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Thursday, June 13, 2019

The FDA granted accelerated approval to polatuzumab vedotin-piiq, a CD79b-directed antibody-drug conjugate indicated in combination with bendamustine and a rituximab product for adult patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL), not otherwise specified, after at least two prior therapies.

Approval was based on Study GO29365 (NCT02257567), an open-label, multicenter clinical trial that included a cohort of 80 patients with relapsed or refractory DLBCL after at least one prior regimen. Patients were randomized (1:1) to receive either polatuzumab vedotin-piiq in combination with bendamustine and a rituximab product (P+BR) or BR for six 21-day cycles. Polatuzumab vedotin-piiq, 1.8 mg/kg by IV infusion, was given on day 2 of cycle 1 and on day 1 of subsequent cycles. Bendamustine (90 mg/m2 intravenously) was administered on days 2 and 3 of cycle 1 and on days 1 and 2 of subsequent cycles. A rituximab product (375 mg/m2 intravenously) was administered on day 1 of each cycle.

Efficacy was based on complete response (CR) rate and response duration, as determined by an independent review committee. At the end of therapy, the CR rate was 40 percent (95% CI: 25-57%) with P+BR compared with 18 percent (95% CI: 7-33%) with BR alone. The best overall response rate (complete and partial responses) was 63 percent with P+BR compared with 25 percent with BR. Of the 25 patients who achieved partial or complete response to P+BR, 16 (64%) had response durations of at least 6x months and 12 (48%) had response durations of at least 12 months.

The most common adverse reactions with P+BR (incidence at least 20%) included neutropenia, thrombocytopenia, anemia, peripheral neuropathy, fatigue, diarrhea, pyrexia, decreased appetite, and pneumonia.

Serious adverse reactions occurred in 64 percent, most often from infection. Cytopenias were the most common reason for treatment discontinuation (18% of all patients).

The prescribing information includes warnings and precautions for peripheral neuropathy, infusion-related reactions, myelosuppression, serious and opportunistic infections, progressive multifocal leukoencephalopathy, tumor lysis syndrome, hepatotoxicity, and embryo-fetal toxicity.

The recommended dose of polatuzumab vedotin-piiq is 1.8 mg/kg as an IV infusion over 90 minutes every 21 days for 6 cycles in combination with bendamustine and a rituximab product. Subsequent infusions may be administered over 30 minutes if the previous infusion is tolerated. Premedicate with an antihistamine and antipyretic, and administer prophylaxis for Pneumocystis jiroveci pneumonia and herpesvirus.

Tuesday, June 11, 2019

The FDA recently approved pembrolizumab for the first-line treatment of patients with metastatic or unresectable recurrent head and neck squamous cell carcinoma (HNSCC).

Pembrolizumab was approved for use in combination with platinum and fluorouracil (FU) for all patients and as a single agent for patients whose tumors express PD‑L1 (Combined Positive Score [CPS] ≥1) as determined by an FDA‑approved test. The FDA also expanded the intended use for the PD-L1 IHC 22C3 pharmDx kit to include use as a companion diagnostic device for selecting patients with HNSCC for treatment with pembrolizumab as a single agent.

Approval was based on KEYNOTE-048 (NCT02358031), a randomized, multicenter, three-arm, open‑label, active‑controlled trial conducted in 882 patients with metastatic HNSCC who had not previously received systemic therapy for metastatic disease or with recurrent disease who were considered incurable by local therapies.

Patients were randomized (1:1:1) to receive one of the following treatments: pembrolizumab as a single agent; pembrolizumab, carboplatin or cisplatin, and FU; or cetuximab, carboplatin or cisplatin, and FU. Randomization was stratified by tumor PD-L1 expression (Tumor Proportion Score [TPS] ≥50% or <50%), HPV status according to p16 IHC (positive or negative), and ECOG PS (0 vs 1). PD-L1 expression (TPS and CPS) was determined using the PD-L1 IHC 22C3 pharmDx kit.

