FDA Approvals in HNSCC and DLBCL, and Encouraging Data in CLL, MDS, and CMML

Today- FDA approvals in head and neck cancer and diffuse large B-cell lymphoma, encouraging data in studies of chronic lymphocytic leukemia as well as myelodysplastic syndrome and chronic myelomonocytic leukemia, and a trial halted in light-chain amyloidosis.

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

The FDA has approved pembrolizumab for the first-line treatment of patients with metastatic or unresectable recurrent head and neck squamous cell carcinoma as monotherapy whose tumors express PD-L1 with a composite positive score of at least 1, or in combination with platinum and fluorouracil for this patient population, irrespective of PD-L1 expression.

The approval is based on findings from the phase III KEYNOTE-048 trial, in which single-agent pembrolizumab led to a 22% reduction in the risk of disease progression or death compared with the standard EXTREME regimen, which comprises cetuximab with carboplatin or cisplatin plus FU, in patients with PD-L1—positive tumors.

In the overall population, the combination of pembrolizumab and chemotherapy led to a 23% reduction in the risk of disease progression or death.

Results of the study also showed that in patients with PD-L1 CPS of 20 or higher, the median OS was 14.9 months versus 10.7 months in those who received pembrolizumab alone versus EXTREME, respectively, and the 2-year OS rate was 38% versus 22%.

Moreover, the ORRs were 23.3% and 36.1% with pembrolizumab and standard therapy, respectively; however, the median DOR was longer with the PD-1 inhibitor at 20.9 months versus 4.5 months.

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In diffuse large B-cell lymphoma, the FDA has granted an accelerated approval to polatuzumab vedotin, known by the trade name Polivy, for use in combination with bendamustine and rituximab for the treatment of patients with relapsed/refractory disease who have received at least 2 prior therapies.

The approval is based on results from the phase Ib/II GO29365 study. Data showed that 40% of patients who received the polatuzumab vedotin regimen achieved a complete response compared with 18% of patients in the BR-alone arm. The addition of the antibody-drug conjugate also led to an improvement in overall survival, with a median OS of 12.4 months versus 4.7 months with BR alone.

No new safety signals have emerged with continued follow-up, and the safety findings have remained consistent with initial trial reports. Overall, the most common grade 3/4 adverse events were infections and cytopenias, and while infection and transfusion rates were similar with BR alone or the addition of polatuzumab vedotin , the rates of grade 3/4 cytopenias were higher in the ADC arm.

The accelerated approval is contingent on the results of a confirmatory trial.

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The fixed-dose combination of cedazuridine and decitabine, known as ASTX727, demonstrated decitabine exposure equivalence of total 5-day dosing compared with intravenous decitabine in patients with intermediate- and high-risk myelodysplastic syndromes or chronic myelomonocytic leukemia, meeting the primary endpoint of the phase III ASCERTAIN trial.

Additionally, safety and clinical activity of the combination were found to be similar to what had been observed in earlier phase I/II trials. Full findings will be presented at an upcoming medical meeting. The developer of cedazuridine, Astex Pharmaceuticals, which is a member of Ostuka, plans to file a new drug application for the combination by the end of 2019.

The combination ASTX727 is a novel, orally administered fixed-dose combination of both cedazuridine and decitabine. By inhibiting cytidine deaminase in the gut and the liver, ASTX727 allows for an oral administration of decitabine at exposures that are equivalent to the approved intravenous form of decitabine administered over 5 days.

The combination was previously evaluated in a phase I/II pharmacokinetic-guided dose-escalation and dose-confirmation trial in patients with MDS and CMML. Results showed that ASTX727 allowed decitabine to be delivered orally at a dose that emulates parenteral PK, as measured by 5-day area under the curve. Moreover, the safety profile of ASTX727 was found to be similar to intravenous decitabine, with a low level of gastrointestinal-related adverse events.

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In chronic lymphocytic leukemia, the combination of acalabrutinib and obinutuzumab demonstrated a statistically significant and clinically meaningful improvement in progression-free survival compared with obinutuzumab/chlorambucil in patients with previously untreated disease in the phase III ELEVATE-TN trial.

Additionally, single-agent acalabrutinib showed a statistically significant and clinically meaningful improvement in PFS compared with obinutuzumab plus chlorambucil, which was a key secondary endpoint of the trial. Acalabrutinib also demonstrated safety and tolerability that were consistent with prior findings of the BTK inhibitor.

Due to these positive data, the trial will end early. Full findings of ELEVATE-TN will be presented at an upcoming medical meeting.

This is the second pivotal trial with acalabrutinib in CLL to meet its primary endpoint early. In May 2019, results of the phase III ASCEND trial showed that single-agent acalabrutinib demonstrated a statistically significant and clinically meaningful improvement in PFS compared with the combination of rituximab and either idelalisib or bendamustine in patients with treatment-naïve CLL. Due to these interim data, it was decided that the trial would end early.

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The combination of ixazomib and dexamethasone did not demonstrate a significant improvement in overall hematologic response compared with standard therapy in patients with relapsed/refractory systemic light-chain amyloidosis, missing one of two primary endpoints in the phase III TOURMALINE-AL1 trial. Because of this, the trial was discontinued.

An Independent Data Monitoring Committee did not raise any concerns with ixazomib’s safety profile in this patient population. Takeda, the manufacturer of ixazomib, stated that patients enrolled on this trial are encouraged to consult with study investigators to address any questions.

In the international, randomized, open-label, multicenter phase III TOURMALINE-AL1 trial, investigators evaluated the combination of 4 mg of ixazomib and 20 mg of dexamethasone versus physician’s choice of chemotherapy in approximately 248 patients with relapsed/refractory systemic AL amyloidosis. The chemotherapy regimens patients could be randomized to were dexamethasone/melphalan, dexamethasone/cyclophosphamide, dexamethasone/thalidomide, dexamethasone/lenalidomide, or dexamethasone alone.

Primary AL amyloidosis arises from a clonal plasma cell that creates atypical immunoglobulin light-chain fragments that aggregate as amyloid deposits in organs and tissues, leading to organ dysfunction and death. The kidneys, heart, liver, and autonomic or peripheral nerves are the most commonly affected nerves. Moreover, there are no FDA-approved therapies for the treatment of patients with AL amyloidosis.

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This week, we sat down with Dr Sai-Hong Ignatius Ou, of the University of California, Irvine School of Medicine, to discuss sequencing with osimertinib in EGFR-mutated non—small cell lung cancer.

That’s all for today.

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