Pola-G-Len Regimen Shows Promise as an Alternative to CAR T Cells in Refractory FL

The combination of obinutuzumab with polatuzumab vedotin, or lenalidomide may be a solution for the toxicity sometimes observed with chimeric antigen receptor T cells in patients with follicular lymphoma.

The combination of obinutuzumab (Gazyva) with polatuzumab vedotin (Polivy) or lenalidomide (Revlimid; Pola-G-Len) achieved high responses in patients with heavily pretreated refractory follicular lymphoma (FL) in a phase 1b/2 clinical trial.

“Our findings demonstrated that the regimen of Pola-G-Len was safe and had a high level of activity in relapsed FL patients, including patients who were multiply relapsed or had high-risk features such as disease progression within 24 months or primary refractory disease with an objective response rate of 76% and a complete response rate of 63%. Our 24 months PFS was 67% and is similar to what has been reported in the Augment study, with a more heavily pretreated and unfavorable population,” lead author Catherine Diefenbach, MD, director of hematology translational research and director of the Clinical Lymphoma Program at NYU Langone Health Perlmutter Cancer Center told Targeted Oncology™ in an interview.

Although the ORR met the prespecified threshold, statistical significance was not reached. The study investigators noted that the results were favorable in comparison with available therapies for FL.

Polatuzumab vedotin, an antibody-drug conjugate, is being investigated in FL as a potential alternative to chimeric antigen receptor (CAR) T-cell therapy. The CAR T agent axicabtagene ciloleucel (Yescarta) was granted approval by the FDA in 2021 for the treatment of relapsed or refractory (r/r) FL after the agent achieved an estimated 12-month progression-free survival (PFS) rate of 74% (95% CI, 63-82) in the phase 2 ZUMA-5 trial (NCT03105336). The toxicities from CAR T cells can be substantial, and therefore, alternatives are needed.

With single-agent polatuzumab vedotin, activity has been demonstrated in FL, and the activity of the agent was improved with the addition of rituximab (Rituxan) and lenalidomide, an FDA approved therapy for r/r FL, as well as with obinutuzumab.

The ongoing phase 1b/2 study (NCT02600897) follows a multicenter, single-arm design, and the study aims to investigate the safety, activity, and pharmacokinetics of Pola-G-Len in patients with r/r FL. The study is also investigating the polutuzumab in combination with rituximab and lenalidomide in a subgroup population of patients with r/r diffuse large B-cell lymphoma (DLBCL), an analysis for which results will be separately reported. The study is being conducted at 18 cancer centers in the United States, the United Kingdom, and Spain.

A total of 22 patients were included for enrollment assessment in phase 1b. These patients were eligible to enroll if they were aged 18 years or older. Had an ECOG performance status of 0, 1, o 2, has histologically documented CD20-positive B0-cell lymphoma as determined by the local laboratory, had fluorodeoxyglucose-avid lymphoma, showed at least 1 bi-dimensionally measurable lesion, and agreed to use contraception during the study. A total of 6 patients were excluded from the study due to either laboratory abnormalities, positive Hepatitis test, history of transformation of indolent disease to DLBCL, and have not received prior chemoimmunotherapy.

Six patients were eligible for the study and entered the induction setting. The patients were then divided into 6 disease cohorts. There were 2 cohorts of patients with r/r FL. In the first cohort, patients receive 6 months of induction at escalating doses to identify the recommended phase 2 dose for polatuzumab vedotin and lenalidomide when combined with a fixed dose of obinutuzumab.

Polatuzumab vedotin is administered via intravenous (IV) infusion at 1.4 or 1.8 mg/kg on day 1 of each 28-day cycle. Lenalidomide is given as oral capsules at doses of 10, 15, or 20 mg on days 1–21 of each 28-day cycle. Finally, a fixed dose of obinutuzumab 1000 mg is administered via IV infusion on day 1 of every month for up to 24 months until disease progression or unacceptable toxicity. 

Post induction, patients with FL are entered into a maintenance cohort in which they are given oral lenalidomide at 10, 15, or 20 mg on days 1–21 of each 28-day cycle for up to 6 cycles in the dose-escalation phase followed by 10 mg once daily on days 1–21 of each subsequent 28-day cycle. The treatment will continue for up to 12 months or until disease progression or unacceptable toxicity. Obinutuzumab 100 mg via IV infusion is administered on days 1, 8, and 15 of cycle 1 and day 1 of cycle 2–6 followed by day 1 every other month for up to 2 years or until disease progression or unacceptable toxicity.

