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FDA Approvals in Urothelial Cancer and GIST, Promising Data in Urothelial Carcinoma, and More

Gina Columbus
Published: Monday, Jan 13, 2020



Today-

FDA approvals in urothelial cancer and gastrointestinal stromal tumor, promising results in urothelial carcinoma, mixed findings in small cell lung cancer, disappointing data in graft-versus-host disease, and a partial clinical hold in T-cell lymphoma.

Welcome to OncLive News Network! I'm Gina Columbus.

The FDA has approved pembrolizumab for the treatment of patients with Bacillus Calmette-Guerin–unresponsive, high-risk, non-muscle invasive bladder cancer with carcinoma in situ with or without papillary tumors who are ineligible for or have elected not to undergo cystectomy.

The approval is based on findings from the phase II KEYNOTE-057 trial, in which the PD-1 inhibitor led to a complete response rate of 41% in patients with high-risk NMIBC with CIS with or without papillary tumors. Additional results showed that the median duration of response was 16.2 months, and 46% of responding patients experienced a complete response lasting at least 12 months.

The approval follows the December 2019 decision by the FDA's Oncologic Drugs Advisory Committee to vote 9 to 4 supporting the approval of a new drug application for pembrolizumab in this patient population.

Moreover, the ongoing KEYNOTE-676 trial is evaluating pembrolizumab plus BCG in patients with high-risk NMIBC that is persistent or recurrent after BCG induction therapy.

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In gastrointestinal stromal tumor, the FDA has approved avapritinib, known by the trade name Ayvakit, for the treatment of adult patients with unresectable or metastatic disease harboring a PDGFRA exon 18 mutation, including PDGFRA D842V mutations.

The approval is based on efficacy results from the phase I NAVIGATOR trial, as well as combined safety data from multiple studies of avapritinib. In the specific PDGFRA exon 18–mutant patient population, avapritinib elicited an 84% overall response rate, which comprised a 7% complete response rate and a 77% partial response rate.

In patients with PDGFRA D842V mutations, the ORR was 89%, which included an 8% CR rate and an 82% PR rate. The median duration of response was not reached in either patient population.

The FDA initially granted a priority review designation to avaprinitib in patients with PDGFRA exon 18–mutant GIST, regardless of prior therapy, as well as for patients with GIST in the fourth-line setting. The agency later decided to split the proposed indications; the action date for the fourth-line GIST application is February 14, 2020.

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Frontline maintenance therapy with avelumab plus best supportive care demonstrated a statistically significant improvement in overall survival compared with best supportive care alone in patients with previously untreated locally advanced or metastatic urothelial carcinoma, regardless of PD-L1 expression, according to a planned interim analysis of the phase III JAVELIN Bladder 100 study.

The PD-L1 inhibitor demonstrated the survival benefit in both coprimary patient populations, which were all randomized patients and those with PD-L1–positive tumors. Additionally, the safety profile with avelumab was found to be consistent with prior trials of the immunotherapy.

Results of the study are expected to be presented at an upcoming medical meeting and will also be discussed with the FDA and other regulatory authorities.

JAVELIN Bladder 100 is the confirmatory trial to convert the existing accelerated approval of avelumab in urothelial carcinoma into a full approval. In 2017, the PD-L1 inhibitor was approved for the treatment of patients with locally advanced or metastatic urothelial carcinoma who have disease progression during or following platinum-containing chemotherapy, or who have disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy.

***********************************

In small cell lung cancer, the frontline combination of pembrolizumab and chemotherapy improved progression-free survival versus chemotherapy alone as a treatment for patients with extensive-stage disease, meeting 1 of 2 primary endpoints of the phase III KEYNOTE-604 trial.

However, the regimen did not show a statistically significant improvement in overall survival.

Results of a prior interim analysis showed that combining the PD-1 inhibitor with etoposide and carboplatin or cisplatin led to a 25% reduction in the risk of disease progression or death versus chemotherapy alone, which was statistically significant.

Yet, at the final analysis, the OS results were not found to be statistically significant as per a prespecified statistical plan, missing the second primary endpoint of the study.

Full findings of the trial will be presented at an upcoming medical meeting, and will also be shared with regulatory authorities.