Overall survival (OS), sequentially tested in the subgroup of patients with CPS ≥20 HNSCC, the subgroup of patients with CPS ≥1 HNSCC and the overall population, was the major efficacy measure.

The trial demonstrated a statistically significant improvement in OS in the overall population for patients randomized to pembrolizumab plus chemotherapy compared with cetuximab plus chemotherapy at a pre-specified interim analysis. The median OS was 13.0 months for the pembrolizumab plus chemotherapy arm and 10.7 months for the cetuximab plus chemotherapy arm (HR 0.77; 95% CI: 0.63, 0.93; p=0.0067). Results were similar in the CPS ≥20 subgroup (HR 0.69; 95% CI: 0.51, 0.94) and CPS ≥1 subgroup (HR 0.71; 95% CI: 0.57, 0.88).

The trial also demonstrated statistically significant improvements in OS for the subgroups of patients with PD‑L1 CPS ≥1 HNSCC and PD-L1 CPS ≥20 HNSCC randomized to pembrolizumab as a single agent compared with cetuximab plus chemotherapy. In the CPS ≥1 subgroup, the median OS was 12.3 months for the pembrolizumab arm and 10.3 months for the cetuximab plus chemotherapy arm (HR 0.78; 95% CI: 0.64, 0.96; p=0.0171). For the CPS ≥20 subgroup, the median OS was 14.9 months for the pembrolizumab arm and 10.7 months for the cetuximab plus chemotherapy arm (HR 0.61; 95% CI: 0.45, 0.83; p=0.0015). At the time of the interim analysis, there was no significant difference in OS between the pembrolizumab as a single agent arm and the cetuximab plus chemotherapy arm for the overall population.

There were no significant differences in progression-free survival for either pembrolizumab-containing arm compared to the cetuximab plus chemotherapy arm in any population.

The most common adverse reactions reported in ≥20 percent of patients who received pembrolizumab as a single agent in KEYNOTE-048 were fatigue, constipation, and rash. The most common adverse reactions reported in ≥20 percent of patients who received pembrolizumab in combination with chemotherapy in KEYNOTE-048 were nausea, fatigue, constipation, vomiting, mucosal inflammation, diarrhea, decreased appetite, stomatitis, and cough.

The recommended pembrolizumab dose for HNSCC is 200 mg administered as an intravenous infusion over 30 minutes every 3 weeks until disease progression, unacceptable toxicity, or up to 24 months in patients without disease progression.



Monday, June 10, 2019

Updated interim data from an ongoing phase I/II study of its investigational monoclonal antibody, cirmtuzumab, in combination with ibrutinib in patients with chronic lymphocytic leukemia (CLL) was presented at the 2019 ASCO Annual Meeting (Abstract 7527). Results from the first 12 patients in the phase I portion of the study showed that the combination was well-tolerated, with an overall objective response rate (ORR) of 91.7 percent, including three patients with clinical or confirmed complete responses.

The study is being conducted in collaboration with the California Institute for Regenerative Medicine (CIRM) and the University of California San Diego (UC San Diego) School of Medicine, and the CIRLL (Cirmtuzumab and Ibrutinib in Relapsed Leukemia and Lymphoma) Study Group.

"The cirmtuzumab and ibrutinib combination has demonstrated impressive clinical activity in this interim assessment of data from these patients with CLL," said Michael Y. Choi, M.D., UC San Diego Moores Cancer Center, and an investigator in the study. "These results support our belief that the receptor tyrosine kinase-like orphan receptor 1 (ROR1)-Wnt5a signaling pathway remains active in ibrutinib-treated CLL and mantle cell lymphoma (MCL). In addition, we believe that inhibition of Bruton's tyrosine kinase (BTK) in CLL cells increases dependence on ROR1 signaling, further enhancing the potential benefit of a ROR1 inhibitor such as cirmtuzumab."

