IN COMBINATION WITH CHEMOTHERAPY OR TARGETS AGENTS
The GO29365 phase 1b/2 clinical trial combined pola with bendamustine plus either rituximab (pola-BR) or obinutuzumab (pola-BG) in patients with relapsed/refractory DLBCL (Table 1).14 Six patients were treated with pola-BR and 6 with pola-BG in the safety run-in phase followed by an expansion cohort of 21 patients treated with pola-BG and a cohort of 80 patients randomized to treatment with BR alone or pola-BR. Notable inclusion criteria were ECOG PS 0–2, receipt of at least 1 prior therapy, baseline PN ≤ grade 1, and ineligibility for SCT (prior autologous SCT was allowed). Patients with transformed FL were excluded. Treatment consisted of six 21-day cycles of bendamustine (90 mg/m2) on days 2+3 of cycle 1 and days 1+2 of subsequent cycles; rituximab on day 1 or obinutuzumab on days 1, 8, and 15 of cycle 1 and day 1 of subsequent cycles; and pola 1.8 mg/kg on day 2 of cycle 1 and day 1 of subsequent cycles. Focusing on the 80 patients randomized to BR or pola-BR, median age was 71 years (range, 30–84) for the BR cohort and 67 years (range, 33–86) for the pola-BR cohort. Most patients had ECOG PS of 0–1 (83% pola-BR and 78% BR). The median number of prior treatments was 2, with most patients being refractory to last therapy (85% BR, 75% pola-BR). Patients were ineligible for autologous SCT most commonly due to age (48% BR, 33% pola-BR) and insufficient response to salvage therapy (30% pola-BR and 23% BR); 15% of the BR cohort and 25% of the pola-BR cohort experienced treatment failure with prior autologous SCT. Patients with double- and triple-hit lymphomas were allowed but none were included. Compared with BR, pola-BR resulted in higher end-of-treatment (EOT) ORR (45% vs 18%) and CR rate (the primary endpoint: 40% vs 18%) as well as higher best response (63% vs 25%) and best CR rates (50% vs 23%), as reviewed by an independent review committee (IRC). Although the clinical trial was not powered to detect a survival benefit, the pola-BR arm had significantly better IRC-assessed PFS (median of 10 vs 4 months; hazard ration (HR) 0.36, 95% confidence interval (CI) 0.21–0.63) and OS (median of 12 vs 5 months; HR 0.42, 95% CI 0.24–0.75). The median DOR was longer with pola-BR (13 vs 8 months) but the difference was not statistically significant. Seven patients treated with pola-BR (18%) had ongoing responses for more than 20 months, including one patient who underwent allogeneic SCT. Bearing in mind the relatively small sample size, pola-BR demonstrated an OS benefit regardless of age (<65 vs ≥65 years), refractoriness to last therapy, number of prior lines of therapy (1 vs ≥2), prior autologous SCT, or DLBCL subtype based on COO by GEP (GCB vs ABC) or MYC/BCL2 double-expression status (available for n=62, present in n=17). Only 46% of patients in the pola-BR cohort and 23% in the BR cohort completed 6 cycles of treatment, with the primary reason for treatment discontinuation being AEs in the pola-BR cohort (33% vs 10% with BR), and disease progression in the BR cohort (54% vs 15% with pola-BR). Grade 3–4 anemia, thrombocytopenia, and neutropenia were more common with pola-BR (28%, 41%, and 46% vs 18%, 23%, and 33%, respectively), but the rate of neutropenic fever was similar in the two cohorts (10% pola-BR, 13% BR). Most patients received at least one dose of granulocyte colony-stimulating factor (G-CSF) (72% pola-BR, 62% BR). Four patients in each arm died of infection. Diarrhea of all grades was more common with pola-BR (39% vs 28%, grade 3–4 of 3% in each). PN occurred in 44% of patients treated with pola-BR (28% grade 1, 15% grade 2) and resolved in 59% of the cases. The baseline characteristics of the 27 patients treated with pola-BG were similar to those treated with pola-BR. Pola-BG was not superior to pola-BR, with EOT ORR of 41% include CR rate of 30%, best ORR of 48%, and best CR rate of 37%, while the median PFS and OS were 6 and 11 months, respectively.14 Based on these results, in June 2019, the FDA granted accelerated approval to pola (1.8 mg/kg) in combination with BR every 3 weeks for 6 cycles in patients with relapsed/refractory DLBCL after at least two prior therapies.