*********************************

The combination of itacitinib and corticosteroids did not induce a statistically significant improvement in overall response rate at day 28 compared with placebo plus corticosteroids in patients with treatment-naïve acute graft-versus-host disease, therefore missing the primary endpoint of the phase III GRAVITAS-301 trial.

Specifically, the ORRs was 74.0% and 66.4% with and without itacitinib, respectively. Additionally, there was no difference reported in nonrelapse mortality at 6 months between the 2 arms, which was a secondary endpoint of the study.

The safety profile of the JAK1 inhibitor combined with corticosteroids was consistent with what has been reported in previous trials. The most common adverse events were thrombocytopenia and anemia.

Results from the study are expected to be presented at an upcoming medical meeting.

*********************************

The FDA has placed a partial clinical hold on the TELLOMAK trial, which is evaluating the efficacy and safety of lacutamab in patients with advanced T-cell lymphoma. Enrollment of new patients has been suspended in the study, except for in Italy where the trial has been suspended.

Innate Pharma SA, the developer of lacutamab, stated in a press release that it has been in discussions with regulatory authorities regarding Good Manufacturing Practice deficiencies at their manufacturing subcontractor site, which manages the fill and finish operations of the drug's clinical trials.

The company's subcontractor, Rentschler Fill Solutions GmbH, unilaterally withdrew its Certificate of Conformity of batches it produced, including the batch of lacutamab that was currently used in the TELLOMAK study; RFS also filed for bankruptcy.

Patients who are currently enrolled on TELLOMAK are permitted to continue treatment, but no new patients are allowed to enroll until there is a new GMP-certified batch. Innate Pharma stated that it is working to transfer the lacutamab fill and finish manufacturing to another contract manufacturing organization, and that it anticipates a new clinical GMP-certified batch to be available in the second half of 2020.

The FDA did not cite any safety issues related to lacutamab.

*********************************

This week, we sat down Dr Yi-Bin A. Chen of Massachusetts General Hospital to discuss the treatment landscape of graft-versus-host disease.

That's all for today.

Thank you for watching OncLive News Network! I'm Gina Columbus.
 
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Today-

FDA approvals in urothelial cancer and gastrointestinal stromal tumor, promising results in urothelial carcinoma, mixed findings in small cell lung cancer, disappointing data in graft-versus-host disease, and a partial clinical hold in T-cell lymphoma.

Welcome to OncLive News Network! I'm Gina Columbus.

The FDA has approved pembrolizumab for the treatment of patients with Bacillus Calmette-Guerin–unresponsive, high-risk, non-muscle invasive bladder cancer with carcinoma in situ with or without papillary tumors who are ineligible for or have elected not to undergo cystectomy.

The approval is based on findings from the phase II KEYNOTE-057 trial, in which the PD-1 inhibitor led to a complete response rate of 41% in patients with high-risk NMIBC with CIS with or without papillary tumors. Additional results showed that the median duration of response was 16.2 months, and 46% of responding patients experienced a complete response lasting at least 12 months.

The approval follows the December 2019 decision by the FDA's Oncologic Drugs Advisory Committee to vote 9 to 4 supporting the approval of a new drug application for pembrolizumab in this patient population.

Moreover, the ongoing KEYNOTE-676 trial is evaluating pembrolizumab plus BCG in patients with high-risk NMIBC that is persistent or recurrent after BCG induction therapy.

***********************************

In gastrointestinal stromal tumor, the FDA has approved avapritinib, known by the trade name Ayvakit, for the treatment of adult patients with unresectable or metastatic disease harboring a PDGFRA exon 18 mutation, including PDGFRA D842V mutations.

The approval is based on efficacy results from the phase I NAVIGATOR trial, as well as combined safety data from multiple studies of avapritinib. In the specific PDGFRA exon 18–mutant patient population, avapritinib elicited an 84% overall response rate, which comprised a 7% complete response rate and a 77% partial response rate.

In patients with PDGFRA D842V mutations, the ORR was 89%, which included an 8% CR rate and an 82% PR rate. The median duration of response was not reached in either patient population.

