Faculty Bibliography

BACKGROUND:Targeted therapies and checkpoint blockade therapy (CBT) have shown efficacy for patients with Hodgkin lymphoma (HL) in the relapsed and refractory (R/R) setting, but once discontinued owing to progression or side effects, it is unclear how successful further therapies will be. Moreover, there are no data on optimal sequencing of these treatments with standard therapies and other novel agents. In a multicenter, retrospective analysis, we investigated whether exposure to CBT could sensitize HL to subsequent therapy. MATERIALS AND METHODS/METHODS:Seventeen centers across the U.S. and Canada retrospectively queried medical records for eligible patients. The primary aim was to evaluate the overall response rate (ORR) to post-CBT treatment using the Lugano criteria. Secondary aims included progression-free survival (PFS), duration of response, and overall survival (OS). RESULTS:Eighty-one patients were included. Seventy-two percent had stage III-IV disease, and the population was heavily pretreated with a median of four therapies before CBT. Most patients (65%) discontinued CBT owing to progression. The ORR to post-CBT therapy was 62%, with a median PFS of 6.3 months and median OS of 21 months. Post-CBT treatment regimens consisted of chemotherapy (44%), targeted agents (19%), immunotherapy (15%), transplant conditioning (14%), chemotherapy/targeted combination (7%), and clinical trials (1%). No significant difference in OS was found when stratified by post-CBT regimen. CONCLUSION/CONCLUSIONS:In a heavily pretreated R/R HL population, CBT may sensitize patients to subsequent treatment, even after progression on CBT. Post-CBT regimen category did not impact OS. This may be a novel treatment strategy, which warrants further investigation in prospective clinical trials. IMPLICATIONS FOR PRACTICE/CONCLUSIONS:Novel, life-prolonging treatment strategies in relapsed and refractory (R/R) Hodgkin lymphoma (HL) are greatly desired. The results of this multicenter analysis concur with a smaller, earlier report that checkpoint blockade therapy (CBT) use in R/R HL may sensitize patients to their subsequent treatment. This approach may potentially enhance therapeutic options or to bridge patients to transplant. Prospective data are warranted prior to practice implementation. As more work is done in this area, we may also be able to optimize sequencing of CBT and novel agents in the treatment paradigm to minimize treatment-related toxicity and thus improve patient quality of life.

Patients with relapsed/refractory (R/R) non-Hodgkin lymphoma (NHL) have limited options for salvage, and checkpoint blockade therapy (CBT) has little efficacy. Usage in solid malignancies suggests that CBT sensitises tumours to subsequent chemotherapy. We performed the first analysis of CBT on subsequent NHL treatment. Seventeen North American centres retrospectively queried records. The primary aim was to evaluate the overall response rate (ORR) to post-CBT treatment. Secondary aims included progression-free survival (PFS), duration of response (DOR) and overall survival (OS). Fifty-nine patients (68% aggressive NHL, 69% advanced disease) were included. Patients received a median of three therapies before CBT. Fifty-three (90%) discontinued CBT due to progression. Post-CBT regimens included chemotherapy (49%), targeted therapy (30%), clinical trial (17%), transplant conditioning (2%) and chimeric antigen receptor T cell (CAR-T) therapy (2%). The ORR to post-CBT treatment was 51%, with median PFS of 6·1 months. In patients with at least stable disease (SD) to post-CBT, the median DOR was significantly longer than to pre-CBT (310 vs. 79 days, P = 0·005) suggesting sensitisation. Nineteen patients were transplanted after post-CBT therapy. Median overall survival was not reached, nor affected by regimen. Prospective trials are warranted, as this may offer R/R NHL patients a novel therapeutic approach.

