, geographic region where treatment was received, chemoresistance status or tumor burden status.

The one exception in which the progression-free survival advantage in a subgroup was not consistent with the overall population was the subgroup of patients with marginal zone lymphoma. “This relates to the fact that there were roughly 30 patients in each arm with (marginal zone lymphoma), which limits these comparisons,” lead study author Dr. John Leonard, associate dean for clinical research and Richard T. Silver Distinguished Professor of Hematology and Medical Oncology at Weill Cornell Medicine and New York-Presbyterian Hospital in New York City, said when presenting the data at the 2018 ASH Annual Meeting. 

Overall survival data across the entire population showed that at a median follow-up of 28.3 months. The two-year overall survival rate was 93% for Revlimid and Rituxan and 87% for Rituxan alone.

In a prespecified subgroup analysis of patients with follicular lymphoma, at a median follow-up of 28.3 months, the two-year overall survival rate was 95% for the combination regimen and 86% for Rituxan alone.

Thirty percent of patients in the Revlimid and Rituxan arm discontinued treatment early compared with 39% of patients in the placebo arm. The primary cause of discontinuation was disease progression, at 12% in the Revlimid and Rituxan arm versus 30% in the control arm. Side effects led to discontinuation in 8% of the Revlimid and Rituxan group versus 4% of the placebo group. Among patients receiving Revlimid, 66% had at least one side effect-related dose interruption.

“The main grade 3/4 (side effect) difference (between the 2 arms) in (side effects was) in neutropenia.” However, the neutropenia generally did not result in febrile neutropenia, with only 3% of patients in the Revlimid and Rituxan arm having febrile neutropenia.

Also of note, six patients in the Revlimid and Rituxan arm and 10 patients in the placebo arm had secondary malignancies. “Venous and arterial thromboembolic (side effects) were relatively low and similar in both arms,” said Leonard. 

FDA Approves Lenalidomide/Rituximab for Indolent Non-Hodgkin Lymphoma

The Food and Drug Administration has approved the combination regimen of Revlimid plus Rituxan for use in patients with previously-treated follicular lymphoma and marginal zone lymphoma.

FDA Approves Revlimid/Rituxan Combo for Indolent Non-Hodgkin Lymphoma

The Food and Drug Administration (FDA) has approved the PI3K inhibitor Piqray (alpelisib) for the treatment of postmenopausal women, and men, with HR-positive, HER2-negative, PIK3CA-mutated, advanced or metastatic 

 following progression on or after an endocrine-based regimen.

The approval is based on data from the phase 3 SOLAR-1 trial. Among a subset of patients in the trial with PIK3CA mutations, the median progression-free survival (time from treatment to disease worsening) by local assessment was 11.0 months for those who received the Piqray combination compared with 5.7 months for those who received placebo plus Faslodex (fulvestrant). Those results, assessed after a median follow-up of 20 months, translated into a 35% reduction in the risk of progression or death, with a hazard ratio of 0.65 in favor of Piqray. There was no advantage to Piqray on median progression-free survival in patients without a 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," Dr. Richard Pazdur, 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, said in a press release.

"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," added Pazdur.

In SOLAR-1, 572 postmenopausal women or men with HR-positive, HER2-negative advanced breast cancer were randomized to oral alpelisib (300 mg/day) or placebo plus intramuscular fulvestrant (500 mg every 28 days and on days 1 and 15 of treatment cycle 1). A total of 341 patients had PIK3CA mutations when tumor tissue was tested, with 169 receiving the alpelisib combination and 172 taking fulvestrant alone.

About half of the patients in each arm had lung or liver metastases and approximately 6% had received prior CDK4/6 therapy.

When progression-free survival was assessed by a blinded independent review committee, the median progression-free survival was 11.1 months in the Piqray arm versus 3.7 months in the placebo arm, for a 7.4-month improvement with the addition of Piqray to Faslodex.

Progression-free survival was analyzed in the nonmutant cohort as a proof of concept. No clinically relevant effect was observed in patients with PIK3CA-nonmutant tumors, with a median progression-free survival of 7.4 months and 5.6 months in the Piqray and placebo arms, respectively.

The overall response rate in the PIK3CA-mutant cohort was 26.6% in the Piqray/Faslodex arm compared with 12.8% in the placebo/Faslodex arm. In the PIK3CA-mutant patients with measurable disease, the overall response rates were 35.7% and 16.2%, respectively.

For the entire study population, the rate of grade 3 or higher side effects was 64.4% in the Piqray/Faslodex arm compared with 30.3% in the placebo/Faslodex arm. Grade 3 or higher hyperglycemia occurred in 32.7% of patients receiving Piqray versus 0.3% receiving placebo.

Grade 3 rash developed in 9.9% of patients randomized to Piqray and 0.3% randomized to placebo. The discontinuation rate of Piqray/Faslodex due to side effects was 5% versus 1% for Faslodex alone.