In addition to DLBCL, the GO29365 clinical trial included a randomly assigned cohort of 80 patients with relapsed/refractory FL treated with pola-BR or BR alone, with interim data presented at the American Society of Clinical Oncology 2018 Annual Meeting (data cut-off October 2017) (Table 1).15 Pola-BR and BR were given at the same dose and schedule as in the DLBCL cohort but treatment cycles were 28 days in duration. The median age was 63 years (range, 39–80) for the BR cohort and 65 years (range, 43–74) for the pola-BR cohort. Most patients had ECOG PS of 0–1 (88% BR, 92% pola-BR) and non-bulky disease (88% BR, 85% pola-BR). The median number of prior therapies was 2 (range, 1–5) for each cohort, with disease refractory to last treatment in 42% of the BR cohort and 41% of the pola-BR cohort, and disease progression within 24 months of initial diagnosis (POD24) in 24% of the BR cohort and 31% the pola-BR cohort. The EOT ORR and CR rates were similar between the two cohorts (77% and 69% with pola-BR and 73% and 63% with BR, respectively). With the limited follow-up duration of 15 months, the median PFS and OS were also similar (17 months and not reached for each cohort, respectively).15
Several clinical trials have established lenalidomide plus rituximab as an effective “non-chemotherapy” treatment option for patients with FL, both in the frontline and relapsed/refractory settings.16,17 Emerging data from phase 1/2 clinical trials also show promising results with the combination of lenalidomide plus obinutuzumab.18–20 Building on these data, the phase 1b/2 GO29834 clinical trial combined pola with obinutuzumab and lenalidomide (pola-G-len) in patients with relapsed/refractory FL (Table 1). Interim results were presented at the American Society of Hematology 2019 annual meeting (data cut-off August 2019).21 Patients in the dose-expansion cohort received induction treatment with six 28-day cycles of pola 1.4 mg/kg on day 1, lenalidomide 20 mg daily on days 1–21, and obinutuzumab 1000 mg on days 1, 8, and 15 of cycle 1 and day 1 of subsequent cycles. In responding patients, a maintenance phase followed with lenalidomide 10 mg daily on days 1–21 of each 28-day cycle for 12 months and obinutuzumab every 2 months for 24 months. For the 56 safety-evaluable patients, median age was 62 years (range, 32–87), 98% had ECOG PS 0–1, 16% had bulky disease, 55% had Follicular Lymphoma International Prognostic Index (FLIPI) ≥3, median number of prior treatments was 3 (range, 1–7) with 59% refractory to last treatment, and 25% had POD24. The most common grade 3–4 AEs were neutropenia (50%), thrombocytopenia (23%), infections (16%), and anemia (14%). G-CSF was used in 55% of the patients during induction and 36% during maintenance. PN occurred in 30% of the patients. AEs leading to any dose reductions or drug discontinuations occurred in 34% and 30%, respectively. For the 46 efficacy-evaluable patients, the EOT ORR was 76% with 63% attaining CR. The ORR/CR rate with pola-G-len were particularly remarkable in high-risk patients: 70%/70% in high-risk FLIPI (n=26), 55%/45% in patients with POD24 (n=11), 68%/60% in patients refractory to last treatment (n=25), and 75%/71% in patients with ≥3 prior therapies (n=24). With a median follow up of 15 months, the 12-month PFS was 83%. These results are certainly encouraging but longer follow-up and validation in other studies are required.
In the frontline setting, pola was evaluated in combination with cyclophosphamide, doxorubicin, and prednisone plus either rituximab or obinutuzumab (R-CHP or G-CHP) in a phase 1b/2 clinical trial (Table 1).22 The dose-escalation portion included any type of B-cell NHL whereas the dose-expansion portion was limited to patients with previously untreated DLBCL. Pola was administered on day 2 of the first two cycles, and on day 1 of subsequent cycles along with standard-dose CHP plus rituximab or obinutuzumab every 3 weeks for 6 or 8 cycles (per investigator discretion). The RP2D of pola was 1.8 mg/kg. For the 66 patients with previously untreated DLBCL who received the RP2D (45 patients with R-CHP and 21 with G-CHP), median age was 68 years (70% >65 years), ECOG PS was 2 in 29%, and 65% had International Prognostic Index (IPI) of 3–5. The most common grade ≥3 AEs at the RP2D were neutropenia (30%), neutropenic fever (18%), and thrombocytopenia (9%). PN occurred in 41% of the patients treated at the RP2D and was grade 1 in 27%, grade 2 in 11%, and grade 3 in 3%. As expected, PN grade 2 or 3 was more common in patients who received >6 cycles (19% and 5%, respectively) compared with those who received 6 cycles (6% and 3%, respectively). PN resolved in the majority of patients (74%) in a median of 2 months for grade 1 and a median of 5 months for grade 2–3. Of the 7 patients with persistent PN, one had grade 2 and the rest had grade 1. Seven patients (11%) discontinued treatment (received <6 cycles) due to an AE (4 patients with G-CHP and 3 with R-CHP). Doxorubicin and cyclophosphamide dose reductions were uncommon (5% and 2%, respectively). Two treatment-related deaths were reported (one complication of atrial fibrillation and one septic shock). The ORR for patients treated at the RP2D was 89% including 77% attaining CR, with PFS at 24 months of 83%. No significant differences in response rates and 12-month PFS were seen between the R-CHP and G-CHP cohorts. PFS was similar regardless of COO by GEP (available for n=51: 16 ABC, 28 GCB, 7 unclassifiable) and MYC/BCL2 double-expression status (available for 41 patients, present in 13 patients). Bearing in mind the small number of patients treated on this trial and the limitations of cross-trial comparisons, these results compared favorably with those of the GOYA trial, which randomized patients with previously untreated DLBCL to 6 or 8 cycles of cyclophosphamide, doxorubicin, vincristine, and prednisone plus either rituximab or obinutuzumab (R-CHOP or G-CHOP).23 Overall, patients treated on GOYA had a more favorable risk-profile as they were younger (median age of 62 vs 68 years), had better ECOG PS (2–3 in 12–14% vs 2 in 29%), and had lower risk disease by IPI (3–5 in 43–47% vs 65%). Pola plus R-CHP/G-CHP resulted in higher CR rate and 1-year PFS compared with R-CHOP/G-CHOP: 77% vs 58% and 91% vs 81%, respectively. In terms of AEs, treatment with pola plus R-CHP/G-CHP resulted in higher rates of grade 3–5 thrombocytopenia (9% vs 1–4%) and all grade PN (41% vs 13%) without an increased risk of grade 3–5 neutropenia (30% vs 46–55%), neutropenic fever (18% vs 15–18%) or infections (15% vs 16–19%). Although these results are encouraging, they require confirmation in a randomized clinical trial. This is the aim of the recently concluded POLARIX trial, which randomized 875 patients with previously untreated DLBCL to pola plus R-CHP vs R-CHOP (Table 2). The results of POLARIX are eagerly awaited.
