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Update on NDA in GIST, Promising Data in Lung Cancer, KRAS G12C-Mutant Cancers, and AML, and European Approval in RCC

Gina Columbus
Published: Monday, Nov 04, 2019



Today-

An update on a new drug application, promising findings in lung cancer, KRAS G12C–mutant cancers, and acute myeloid leukemia, and a European approval in renal cell carcinoma.

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

The FDA intends to split proposed indications for avapritinib into two separate new drug applications for patients with gastrointestinal stromal tumor. The applications would be split into one for patients with PDGFRA exon 18–mutant disease regardless of prior therapy, and one for fourth-line GIST.

Additionally, the FDA has requested topline findings from the phase III VOYAGER trial of avapritinib versus regorafenib in the third- or fourth-line setting for patients with GIST. These data, which the agency stated would be informative in its review of the fourth-line indication, are slated to become available in the second quarter of 2020.

The update follows a priority review designation the FDA granted to the NDA for avapritinib for the treatment of adult patients with PDGFRA exon 18–mutant GIST, regardless of prior therapy, as well as for patients with GIST in the fourth-line setting.

It is likely that there will be an extended review period for the NDA for avapritinib in fourth-line GIST, in order to provide the FDA with the topline VOYAGER results. The initial action date for the FDA was February 14, 2020.

Should avapritinib receive initial approval, Blueprint Medicines, the developer of avapritinib, plans to submit a supplemental NDA to the FDA for avapritinib for third-line GIST in the second half of 2020.

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

In non–small cell lung cancer, the addition of durvalumab to platinum-based chemotherapy demonstrated a statistically significant and clinically meaningful improvement in progression-free survival versus chemotherapy alone in patients with previously untreated metastatic disease, according to topline findings of the final PFS analysis from the phase III POSEIDON trial.

Additionally, the triplet regimen of durvalumab, tremelimumab, and chemotherapy also led to a statistically significant and clinically meaningful improvement in PFS compared with chemotherapy alone.

The safety and tolerability of durvalumab was found to be consistent with durvalumab’s known safety profile, and the triplet regimen with tremelimumab did not lead to an increased discontinuation of therapy.

The findings will be submitted for presentation at an upcoming medical meeting. AstraZeneca, the developer of the PD-L1 and CTLA-4 inhibitors, stated that it plans to share the results with regulatory authorities, and investigators will continue to assess overall survival, with data anticipated in 2020.

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

Preliminary data of a phase I/II trial showed that the investigational KRAS G12C inhibitor MRTX849 demonstrated clinical activity in patients with non–small cell lung cancer and colorectal cancer.

Findings showed that at the highest dose of 600 mg twice daily, 3 of 5 evaluable patients with KRAS G12C–positive NSCLC and 1 of 2 evaluable patients with KRAS G12C–positive CRC achieved a partial response, and the remaining patients had stable disease.

Additional data showed that across all dose levels, 3 of 6 patients with NSCLC and 1 of 4 patients with CRC achieved a PR. Two responding patients, 1 with NSCLC and 1 with CRC, achieved confirmed PRs and continued to experience tumor shrinkage after their first scan. The other 2 patients with NSCLC who had PRs remain on study, but have not yet had confirmatory scans.

Regarding PK, results showed that the twice-daily dose of 600 mg led to drug levels that meet or exceed those likely to lead to full inhibition of KRAS G12C signaling. Treatment-related adverse events were mostly of grade 1 severity.

Moreover, the MTD has not yet been established and further dose escalation may be explored. Enrollment into dose expansion at the 600-mg twice-daily dose is ongoing.

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

In acute myeloid leukemia, treatment with iodine-131 apamistamab, knowns as Iomab-B, led to a high bone marrow transplant rate compared with salvage chemotherapy in elderly patients with relapsed/refractory disease, according to interim findings of the first 75 patients enrolled on the phase III SIERRA trial.

All patients who received a therapeutic dose of Iomab-B underwent a bone marrow transplant and were rapidly engrafted without experiencing delays in blood count recovery, versus an initial complete response of 18% in the control arm who could proceed to conventional bone marrow transplant.

Results also showed that the 100-day non-relapse transplant-related mortality remains lower in the Iomab-B arm at 3% versus 29% for patients in the control arm who received conventional transplants.

Of the 31 patients who received Iomab-B in the study arm, 30 could be evaluable for the primary endpoint versus 5 in the control arm, which remains consistent with interim data reported at 25% of enrollment.

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

The European Commission has approved the combination of avelumab and axitinib for the frontline treatment of adult patients with advanced renal cell carcinoma.

The approval is based on results from the phase III JAVELIN Renal 101 trial, which showed that the combination was associated with a 31% reduction in the risk of disease progression or death compared with sunitinib in an intent-to-treat population of patients with treatment-naïve advanced RCC, regardless of PD-L1 expression.

In the PD-L1–positive population, the median PFS was 13.8 months with avelumab and axitinib versus 7.2 months with sunitinib, leading to a 39% reduction in the risk of disease progression or death. The objective response rate with the combination was 55.2%, which included 4 complete responses and 51 partial responses; the ORR with sunitinib was 25.5%. Twenty-seven patients in the combination arm had stable disease and 11 had progressive disease.

In the overall population, the median PFS with the combination of avelumab and axitinib versus sunitinib was 13.8 months and 8.4 months, respectively. The ORR with avelumab/axitinib was 51.4% and 25.7% with sunitinib. In the combination arm, the ORR included 3 CRs and 48 PRs; 30 patients had SD and 12 patients had PD.

In May 2019, the FDA approved this combination in the frontline setting for patients with advanced renal cell carcinoma.