BACKGROUND:Recognising that the immune suppressive microenvironment promotes tumour growth in Hodgkin lymphoma, we hypothesised that activating immunity might augment the activity of targeted chemotherapy. We evaluated the safety and activity of combinations of brentuximab vedotin with nivolumab or ipilimumab, or both in patients with relapsed or refractory Hodgkin lymphoma. METHODS:In this multicentre, open-label, phase 1/2 trial, patients with relapsed or refractory Hodgkin lymphoma aged 18 years or older who had relapsed after at least one line of therapy, with an Eastern Cooperative Oncology Group performance status of 2 or lower, and adequate organ and marrow function, with no pulmonary dysfunction were eligible for inclusion. Phase 1 primary objectives were to determine the maximum tolerated dose and dose limiting toxicities of brentuximab vedotin combined with ipilimumab (ipilimumab group), nivolumab (nivolumab group), or both (triplet therapy group) using a 3 + 3 dose escalation design with expansion cohorts. During the dose escalation phase, patients were enrolled sequentially into one of six cohorts: in the ipilimumab group fixed brentuximab vedotin 1·8 mg/kg with ipilimumab 1 mg/kg (cohort A) or 3 mg/kg (cohort B); in the nivolumab group fixed nivolumab 3 mg/kg with brentuximab vedotin 1·2 mg/kg (cohort D) or 1·8 mg/kg (cohort E); and in the triplet therapy group fixed nivolumab 3 mg/kg and ipilimumab 1 mg/kg with brentuximab vedotin 1·2 mg/kg (cohort G) or 1·8 mg/kg (cohort H). Additional patients were enrolled in the expansion phase at the same doses of cohorts B, E, and H. All drugs were given intravenously; brentuximab vedotin and nivolumab were given every 3 weeks, ipilimumab was given every 6 weeks in the ipilimumab group and every 12 weeks in the triplet therapy group. All eligible and treated patients were included in the analysis. This phase 1/2 study is registered with ClinicalTrials.gov, NCT01896999. The phase 2, randomised portion of the trial is still enrolling. FINDINGS/RESULTS:Between March 7, 2014, and Dec 28, 2017, 64 patients were enrolled; two patients in the ipilimumab group and one patient in the nivolumab group were excluded due to ineligibility after enrolment and 61 were evaluable. A total of six dose limiting toxicities were reported in four patients, and the doses used in cohorts B, E, and H were established as maximum tolerated doses and patients were subsequently enrolled onto expansion cohorts (C, F, and I) with these schedules. There were ten (43%) grade 3-4 treatment related adverse events in the ipilimumab group, three (16%) in the nivolumab group, and 11 (50%) in the triplet therapy group including: eight (13%) of 64 patients reporting rash, and colitis, gastritis, pancreatitis and arthritis, and diabetic ketoacidosis each occurring in one (2%) patient. There were two (3%) treatment related deaths, one in the nivolumab group and one in the triplet therapy group. The overall response rate was 76% (95% CI 53-92) in the ipilimumab group, 89% (65-99) in the nivolumab group, and 82% (60-95) in the triplet therapy group, and the complete response rate was 57% (95% CI 34-78%) in the ipilimumab group, 61% (36-83%) in the nivolumab group, and 73% (50-89%) in the triplet therapy group. With a median follow-up of 2·6 years (IQR 1·8-2·9) in the ipilimumab group, 2·4 years (2·2-2·6) in the nivolumab group, and 1·7 years (1·6-1·9) in the triplet therapy group, median progression-free survival is 1·2 years (95% CI 1·7-not reached) in the ipilimumab group, but was not reached in the other two treatment groups. Median overall survival has not been reached in any of the groups. INTERPRETATION/CONCLUSIONS:There are clear differences in activity and toxicity of the three combination regimens. The tolerability and preliminary activity for the two most active regimens, brentuximab vedotin with nivolumab and the triplet therapy, are being compared in a randomised phase 2 trial (NCT01896999). FUNDING/BACKGROUND:Eastern Cooperative Oncology Group-American College of Radiology Imaging Network and the National Cancer Institute of the National Institutes of Health.

Atypical response patterns following immune checkpoint blockade (ICB) in Hodgkin lymphoma (HL) led to the concept of continuation of treatment beyond progression (TBP); however, the longitudinal benefit of this approach is unclear. We therefore performed a retrospective analysis of 64 patients treated with ICB - 20 who received TBP (TBP cohort) and 44 who stopped ICB at initial progression (non-TBP cohort). The TBP cohort received ICB for a median of 4.7 months after initial progression and delayed subsequent treatment by a median of 6.6 months. Despite receiving more prior lines of therapy, the TBP cohort achieved longer progression-free survival with post-ICB treatment (median 17.5m vs 6.1m, p=0.035) and longer time-to-subsequent treatment failure (TTSTF), defined as time from initial ICB progression to failure of subsequent treatment (median 34.6m vs 9.9m, p=0.003). With the limitations of a retrospective study, these results support the clinical benefit of TBP with ICB for selected patients.