None of the previously mentioned clinical trials were able to establish predictive or prognostic biomarkers for response to treatment with pola. CD79b expression by IHC was present in virtually all cases of DLBCL and FL, and even in the very few cases with negative expression by IHC (4% in one study),14 CD79b RNA expression was present.13,14,22 CD79b expression levels in patients with DLBCL or FL did not correlate with response to treatment with pola alone or when combined with chemoimmunotherapy.13,14,22 Response to treatment with pola was similar across DLBCL subtypes regardless of COO13,14 or MYC/BCL2 double-expression status,14,22 albeit the relatively small number of patients in each trial limits any firm conclusions.
CLINICAL PRACTICE POINTS
The FDA-approved dose of pola is 1.8 mg/kg administered in combination with BR every 3 weeks for 6 cycles. Pola is administered intravenously over 90 minutes with premedication with an antipyretic and an antihistamine. Subsequent doses may be administered over 30 minutes if prior infusions were tolerated.24 Infusion reactions were reported in 7% of patients treated with pola-BR/pola-BG (despite premedications) with one-third of the cases being grade 2 (25%) or 3 (8%).
As discussed previously, myelosuppression is common with pola especially when combined with chemotherapy or other myelosuppressive agents. Grade 3–4 neutropenia occurred in 46% of patients with DLBCL treated with pola-BR. Prophylaxis with G-CSF was optional on the GO29365 clinical trial but 42% of patients treated with pola-BR received primary G-CSF prophylaxis. When pola is given with BR, prophylaxis for Pneumocystis jiroveci pneumonia and herpesvirus is recommended.
Similar to other MMAE-containing ADCs (such as brentuximab), PN is common with pola and is dose- and duration-dependent. Importantly, PN is common in patients with DLBCL treated with vinca alkaloids and/or platinum agents, and patients with baseline PN of grade ≥2 were excluded from the previously described trials of pola. When dosed at 1.8 mg/kg, pola-induced PN occurred in 40–45% of the patients with the majority reported being grade 1 (27–28%) whereas grade 2 and 3 occurred in 11–15% and 0–3%, respectively. PN resolved in 59–75% of the patients with a median time to resolution of 2 months for grade 1 and 5 months for grades 2–3. For patients with pola-induced grade ≥2 PN, holding treatment with pola is recommended until PN improves to grade ≤1. Pola may be resumed with the next cycle at a permanently reduced dose of 1.4 mg/kg if the PN resolves to grade ≤1 by 2 weeks. Treatment with pola should be discontinued if the PN does not resolve to grade ≤1 by 2 weeks, PN grade ≥2 recurs despite dose reduction, or the PN is grade 4.24
Grade 3 and 4 transaminase elevations were each reported in 1.9% of the patients treated with pola on the GO29365 clinical trial. Based on the US Prescribing Information, pola use should be avoided in patients with moderate to severe hepatic impairment (total bilirubin > 1.5 upper limit of normal [ULN]) because hepatic impairment could increase the exposure to MMAE. No dose adjustment is required in patients with mild hepatic impairment (total bilirubin >1–1.5 times ULN).24 The effect of severe renal impairment (CrCl <30 mL/minute) or end-stage renal disease on the pharmacokinetics of pola is unknown, whereas no clinically significant pharmacokinetic differences were observed based in mild to moderate renal impairment (CrCl 30–89 mL/minute).
Anti-pola antibodies were detected in 2.6% of pola-treated patients,24 including antibodies against both the antibody and the linker-MMAE components of pola.12 The significance of these anti-pola antibodies on pola’s safety or efficacy is unclear at this point.24
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