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

This week, we sat down with Dr Brian Van Tine, of Washington University in St. Louis, to discuss the historical management of gastrointestinal stromal tumors.

That’s all for today.

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

An update on a new drug application, promising findings in lung cancer, KRAS G12C–mutant cancers, and acute myeloid leukemia, and a European approval in renal cell carcinoma.

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

The FDA intends to split proposed indications for avapritinib into two separate new drug applications for patients with gastrointestinal stromal tumor. The applications would be split into one for patients with PDGFRA exon 18–mutant disease regardless of prior therapy, and one for fourth-line GIST.

Additionally, the FDA has requested topline findings from the phase III VOYAGER trial of avapritinib versus regorafenib in the third- or fourth-line setting for patients with GIST. These data, which the agency stated would be informative in its review of the fourth-line indication, are slated to become available in the second quarter of 2020.

The update follows a priority review designation the FDA granted to the NDA for avapritinib for the treatment of adult patients with PDGFRA exon 18–mutant GIST, regardless of prior therapy, as well as for patients with GIST in the fourth-line setting.

It is likely that there will be an extended review period for the NDA for avapritinib in fourth-line GIST, in order to provide the FDA with the topline VOYAGER results. The initial action date for the FDA was February 14, 2020.

Should avapritinib receive initial approval, Blueprint Medicines, the developer of avapritinib, plans to submit a supplemental NDA to the FDA for avapritinib for third-line GIST in the second half of 2020.

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

In non–small cell lung cancer, the addition of durvalumab to platinum-based chemotherapy demonstrated a statistically significant and clinically meaningful improvement in progression-free survival versus chemotherapy alone in patients with previously untreated metastatic disease, according to topline findings of the final PFS analysis from the phase III POSEIDON trial.

Additionally, the triplet regimen of durvalumab, tremelimumab, and chemotherapy also led to a statistically significant and clinically meaningful improvement in PFS compared with chemotherapy alone.

The safety and tolerability of durvalumab was found to be consistent with durvalumab’s known safety profile, and the triplet regimen with tremelimumab did not lead to an increased discontinuation of therapy.

The findings will be submitted for presentation at an upcoming medical meeting. AstraZeneca, the developer of the PD-L1 and CTLA-4 inhibitors, stated that it plans to share the results with regulatory authorities, and investigators will continue to assess overall survival, with data anticipated in 2020.

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

Preliminary data of a phase I/II trial showed that the investigational KRAS G12C inhibitor MRTX849 demonstrated clinical activity in patients with non–small cell lung cancer and colorectal cancer.

Findings showed that at the highest dose of 600 mg twice daily, 3 of 5 evaluable patients with KRAS G12C–positive NSCLC and 1 of 2 evaluable patients with KRAS G12C–positive CRC achieved a partial response, and the remaining patients had stable disease.

Additional data showed that across all dose levels, 3 of 6 patients with NSCLC and 1 of 4 patients with CRC achieved a PR. Two responding patients, 1 with NSCLC and 1 with CRC, achieved confirmed PRs and continued to experience tumor shrinkage after their first scan. The other 2 patients with NSCLC who had PRs remain on study, but have not yet had confirmatory scans.

Regarding PK, results showed that the twice-daily dose of 600 mg led to drug levels that meet or exceed those likely to lead to full inhibition of KRAS G12C signaling. Treatment-related adverse events were mostly of grade 1 severity.

Moreover, the MTD has not yet been established and further dose escalation may be explored. Enrollment into dose expansion at the 600-mg twice-daily dose is ongoing.

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

In acute myeloid leukemia, treatment with iodine-131 apamistamab, knowns as Iomab-B, led to a high bone marrow transplant rate compared with salvage chemotherapy in elderly patients with relapsed/refractory disease, according to interim findings of the first 75 patients enrolled on the phase III SIERRA trial.

All patients who received a therapeutic dose of Iomab-B underwent a bone marrow transplant and were rapidly engrafted without experiencing delays in blood count recovery, versus an initial complete response of 18% in the control arm who could proceed to conventional bone marrow transplant.

Results also showed that the 100-day non-relapse transplant-related mortality remains lower in the Iomab-B arm at 3% versus 29% for patients in the control arm who received conventional transplants.

Of the 31 patients who received Iomab-B in the study arm, 30 could be evaluable for the primary endpoint versus 5 in the control arm, which remains consistent with interim data reported at 25% of enrollment.

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

The European Commission has approved the combination of avelumab and axitinib for the frontline treatment of adult patients with advanced renal cell carcinoma.

The approval is based on results from the phase III JAVELIN Renal 101 trial, which showed that the combination was associated with a 31% reduction in the risk of disease progression or death compared with sunitinib in an intent-to-treat population of patients with treatment-naïve advanced RCC, regardless of PD-L1 expression.

In the PD-L1–positive population, the median PFS was 13.8 months with avelumab and axitinib versus 7.2 months with sunitinib, leading to a 39% reduction in the risk of disease progression or death. The objective response rate with the combination was 55.2%, which included 4 complete responses and 51 partial responses; the ORR with sunitinib was 25.5%. Twenty-seven patients in the combination arm had stable disease and 11 had progressive disease.

In the overall population, the median PFS with the combination of avelumab and axitinib versus sunitinib was 13.8 months and 8.4 months, respectively. The ORR with avelumab/axitinib was 51.4% and 25.7% with sunitinib. In the combination arm, the ORR included 3 CRs and 48 PRs; 30 patients had SD and 12 patients had PD.

In May 2019, the FDA approved this combination in the frontline setting for patients with advanced renal cell carcinoma.

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

This week, we sat down with Dr Brian Van Tine, of Washington University in St. Louis, to discuss the historical management of gastrointestinal stromal tumors.

That’s all for today.

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