PURPOSE OF REVIEW/OBJECTIVE:Antibody-drug conjugates are a new class of therapeutic agents in the treatment of B cell malignancies. In this review, we summarize the recent developments of polatuzumab vedotin in the treatment of relapsed or refractory diffuse large B cell lymphoma (DLBCL) and follicular lymphoma (FL). RECENT FINDINGS/RESULTS:Polatuzumab vedotin recently received its first FDA approval in combination with bendamustine and rituximab for the treatment of patients with relapsed or refractory DLBCL. Polatuzumab vedotin has been evaluated and is being studied in combinations with chemoimmunotherapy, immunomodulating agents, bispecific antibodies, and venetoclax. These studies have shown promising results in early phase trials. While further studies in a larger patient population are needed in order to determine an optimal combination regimen for polatuzumab vedotin, the ongoing trials represent a growing list of potential therapeutic options for the patients with relapsed or refractory NHL and newly diagnosed NHL alike.

In a Phase Ib/II trial of patients (pts) with relapsed/refractory follicular lymphoma (R/R FL), polatuzumab vedotin (Pola) + obinutuzumab (G) showed activity and tolerability (Phillips et al. Blood 2016). A Phase II study of the doublet combination of G + lenalidomide (Len) showed activity and acceptable safety in pts with R/R FL (Morschhauser et al. Lancet 2019). Here, we present the full primary analysis of efficacy and safety of Pola-G-Len in pts with R/R FL from the Phase Ib/II study, GO29834 (NCT02600897). GO29834 is an open-label, multicentre study of pts with R/R FL (Grade <3b) who had received >=1 prior anti-CD20-containing chemo-immunotherapy regimen. The recommended Phase II dose (RP2D) for Pola+Len was defined in a 3+3 dose-escalation phase. In the Phase II expansion cohort, pts received induction treatment with six 28-day cycles of: G 1000 mg IV (Cycle [C]1: Day [D]1, D8, D15; C2-6: D1); Pola 1.4 mg/kg IV (D1), Len 20 mg PO (D1-21). Responders received maintenance treatment for 24 months: G 1000 mg (D1 every 2 months); Len 10 mg (D1-21, Months 1-12). The primary endpoint was Independent Review Committee (IRC)-assessed complete response (CR) at end of induction (EOI), based on positron emission tomography-computed tomography (PET-CT) scans (modified Lugano 2014 criteria). Progression-free survival (PFS) was assessed by the investigator. As of 12 August 2019, 56 pts were enrolled and had entered induction (Phase Ib/II cohorts); median follow-up was 16.6 and 15.1 months in safety- and efficacy-evaluable populations, respectively. Baseline characteristics were: median age, 62 years; male, 59%; Ann Arbor Stage III-IV, 88%; Follicular Lymphoma International Prognostic Index high-risk (>=3), 55%; bulky disease (>=7 cm), 16%; >=2 prior lines of therapy, 77%; refractory to last line of prior therapy/ any anti-CD20 treatment, 59%/71%, respectively. All pts had >=1 adverse event (AE), 32 (57%) had a serious AE, 47 (84%) had a Grade 3-4 AE. The most common Grade 3-4 AEs were neutropenia (n = 31, 55%), thrombocytopenia (n = 15, 27%), infections (n = 11, 20%), and anaemia (n = 8, 14%). AEs led to dose reduction or interruption of any drug in 19 (34%) and 43 (77%) of pts, respectively; the majority were modifications of Len. AEs led to the discontinuation of any study drug in 17 (30%) pts. One Grade 5 AE was reported (septic shock); this was not considered study treatmentrelated as the pt was receiving a new anti-lymphoma treatment following disease progression (PD). In the primary efficacy population (n = 46), the IRC-assessed objective response rate was 76%, the CR rate was 63% (Table). Subgroup analysis showed that 60% (15/25) of pts who were refractory to their last treatment achieved a CR. Median PFS was not reached. Our study of the novel triplet combination, Pola-G-Len demonstrates a safety profile consistent with the known profiles of the individual drugs. CR rates at EOI were high in this heavily pre-treated and refractory population, which compares favourably with currently available R/R FL therapies. These findings support further investigation of Pola-G-Len in a larger pt population. Follow-up is ongoing to determine the median PFS