Among 18 CLL patients evaluated in the interim safety assessment of the study, the cirmtuzumab + ibrutinib combination was well-tolerated, with adverse events that were typical for those reported in the literature for patients receiving ibrutinib alone. No dose-limiting toxicities were attributed to cirmtuzumab. Two patients discontinued treatment: one patient due to worsening heart failure unrelated to the combination treatment; and one patient secondary to atrial fibrillation, pericardial effusion and tamponade, which was not attributed to cirmtuzumab.

Twelve CLL patients received 24 weeks or more of treatment on the study, and so were evaluable for efficacy. The on-treatment ORR was 91.7 percent, with 11 of the 12 patients achieving a partial response (PR) or complete response (CR) as of the data cutoff of May 22, 2019. None of the patients experienced progressive disease (PD). Three patients completed the full one year of treatment specified in the protocol, and one out of these three patients met all International Working Group CLL (iwCLL) criteria for a CR, including no enlarged lymph nodes or splenomegaly, an absolute lymphocyte count (ALC) in the normal range, and no evidence of a lymphoid infiltrate or increased lymphocytes in the bone marrow. Two patients experienced a clinical CR, one at 34 weeks and another at 42 weeks of treatment, including no enlarged lymph nodes or splenomegaly, and an ALC in the normal range, pending bone marrow assessment.

Patients treated with ibrutinib commonly experience a redistributive lymphocytosis, with a transient increase in ALC. The increase in ALC following cirmtuzumab + ibrutinib treatment was markedly blunted and fell to below baseline more rapidly compared to historical data for treatment with ibrutinib alone.

Six patients with MCL have also been treated in a separate cohort of the phase I/II study. Data from this cohort will be presented at a future medical conference. One patient with MCL who had relapsed following an allogeneic stem cell transplant experienced a confirmed complete response after 3 months of cirmtuzumab + ibrutinib treatment, including complete resolution of a large mediastinal mass. This CR has been confirmed at 6 and 9 months of combination therapy.

The CIRLL Study (CIRM-0001) is a phase I/II clinical trial evaluating cirmtuzumab in combination with ibrutinib and is actively enrolling patients with CLL or MCL. Part 1 is a dose-finding portion designed to determine the recommended dosing regimen (RDR), Part 2 is an expansion cohort to confirm the RDR, and Part 3 will randomize patients with CLL to receive either ibrutinib alone or ibrutinib plus cirmtuzumab. The data presented at ASCO 2019 are the results of a planned, interim assessment of the CLL patients enrolled in Part 1. 

Monday, June 10, 2019

By Catlin Nalley

CHICAGO—At this time there is not a lot of current data on CAR T-cell therapies for chronic lymphocytic leukemia (CLL). "At some point, CLL can become more aggressive and resistant to even the new targeted therapies," study author Tanya Siddiqi, MD, said in a statement. "Therefore, novel therapeutics are needed, especially for patients with high-risk disease (having markers like deletion 17p, complex cytogenetics, unmutated IGVH) or those who have not responded to other therapies."

Siddiqi and her team assessed safety, pharmacokinetics, and efficacy of lisocabtagene maraleucel (liso-cel), an investigational, anti-CD19 CAR T-cell product administered as a defined composition of CD4+/CD8+ CAR T cells, in the ongoing phase I/II TRANSCEND CLL 004 study (Abstract 7501).

Safety & Efficacy

Eligible patients received ≥2 prior lines of therapy (including Bruton's tyrosine kinase inhibitors unless medically contraindicated), and had ECOG PS ≤1, according to researchers.

Primary objectives of the study included safety and determination of the recommended dose.

Patients received liso-cel infusion at either dose level (DL)1=50 × 106 or DL2=100 × 106 total CAR+ T cells.

In terms of safety, almost all patients had grade 3 or higher toxicities across the two dose levels and the majority of grade 3 or higher toxicities were cytopenias related to the chemotherapy, Siddiqi reported during her presentation. "There were two dose-limiting toxicities, both in DL2," she noted.

