The 1.8-mg/kg dose of polatuzumab vedotin is as effective as the 2.4-mg/kg dose on the endpoint of progression-free survival in patients with relapsed/refractory non-Hodgkin lymphoma while improving tolerability, according to a pooled analysis of phase I and phase II clinical studies.
Ranjana H. Advani, MD
The 1.8-mg/kg dose of polatuzumab vedotin is as effective as the 2.4-mg/kg dose on the endpoint of progression-free survival (PFS) in patients with relapsed/refractory non-Hodgkin lymphoma (NHL) while improving tolerability, according to a pooled analysis of phase I and phase II clinical studies.
“Polatuzumab may represent a clinically meaningful treatment option for patients with NHL at the 1.8-mg/kg dose with a fixed duration of therapy,” said the study’s lead investigator, Ranjana H. Advani, MD, at the 2015 ASCO Annual Meeting.
Clinical activity of polatuzumab was observed in relapsed/refractory NHL at doses >1.8 mg/kg administered every 3 weeks in a phase I trial. Subsequently, two dose levels1.8 mg/kg and 2.4 mg/kg—were assessed in a phase II trial known as ROMULUS in patients with relapsed/refractory follicular lymphoma.
In the current study, data were pooled from two trials, the phase I trial in which polatuzumab was administered at 2.4 mg/kg with rituximab at standard doses, and the phase II ROMULUS trial. In ROMULUS, 2.4 mg/kg of polatuzumab was administered with rituximab, but the study was subsequently amended to evaluate a lower dose (1.8 mg/kg). Rituximab was given at 375 mg/m2every 21 days until progression or unacceptable toxicity. Treatment-emergent adverse events were graded according to the NCI CTCAE version 4.0. Antitumor activity was evaluated per revised IWG criteria every 3 months; PET scans were performed at the discretion of the investigator. The study evaluated 20 patients treated with 1.8 mg/kg and 25 patients treated with 2.4 mg/kg.
Almost all of the patients in the study received prior rituximab. About one third were rituxumab refractory within 6 months of a rituximab-based regimen.
The median number of treatment cycles was 13.5 in the 1.8-mg/kg dose group and 10.0 in the 2.4-mg/kg dose group. The median duration of treatment was longer in the lower dose group (9.4 months vs 7.6 months). The median duration of follow-up was shorter in the lower dose group because of the ROMULUS study amendment (13.1 months vs. 17.7 months).
Dose reductions were not permitted at the 1.8 mg/kg dose level because 1.8 mg/kg was the dose below which no efficacy was observed in the phase I trial, said Advani, medical oncologist at Stanford Cancer Center, Palo Alto, California. About half (52%) needed dose reduction in the 2.4-mg/kg group.
Less Toxicity at 1.8 mg/kg
Neutropenia occurred at both dose levels and was observed through cycle 8 or through the end of completion. The rate of grade ≥3 neutropenia was similar across the cohorts and did not lead to treatment discontinuation.
“Neuropathy is a side effect of the class of MME drugs, which is a tubulin toxin, but most of the events were grade 1 or 2,” she said. There was one case of grade 3 peripheral neuropathy in each group through the end of treatment. Eighty percent in the lower group and 88% in higher dose group had peripheral neuropathy events. The time to developing grade ≥2 peripheral neuropathy was 6.7 months at the lower dose level and 5.5 months at the higher dose level.
The time to onset of any serious adverse event was 2.4 months at 1.8 mg/kg and 2.1 months at 2.4 mg/kg. The time to grade ≥3 neutropenia was 0.72 months versus 0.53 months, the time to grade ≥2 peripheral neuropathy was 6.7 months versus 5.5 months, and the time to adverse events leading to study drug discontinuation was 5.4 months versus 6.2 months, respectively. Peripheral neuropathy was the main adverse event leading to study drug discontinuation.
“The median times to adverse events leading to grade ≥2 peripheral neuropathy and study drug discontinuation suggest that capping the treatment at 8 cycles, which is approximately 5.5 months, may mitigate some of these treatment-emergent toxicities,” said Advani.
There were fewer grade ≥2 peripheral neuropathy events through cycle 8 compared with end of treatment, and there was fewer grade ≥2 peripheral neuropathy events at the 1.8-mg/kg dose compared with the 2.4-mg/kg dose. Overall, there were fewer adverse events leading to discontinuation through cycle 8 compared with the end of treatment.
Activity at Both Dose Levels
Higher response rates were observed with the higher polatuzumab dose level and with longer treatment duration. Through cycle 8, overall response (OR) rates were 40% and 60% in the lower and higher dose groups, respectively; and through end of treatment, the OR rates were 70% and 76%, respectively. “Efficacy is seen at both dose levels, with a similar objective response rate, similar median time to onset of first response and best response, and a similar PFS [progression-free survival] and duration of response, despite the higher number of complete remissions observed at the higher dose,” said Advani.
The median time to first response (2.8 months at 1.8 mg/kg vs 2.8 months at 2.3 mg/kg) and the median time to best response (5.4 months vs 5.3 months) were similar at the two dose levels. The median duration of response has not been reached at the 1.8 mg/kg dose and is 10 months in the 2.4 mg/kg dose.
PFS was identical between the study doses. The 12-month estimated PFS is 61.1% at the 1.8 mg/kg dose and 66.8% at the 2.4 mg/kg dose.
Advani RH, Flinn I, Sharman J, et al. Two doses of polatuzumab vedotin (PoV, anti-CD79b antibody-drug conjugate) in patients (pts) with relapsed/refractory (RR) follicular lymphoma (FL): Durable responses at lower dose level.J Clin Oncol