A MESSAGE FROM ASCO’S PRESIDENT/UNASSIGNED:report tells part of this story, sharing the most transformative research of the past year. The report also includes our latest thinking on the most urgent research priorities in oncology.ASCO's 2020 Advance of the Year-Refinement of Surgical Treatment of Cancer-highlights how progress drives more progress. Surgery has played a fundamental role in cancer treatment. It was the only treatment available for many cancers until the advent of radiation and chemotherapy. The explosion in systemic therapies since then has resulted in significant changes to when and how surgery is performed to treat cancer. In this report, we explore how treatment successes have led to less invasive approaches for advanced melanoma, reduced the need for surgery in renal cell carcinoma, and increased the number of patients with pancreatic cancer who can undergo surgery.Many research advances are made possible by federal funding. With the number of new US cancer cases set to rise by roughly a third over the next decade, continued investment in research at the national level is crucial to continuing critical progress in the prevention, screening, diagnosis, and treatment of cancer.While clinical research has translated to longer survival and better quality of life for many patients with cancer, we can't rest on our laurels. With ASCO's Research Priorities to Accelerate Progress Against Cancer, introduced last year and updated this year, we've identified the critical gaps in cancer prevention and care that we believe to be most pressing. These priorities are intended to guide the direction of research and speed progress.Of course, the effectiveness or number of new treatments is meaningless if patients don't have access to them. High-quality cancer care, including clinical trials, is out of reach for too many patients. Creating an infrastructure to support patients is a critical part of the equation, as is creating connections between clinical practices and research programs. We have much work to do before everyone with cancer has equal access to the best treatments and the opportunity to participate in research. I know that ASCO and the cancer community are up for this challenge.Sincerely,Howard A. "Skip" Burris III, MD, FACP, FASCOASCO President, 2019-2020.

PURPOSE OF REVIEW/OBJECTIVE:The landscape of relapsed or refractory (R/R) Hodgkin lymphoma (HL) treatment has changed significantly since the FDA approval of brentuximab vedotin in 2011. In this review, we summarize the recent advances in the therapy for R/R classical Hodgkin lymphoma (cHL). RECENT FINDINGS/RESULTS:Immunotherapies with pembrolizumab, nivolumab, and ipilimumab, and chimeric antigen receptor (CAR) T cell therapies have shown promising results in early phase trials. Other novel agents under investigation include targeted therapies with histone deacetylase inhibitors, Janus kinase 2 inhibitors, and immunomodulators. While further studies with larger populations and longer follow-up times are needed to determine the safe and effective combinations, these novel approaches represent a growing list of treatment options that are on the horizon to improve the cure rate and increase duration of remission for R/R HL patients.

BACKGROUND:Salvage immunochemotherapy followed by high-dose chemotherapy and autologous stem cell transplantation is the standard-of-care second-line treatment for patients with relapsed/refractory diffuse large B-cell lymphoma after first-line R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone). Outcomes after receipt of second-line immunochemotherapy in patients with aggressive B-cell lymphomas who relapse or are refractory to intensive first-line immunochemotherapy regimens (etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab [R-EPOCH], rituximab, hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone alternating with methotrexate and cytarabine [R-HyperCVAD], rituximab, cyclophosphamide, vincristine, doxorubicin, and high-dose methotrexate alternating with ifosfamide, etoposide, and cytarabine [R-CODOX-M/IVAC]) remain unknown. METHODS:Outcomes of patients with non-Burkitt, aggressive B-cell lymphomas and relapsed/refractory disease after first-line treatment with intensive immunochemotherapy regimens who received platinum-based second-line immunochemotherapy were reviewed retrospectively. Analyses were performed to determine progression-free survival (PFS) and overall survival (OS) from the time of receipt of second-line immunochemotherapy. RESULTS:In total, 195 patients from 19 academic centers were included in the study. The overall response rate to second-line immunochemotherapy was 44%, with a median PFS of 3 months and a median OS of 8 months. Patients with early treatment failure (primary refractory or relapse <12 months from completion of first-line therapy) experienced inferior median PFS (2.8 vs 23 months; P < .001) and OS (6 months vs not reached; P < .001) compared with patients with late treatment failure. Although the 17% of patients with early failure who achieved a complete response to second-line immunochemotherapy experienced prolonged survival, this outcome could not be predicted by clinicopathologic features at the start of second-line immunochemotherapy. CONCLUSIONS:Patients with early treatment failure after intensive first-line immunochemotherapy experience poor outcomes after receiving standard second-line immunochemotherapy. The use of standard-of-care or experimental therapies currently available in the third-line setting and beyond should be investigated in the second-line setting for these patients.