The coprimary end points for the study included the percentage of patients with a complete response (CR) per independent review committee (IRC), the percentage of patients with adverse events (AEs), and the percentage of patients with dose-limiting toxicities (DLTs).

In phase 2, 54 patients were included for enrollment assessment of which 14 were excluded due to laboratory abnormalities, confirmatory biopsies, positive Hepatitis tests, or other reasons. A total of 40 patients were eligible to enter the induction phase at the RP2D. Of those who received induction therapy, 29 completed all 6 cycles and entered the maintenance phase. At the time of data cutoff, 6 patients remained on maintenance therapy and 34 entered follow-up.

In the efficacy-evaluable population (n = 46), the median age was 62 years (range, 52-69), with most patients being male (65%) and self-identified as not Hispanic or Latino (87%). The baseline ECOG performance status was 0 or 1 in 98% of patients, and the Ann Arbor stage was III or IV for 87% of patients. Fifteen percent of the efficacy-evaluable population had bulky disease; the majority (57%) had a FLIPI score of 3 to 5. The median number of prior treatment lines in the group was 3 (range 2-4) with 53% having received 3 or more prior treatments. Previous hematopoietic stem-cell transplantation (HSCT) was received by 26% of the population, 54% of the patients were refractory to the most recent therapy, and 70% were refectory to any line of anti-CD20 therapy. Twenty-six percent of efficacy-evaluable patients showed POD24 on frontline therapy.

Per IRC assessment per modified Lugano guidelines 2015, the objective response rate (ORR) was 76% (90% CI, 64-86). Responses included CRs in 63% of patients. The remaining patients had either a partial response (13%), stable disease (9%), or disease progression (2%). Efficacy data were missing for 13% of the population.

The median progression-free survival was not estimable for those assessed because it had not yet been reached (95 CI, NE-NE). However, at 12 months the PFS rate was 86% (95% CI, 75-96) and at 24 months the PFS rate was 67% (95% CI, 51-83).

In the safety-evaluable population (n = 56), the median age was 62 years (range, 53-69), and the group was 59% male. Not patients identified as not Hispanic or Latino. The ECOG performance status at baseline was 0 or 1 in 98% of patients. Baseline information also showed that 88% of patients in the safety population had Ann Arbor stage III or IV disease, 16% had bulky disease, most patients did not have bone marrow infiltration, and 55% had a FLIPI score of 3-5.

The majority of patients in the safety group (52%) had a median of 3 or more prior lines of therapy. Notably, therapy consisted of HSCT for 29% of patients, 59% were refractory to their most recent prior treatment, 71% were refractory to any line of anti CD20 therapy, and 27% has disease progression within 24 months (POD24) om frontline therapy.

During phase 1b, only 2 DLTs were observed and the RP2D was determined to be polatuzumab vedotin 1.4 mg/kg with lenlidomide 20 mg.

The most common grade 3 and 4 AEs observed during the study were neutropenia in 55% of patients and thrombocytopenia in 25%. A total of 61 serious AEs occurred in 63% of patients. The most common serious AE was febrile neutropenia (9%). One patient died as a result of a fatal AE of grade 5 septic shock, but the death was not related to study treatment according to the investigator assessment.

"The safety signals seen with this combination were in line with the toxicities reported with the single agents of these drugs and there were no new safety signals that were reported. The most common toxicities were myelosuppression (neutropenia and thrombocytopenia) both were managed with supportive care and dose reductions or dose interruptions as needed. There was no excess signal of peripheral neuropathy beyond that which is seen with single-agent polatuzumab,” Diefenbach stated.

Based on these phase 1b/2 findings, Diefenbach et al suggest that the Pola-G-Len regimen be investigated in a larger population of patients. 

“I believe this is a well-tolerated highly active regimen, that should have a place in the management of relapsed FL. How this integrates with other exciting therapies that are in development, such as the bispecifics like mosunutuzumab which has accelerated approval in FL, is uncertain. A randomized trial could compare: Pola-G-Len to G-Len or substitute R for G and compare R-Pola-Len to R2. This would be a straightforward trial to design, Diefenbach told Targeted Oncology™.

Diefenbach also noted that the combination of lenalidomide and rituximab would be the best direct comparator to Pola-G-Len in a larger study.

References:

Polatuzumab vedotin plus obinutuzumab and lenalidomide in patients with relapsed or refractory follicular lymphoma: a cohort of a multicentre, single-arm, phase 1b/2 study. Lancet Haematol. 2021; 8(12): 891-901. doi: 10.1016/S2352-3026(21)00311-2