The FDA initially granted a priority review designation to avaprinitib in patients with PDGFRA exon 18–mutant GIST, regardless of prior therapy, as well as for patients with GIST in the fourth-line setting. The agency later decided to split the proposed indications; the action date for the fourth-line GIST application is February 14, 2020.

***********************************

Frontline maintenance therapy with avelumab plus best supportive care demonstrated a statistically significant improvement in overall survival compared with best supportive care alone in patients with previously untreated locally advanced or metastatic urothelial carcinoma, regardless of PD-L1 expression, according to a planned interim analysis of the phase III JAVELIN Bladder 100 study.

The PD-L1 inhibitor demonstrated the survival benefit in both coprimary patient populations, which were all randomized patients and those with PD-L1–positive tumors. Additionally, the safety profile with avelumab was found to be consistent with prior trials of the immunotherapy.

Results of the study are expected to be presented at an upcoming medical meeting and will also be discussed with the FDA and other regulatory authorities.

JAVELIN Bladder 100 is the confirmatory trial to convert the existing accelerated approval of avelumab in urothelial carcinoma into a full approval. In 2017, the PD-L1 inhibitor was approved for the treatment of patients with locally advanced or metastatic urothelial carcinoma who have disease progression during or following platinum-containing chemotherapy, or who have disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy.

***********************************

In small cell lung cancer, the frontline combination of pembrolizumab and chemotherapy improved progression-free survival versus chemotherapy alone as a treatment for patients with extensive-stage disease, meeting 1 of 2 primary endpoints of the phase III KEYNOTE-604 trial.

However, the regimen did not show a statistically significant improvement in overall survival.

Results of a prior interim analysis showed that combining the PD-1 inhibitor with etoposide and carboplatin or cisplatin led to a 25% reduction in the risk of disease progression or death versus chemotherapy alone, which was statistically significant.

Yet, at the final analysis, the OS results were not found to be statistically significant as per a prespecified statistical plan, missing the second primary endpoint of the study.

Full findings of the trial will be presented at an upcoming medical meeting, and will also be shared with regulatory authorities.

*********************************

The combination of itacitinib and corticosteroids did not induce a statistically significant improvement in overall response rate at day 28 compared with placebo plus corticosteroids in patients with treatment-naïve acute graft-versus-host disease, therefore missing the primary endpoint of the phase III GRAVITAS-301 trial.

Specifically, the ORRs was 74.0% and 66.4% with and without itacitinib, respectively. Additionally, there was no difference reported in nonrelapse mortality at 6 months between the 2 arms, which was a secondary endpoint of the study.

The safety profile of the JAK1 inhibitor combined with corticosteroids was consistent with what has been reported in previous trials. The most common adverse events were thrombocytopenia and anemia.

Results from the study are expected to be presented at an upcoming medical meeting.

*********************************

The FDA has placed a partial clinical hold on the TELLOMAK trial, which is evaluating the efficacy and safety of lacutamab in patients with advanced T-cell lymphoma. Enrollment of new patients has been suspended in the study, except for in Italy where the trial has been suspended.

Innate Pharma SA, the developer of lacutamab, stated in a press release that it has been in discussions with regulatory authorities regarding Good Manufacturing Practice deficiencies at their manufacturing subcontractor site, which manages the fill and finish operations of the drug's clinical trials.

The company's subcontractor, Rentschler Fill Solutions GmbH, unilaterally withdrew its Certificate of Conformity of batches it produced, including the batch of lacutamab that was currently used in the TELLOMAK study; RFS also filed for bankruptcy.

Patients who are currently enrolled on TELLOMAK are permitted to continue treatment, but no new patients are allowed to enroll until there is a new GMP-certified batch. Innate Pharma stated that it is working to transfer the lacutamab fill and finish manufacturing to another contract manufacturing organization, and that it anticipates a new clinical GMP-certified batch to be available in the second half of 2020.

The FDA did not cite any safety issues related to lacutamab.

*********************************

This week, we sat down Dr Yi-Bin A. Chen of Massachusetts General Hospital to discuss the treatment landscape of graft-versus-host disease.

That's all for today.

Thank you for watching OncLive News Network! I'm Gina Columbus.
 
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