Polatuzumab vedotin plus rituximab and lenalidomide in patients with relapsed or refractory diffuse large B-cell lymphoma: a cohort of a multicentre, single-arm, phase 1b/2 study.

BACKGROUND: Diffuse large B-cell lymphoma comprises nearly 30% of non-Hodgkin lymphoma cases and patients with relapsed or refractory diffuse large B-cell lymphoma who are ineligible for stem-cell transplantation have few treatment options and poor prognoses. We aimed to determine whether the novel combination of polatuzumab vedotin in combination with rituximab and lenalidomide (Pola+R+Len) would provide a tolerable treatment option with enhanced antitumour response in patients with relapsed or refractory diffuse large B-cell lymphoma. METHODS: This completed phase 1b/2, open-label, multicentre, single-arm study (GO29834) evaluated the safety and efficacy of Pola+R+Len in patients with relapsed or refractory diffuse large B-cell lymphoma at 19 sites in three countries (USA, Spain, and UK). Patients (≥18 years old) were eligible for inclusion if they had histologically documented CD20-positive relapsed or refractory diffuse large B-cell lymphoma and Eastern Cooperative Oncology Group performance status of 2 or lower, had received at least one previous line of chemoimmunotherapy, including an anti-CD20 agent, and were ineligible for stem-cell transplantation. The dose-escalation phase (1b) used escalating doses of lenalidomide to find the recommended phase 2 dose. Patients received six 28-day cycles of induction treatment with intravenous rituximab 375 mg/m2 and intravenous polatuzumab vedotin 1·8 mg/kg (all cohorts) plus oral lenalidomide at the following doses: 10 mg (cohort A); 15 mg (cohort B); and 20 mg (cohort C). Rituximab and polatuzumab vedotin were administered on day 1 and lenalidomide on days 1-21 of each 28-day cycle. During the dose-expansion phase (2), patients received six 28-day cycles of Pola+R+Len at the recommended phase 2 dose established during dose escalation. In both phases, patients with a complete response or partial response at the end of induction were eligible for post-induction therapy with rituximab 375 mg/m2 on day 1 and lenalidomide 10 mg/day on days 1-21 of each 28-day cycle for a maximum of 6 cycles. The primary safety objective of the dose-escalation phase was identification of the maximum tolerated dose through incidence of dose-limiting toxic effects. The primary efficacy outcome of the dose-expansion phase was Independent Review Committee-assessed complete response rate at end of induction, based on PET-CT. Analyses were conducted in the safety population, which included all patients who received at least one dose of any study drug, and the efficacy population, which included all patients who received at least one dose of any study drug at the recommended phase 2 dose. This study is registered with ClinicalTrials.gov, number NCT02600897. FINDINGS: Between July 11, 2017 and Feb 3, 2020, 57 patients were enrolled (median age 71 years [IQR 60-75]; 38 [67%] were male and 19 (33%) were female; 47 [82%] were not Hispanic or Latino; and the median previous lines of therapy was 2 [IQR 1-3]). 18 participants were included in phase 1b and 39 were included in phase 2. Phase 1b confirmed a 20 mg recommended phase 2 dose for lenalidomide. After a median follow-up of 11·8 months (IQR 4·7-25·8), the complete response rate, as assessed by the Independent Review Committee, was 31% (90% CI 20-43). The most common grade 3-4 adverse events were neutropenia (35 [61%] of 57) and thrombocytopenia (eight [14%] of 57). Serious adverse events were reported in 23 (40%) of 57 patients and one patient died due to a treatment-related adverse event (neutropenic sepsis). INTERPRETATION: Although the combination of Pola+R+Len did not meet the prespecified activity threshold, some patients derived clinical benefit and the regimen had a tolerable safety profile in patients with relapsed or refractory diffuse large B-cell lymphoma. FUNDING: Genentech/F Hoffmann-La Roche.

Surgical management of recurrent ovarian cancer: the advantage of collaborative surgical management and a multidisciplinary approach.

OBJECTIVE: Primary cytoreductive surgery is well accepted in the initial management of ovarian cancer with a goal of maximal tumor reduction. The role of cytoreductive surgery at disease recurrence is controversial and guidelines are not standardized. We aimed to review cases of women with recurrent ovarian cancer who were collaboratively managed by two teams of oncologic surgeons with different areas of surgical expertise. METHODS: A list of 616 patients with recurrent ovarian cancer from 1995 to 2009 was generated at a single institution. 20 cases of recurrent ovarian cancer were identified that were managed collaboratively. Data collected included date of diagnosis, initial treatment, recurrence date, location and number of sites of recurrence, secondary cytoreductive procedure performed, residual disease after surgery, pre-operative status, post-operative course, and pathologic findings. RESULTS: Of the 20 cases that fit eligibility criteria, 11 were completely resected, 5 were incompletely resected, and 4 were biopsied only. Median disease-free interval following primary surgery was 18 months (6-147). Median interval from diagnosis to collaborative cytoreduction was 63 months (13-170). Our patients had metastatic disease to the liver (11), lymph nodes (8), the diaphragm (7), other locations including colon, pancreas, lung, adrenal, kidney (9). Two patients had additional miliary disease. All patients underwent joint surgical management by gynecologic and surgical oncologists. There were no deaths in the immediate post-operative period. The 5 year survival rate was 45% following the joint surgical effort, with a median post-collaborative surgery survival duration of 42 months. CONCLUSIONS: Previous studies document survival benefit of surgery for women with recurrent ovarian cancer when there has been a long disease-free interval, localized pelvic or intra-abdominal recurrences and an optimal performance status. Most gynecologic oncologists do not perform extensive liver or diaphragm resections or lymph node excision above the renal vessels; thus, collaboration with a surgical oncologist is a viable option. In this small descriptive study, the feasibility of this reasonably well-tolerated approach, with possible survival benefit, is documented.