The Food and Drug Administration has approved the PI3K inhibitor Piqray (alpelisib) for the treatment of postmenopausal women, and men, with HR-positive, HER2-negative, PIK3CA-mutated, advanced or metastatic breast cancer following progression on or after an endocrine-based regimen.

FDA Approves Piqray to Treat Breast Cancer

 (FDA)’s Oncologic Drugs Advisory Committee (ODAC) voted 8 to 3 against approving a new drug application for 

 for adult patients with relapsed/refractory FLT3-ITD—positive acute myeloid leukemia (AML).

With this, the FDA will now make a decision on the quizartinib indication by Aug. 25, 2019.

The FLT3 inhibitor’s new drug application was based on findings from the phase 3 QuANTUM-R study, in which quizartinib reduced the risk of death by 24% compared with salvage chemotherapy in patients with FLT3-ITD—positive relapsed/refractory 

 after first-line treatment with or without hematopoietic stem cell transplantation (HSCT). At a median follow-up of 23.5 months, the median overall survival was 6.2 months with quizartinib, compared with 4.7 months with salvage chemotherapy.

Prior to the ODAC meeting, the FDA conducted its own efficacy analysis, and determined the median overall survival was 26.9 weeks with quizartinib compared with 20.4 weeks with chemotherapy.

The phase 3 trial also showed that the median event-free survival was 1.4 months with quizartinib versus 0.9 months with salvage chemotherapy. Meanwhile, the internal FDA analysis also did not demonstrate a significant event-free survival benefit with quizartinib versus chemotherapy (6.0 vs. 3.7 weeks).

In addition, the trial data showed that the overall response rate was 69% with quizartinib versus 30% with salvage chemotherapy. The composite complete remission rate was 48% versus 27% and the partial response rate was 21% versus 3%, respectively. The median duration of composite complete remission was 12.1 weeks versus 5.0 weeks, respectively.

Although this analysis confirmed a benefit with quizartinib, the FDA explained in its ODAC briefing document that it found issues in its review raising concerns over the “credibility” and “generalizability” of the trial data.

“I voted no based on the data available. The efficacy results that we were shown are a modest six weeks. And if I felt confident in those data, that would have been enough for me in the setting of AML, but a lot of the questions that were raised with respect to bias, confounding, and I do think the issue of equipoise is a real one in the setting of this particular study—it raises questions about whether or not that survival benefit is real,” said Dr. Heidi D. Klepin, associate professor of internal medicine in the section of hematology and oncology at Wake Forest University Health Sciences.

Moreover, the FDA’s internal safety analysis of the QuANTUM-R study was mostly consistent with the safety findings included in the new drug application, which listed the most common treatment-emergent side effects as nausea, anemia, electrocardiogram QT prolonged, thrombocytopenia, pyrexia, hypokalemia, febrile neutropenia, vomiting, fatigue, diarrhea, neutropenia, white blood cell count decreased, platelet count decreased, neutrophil count decreased, headache and decreased appetite.

The application also listed side effects of special interest, including infection (77%), hemorrhage (49%), hepatic disorders (32%), QT prolongation (31%), cardiac arrhythmias (12%) and cardiac failure (2%).

In its ODAC briefing document, the FDA focused on cardiac toxicity as a key concern with quizartinib, noting the risk of cardiac side effects was substantially higher with quizartinib versus chemotherapy. Additional safety issues identified in the FDA safety analysis included potentially fatal differentiation syndrome, acute febrile neutrophilic dermatosis and prolonged cytopenias.

“In the realm of hematology/oncology, there are no patients sicker than acute leukemia patients, and no physicians more intensely watching the details than leukemia doctors, and so I’m not particularly worried that this cardiac safety question will somehow fall through the cracks,” said Dr. Philip C. Hoffman, professor of medicine at The University of Chicago Section of Hematology/Oncology in the Department of Medicine.

“I agree with some of the others, that I don’t get the sense that, at least based on the data right now, that this is a blockbuster (drug), but it does seem like it’s one more agent in the armamentarium that can be useful in leukemia patients, perhaps as a way to get patients in sufficient remission to move toward a transplant,” he added.

This article was adapted from an article that originally appeared on 

FDA Panel Votes Against Quizartinib Approval for AML

The Food and Drug Administration’s Oncologic Drugs Advisory Committee voted against approving a new drug application for quizartinib for adult patients with relapsed/refractory FLT3-ITD–positive AML.

 

Author | Jason M Broderick

FDA Grants Polivy Accelerated Approval for DLBCL

FDA Approves Revlimid/Rituxan Combo for Indolent Non-Hodgkin Lymphoma

FDA Approves Piqray to Treat Breast Cancer

FDA Panel Recommends Against Quizartinib Approval for Acute Myeloid Leukemia