Best overall response rate was 81.8 percent with 45.5 percent complete remissions in the 22 evaluable patients with a median follow-up of 9 months.

The majority of responses (68%) and undetectable MRD (60%) were achieved by Day 30, Siddiqi reported. Additionally, 27 percent of patients showed deepening responses over time.

"Durable objective responses (67%) and undetectable MRD (64%) are maintained at 6 months post-dose," she outlined. "Eighty-three percent of patients with CR at 6 months remain in CR, including three patients who maintain CR beyond 12 months."

Ongoing Research

"Liso-cel demonstrated manageable toxicities and promising clinical activity in a heavily pretreated patient population with high-risk CLL, all of whom had received prior ibrutinib, with over half also having received prior venetoclax," Siddiqi summarized. "Clinical responses are rapid and they improve over time and are deep and durable."

"These findings justify the conduct of the phase II portion of the study, which is currently enrolling at dose level 2 (100x106 CAR+ T cells)," she concluded. "Additionally, there is a phase I portion of the study, which is also currently enrolling in a separate cohort of patients with lido-cel in combination with ibrutinib to see if responses can be improve even further."

Catlin Nalley is a contributing writer.


Monday, June 10, 2019

By Catlin Nalley

CHICAGO—In a phase Ib/II trial, researchers evaluated the activity and tolerability of acalabrutinib, a Bruton tyrosine kinase inhibitor, with the CD20 antibody obinutuzumab in treatment-naive (TN) and relapsed/refractory (R/R) chronic lymphocytic leukemia.

Jennifer Woyach, MD, first author of the study, presented 3-year follow-up results during the 2019 ASCO Annual Meeting (Abstract 7500).

The study enrolled 19 patients with TN CLL and 26 patients with R/R disease. "Acalabrutinib was initially administered at 200 mg daily in the first 15 patients, but after data from the phase I study showed higher BTK occupancy with twice-daily dosing, all patients were treated with 100 mg twice daily going forward," according to Woyach.

Obinutuzumab was started in cycle 2 and administered in standard fashion from cycles 2 to 7, she outlined during her presentation. The primary endpoints, included overall response rate (ORR) and safety. Key primary endpoints were duration of response, progression-free survival, overall survival, minimal residual disease status, and pharmacodynamics.

At a follow-up of about 3 years, 78 percent remain on therapy in remission, Woyach reported. Only two patients have discontinued treatment in the TN group compared to eight in the R/R cohort.

The ORR was 95 percent in the TN group and 92 percent among patients with R/R disease. "As is common with BTK inhibitors, responses have deepened over time," noted Woyach. "[A total of] 31.6 percent of patients TN group have achieved a CR and 7.7 percent in the R/R group.

"In this study, we only performed bone marrow biopsies to confirm CR in patients who had achieved a MRD-negative response in their peripheral blood. So we have potentially underestimated the rate of complete responses by calling some of those MRD-positive potential CRs partial responses."

This combination was generally well-tolerated. Common adverse events (AEs; any grade) included upper respiratory tract infection (71%), increased weight (71%), maculopapular rash (67%), cough (64%), diarrhea (62%), headache (56%), nausea (53%), arthralgia (51%), and dizziness (47%).

Common grade 3/4 AEs were decreased neutrophil count (24%), syncope (11%), decreased platelet count, increased weight, and cellulitis (9% each). There were two (4%) grade 3 bleeding events (hematuria, muscle hemorrhage) and one (2%) grade 3 atrial fibrillation event, according to study authors.

"Treatment with acalabrutinib plus obinutuzumab yielded high response rates that have been durable, irrespective of high-risk disease status," Woyach said. "The combination has been very well-tolerated and most patients have remained on treatment and in remission at 3.5 years.

"Two additional cohorts for this study, one in TN and one in R/R disease, have already been accrued and this includes acalabrutinib with a CD20 antibody with venetoclax. And this particular combination of acalabrutinib plus obinutuzumab is under evaluation as part of a phase III in TN CLL."

Catlin Nalley is a contributing writer.