Targeted Oncology
Targeted Oncology
Targeted Oncology

TGR-1202 Combined With Ibrutinib Demonstrates High Response Rate in CLL/MCL

Silas Inman
Published Online:4:13 PM, Thu December 8, 2016

Matthew S. Davids, MD

Combining the PI3 kinase inhibitor TGR-1202 and ibrutinib (Imbruvica) for patients with relapsed/refractory chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL) demonstrated a high response rate without dose-limiting toxicities (DLTs), according to findings from a phase I/Ib study presented at the 2016 ASH Annual Meeting.

The objective response rate (ORR) with TGR-1202 and ibrutinib was 88% for those with CLL and 73% for patients with MCL. In a preliminary analysis, the 1-year progression-free survival (PFS) and the 1-year overall survival (OS) rates were 94% each for patients with CLL (n = 17). In those with MCL, the 1-year PFS rate was 37% and the 1-year OS was 52%.

"We report to our knowledge the first clinical data on a PI3 kinase plus BTK inhibitor doublet in B cell malignancies. The preliminary efficacy results certainly show a high response rate," said lead investigator Matthew S. Davids, MD, Department of Medical Oncology, Dana-Farber Cancer Institute. "This approach of dual targeting the B cell receptor pathway is potentially a feasible strategy."

TGR-1202 is a PI3K delta inhibitor with higher selectivity for the alpha isoform and lower selectivity for beta isoform compared with idelalisib (Zydelig). Studies assessing the drug to date suggest the agent has fewer PI3K-associated adverse events (AEs) compared with other agents in the class, Davids noted.

"The rates of autoimmune complications are significantly less than what has been observed with idelalisib and duvelisib. There were low cases of pneumonia and pneumonitis," he said. "Only 8% of patients have come off study due to adverse events in sample datasets."

In the phase I/Ib study, patients were enrolled simultaneously into the CLL (n = 18) and MCL cohorts (n = 13). In the CLL group, ibrutinib was administered at 420 mg daily and in the MCL arm the BTK inhibitor was given at 560 mg daily. The dose of TGR-1202 was escalated from 400 mg to 800 mg over the course of the study. There were no DLTs and the maximum tolerated dose was not reached.

Across all patients in the study (N = 31), the median age was 67 years and most were males (64.5%). The median number of prior therapies was 2 (range, 1-6; CLL median, 1.5; MCL median, 3). Thirteen percent of patients had received a prior autologous transplant, all in the MCL arm, and patients had received prior ibrutinib (13%; 2 in each arm) and a PI3K inhibitor (13%; all in the CLL arm). "Patients were not refractory to these therapies," Davids emphasized.

In the CLL group, 24% of patients had a 17p deletion and 41% had an 11q deletion. Thirty-five percent of patients had unmutated IGHV, and TP53 mutations were present for 17% of patients. Two patients had NOTCH mutations, although there was limited testing for this alteration. "This was a relatively high-risk patient population," said Davids.
 
Lymphocytosis, which is commonly seen with ibrutinib, occurred following treatment for patients with CLL but not for those with MCL. These events were transients and resolved more rapidly with the combination than is typically seen for ibrutinib monotherapy, Davids said. In most cases, lymphocytosis resolved by cycle 4 or 5, he added.

In the CLL arm, responses included 1 complete remission (CR; 6%) and 14 partial remissions (PRs) or PRs with lymphocytosis (82%). Three of the patients (75%) treated with a prior PI3K inhibitor responded, as did 1 of the ibrutinib pretreated patients (25%). There were 5 patients with a PR that had a >80% reduction in tumor size. These responses were nearing a radiographic CR, Davids noted.

"Some of the patients who started earlier in the study are now approaching radiographic CR, many have lymph nodes that are decreasing with each new response evaluation," he said.

In the MCL arm, all responses had PRs (73%) and an additional 2 patients had stable disease. Six patients in this group had died at the time of the follow-up, 5 from progressive disease and 1 due to toxicity from a subsequent therapy.

The most common hematologic toxicities with the combination were neutropenia, thrombocytopenia, and anemia. All-grade neutropenia was experienced by 38% of patients in each arm. Grade 3/4 neutropenia was seen in 17% of those with CLL and in 7.7% of those with MCL. All-grade thrombocytopenia occurred in 11% and 38% of patients with CLL (all grade 1) and MCL (7.7% grade 3), respectively. Fifteen percent of patients with CLL had anemia (all grade 1/2). In the MCL arm, 31% had anemia (7.7% grade 3).

Looking specifically at toxicities of special interest across all patients (N = 31), 35% experienced diarrhea, of which 29% was grade 1 and 6% was grade 2. No patients experienced inflammatory colitis, Davids noted. Transaminitis occurred in 23% of patients, all of which was grade 1 and did not require dose interruptions. Infections occurred for 23% of patients, 4 of which were grade 1/2, 2 were grade 3 (CNS aspergillus, C. diff), and 1 patient had grade 4 influenza.

One patient had grade 1 pneumonitis and grade 1 bleeding events occurred in 3 patients (9%) with CLL (epistaxis, hematuria, and vitreous hemorrhage). Two patients experienced atrial fibrillation, both of which were grade 3.

"The toxicities of TGR-1202 plus ibrutinib are manageable and comparable to the additive toxicity profiles of the two agents given individually," said Davids. "There were no dose limiting toxicities observed, and the recommended phase II dose is 800 mg daily."

While the CLL arm of the phase I/Ib arm is fully enrolled, the MCL cohort of the study continues to recruit participants (NCT02268851). Additionally, a phase II study is exploring the efficacy and safety of TGR-1202 with ibrutinib for patients with relapsed or refractory diffuse large B-cell lymphoma (NCT02874404).
 
 
Reference:
Davids MS, Kim HT, Nicotra A, et al. TGR-1202 in Combination with Ibrutinib in Patients with Relapsed or Refractory CLL or MCL:  Preliminary Results of a Multicenter Phase I/Ib Study. Presented at: 58th ASH Annual Meeting and Exposition; San Diego, California; December 2-6, 2016. Abstract 641.


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