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Update on Newer Treatments in Non-Hodgkin Lymphomas


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Syed Ali Abutalib, MD

Syed Ali Abutalib, MD

Matthew Lunning, DO

Matthew Lunning, DO

AS PART of The ASCO Post’s continued coverage of the 2018 American Society of Hematology (ASH) Annual Meeting & Exposition, here is an update on several different studies on new therapeutics in non-Hodgkin lymphomas (NHLs), including follicular lymphoma, diffuse large B-cell lymphoma (DLBCL), primary mediastinal B-cell lymphoma, and CD30-positive peripheral T-cell lymphoma.

Follicular Lymphoma

ABSTRACT 445: Lenalidomide plus rituximab (R2; n = 178) vs rituximab/placebo (n = 180) in relapsed or refractory indolent NHL1

Methods: AUGMENT (ClinicalTrials.gov identifier NCT01938001) is a multicenter, double-blind, randomized phase III study of R2 vs rituximab/placebo in patients with grade 1 to 3a follicular lymphoma (82%) or marginal zone lymphoma (18%). The study population included patients who were previously treated with at least one prior systemic therapy with documented relapsed or refractory disease, but who were not refractory to rituximab (refractory was defined as a less than partial response to rituximab or rituximab/chemotherapy or disease progression less than 6 months after the last rituximab dose).

“[Lenalidomide plus rituximab] represents an important new treatment option in patients with previously treated follicular and marginal zone lymphomas who are not refractory to rituximab, with meaningful advantages over single-agent rituximab.”
— Syed Ali Abutalib, MD, and Matthew Lunning, DO

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Key Findings: In this phase III randomized study, at a median follow-up of 28.3 months, the study met its primary endpoint of progression-free survival, with a hazard ratio of 0.46 (95% CI = 0.34–0.62; P < .0001). The median progression-free survival was 39.4 months with R2 vs 14.1 months without. The overall response rate with R2 was 78% vs 53% with the control (P < .0001). The complete response rate was 34% with R2 vs 18% with the control (P = .001). The median duration of response was 36.6 and 21.7 months for the R2 and control arms, respectively. The time to the next antilymphoma treatment was improved with R2, with a hazard ratio of 0.54 (95% CI = 0.38–0.78; P = .0007). Overall survival data were not mature, with 16 deaths reported in the R2 arm vs 26 deaths in the control arm (HR = 0.61 [95% CI = 0.33–1.13]).

Grade 3 to 4 adverse events were reported in 69% of patients treated with R2 and 32% of the control patients. Of those treated with R2, 71% completed all 12 cycles of planned treatment vs 61% of the control patients. Disease progression was the leading reason for discontinuation of rituximab/placebo.

Clinical Implications: The R2 regimen demonstrated superior efficacy over rituximab monotherapy (plus placebo) as measured by the primary endpoint of progression-free survival as well as the secondary endpoints of overall response rate, complete response, duration of response, and time-to-next antilymphoma treatment in patients with relapsed or refractory follicular lymphoma and marginal zone lymphoma. At this early analysis, fewer deaths have been observed in the R2 arm. Despite additional hematologic toxicity, greater efficacy of the R2 regimen (and fewer cases of early disease progression) allowed more patients to complete the planned therapy and delayed the need for subsequent therapy. R2 represents an important new treatment option in patients with previously treated follicular and marginal zone lymphomas who are not refractory to rituximab, with meaningful advantages over single-agent rituximab.

Diffuse Large B-Cell Lymphoma

ABSTRACT 781: Young adults with protocol-defined, favorable-prognosis diffuse large B-cell lymphoma (DLBCL) in the Flyer trial2

Methods: Patients between the ages of 18 and 60 years with Eastern Cooperative Oncology Group (ECOG) performance status score of 1 to 2, normal lactate dehydrogenase, and nonbulky (< 7.5 cm) stage I/II disease. Radiotherapy was not planned to be given except for prophylactic radiotherapy of the contralateral testis in patients with testicular lymphoma.

Key Findings: In this study of 588 patients, the progression-free, event-free, and overall survival after 4 R-CHOP + 2 rituximab (4 + 2; n = 293) were noninferior to those after 6 R-CHOP (n = 295). After 66 months of median observation, the 3-year progression-free survival rate with 4 + 2 was 96% vs 94% with 6 cycles of R-CHOP (P = .760). The lower limit of the 95% confidence interval of the difference between the treatment arms was 0% and excludes –5.5%, demonstrating noninferiority. The 3-year event-free survival was identical (89%) in both treatment arms. The 3-year overall survival was 99% with 4 + 2 and 98% with 6 cycles of R-CHOP. In a multivariable analysis, the hazard ratio of 4 + 2 compared with 6 cycles of R-CHOP was 1.0 (95% CI = 0.7–1.6; P = .896) for event-free survival, 0.9 (95% CI = 0.5–1.6; P = .797) for progression-free survival, and 0.8 (95% CI = 0.4–1.9; P = .671) for overall survival. With respect to relapse, there was also no significant difference between the two treatment arms.

Clinical Implications: In young patients with favorable-prognosis DLBCL, outcomes after 4 R-CHOP + 2 rituximab is noninferior to the previous standard of 6 R-CHOP.

ABSTRACT 782: Front-line therapy with venetoclax plus R-CHOP in BCL2-positive DLBCL: Phase II CAVALLI study3

Methods: Eligible patients had an ECOG performance status score ≤ 2; International Prognostic Index (IPI) score 2 to 5; ≥ 1 measurable lesion > 1.5 cm (n = 208). They were assigned to receive six 3-weekly cycles of R-CHOP plus venetoclax (800 mg) daily for the first 10 days of each cycle (except days 4–10 of cycle 1), followed by an additional two 3-weekly cycles of venetoclax on days 1 to 10 plus rituximab on day 1.

Endpoints: The primary endpoint was positron-emission tomography (PET)-computed tomography response 6 to 8 weeks after the last rituximab dose (end of therapy), according to a modified version of Lugano 2014 criteria. Secondary endpoints were progression-free survival and safety. The results of CAVALLI were compared with R-CHOP–treated patients with an IPI score between 2 and 5 on the GOYA trial (n = 554). GOYA4 (ClinicalTrials.gov identifier NCT01287741) was an open-label, randomized, phase III study of the efficacy and safety of R-CHOP vs obinutuzumab plus CHOP in previously untreated patients with DLBCL.

Key Findings: The CAVALLI study of 208 patients compared outcomes with venetoclax plus R-CHOP with outcomes in patients treated with an IPI score between 2 and 5 on the GOYA trial4 (n = 554), which was an open-label, randomized, phase III study of R-CHOP vs obinutuzumab plus CHOP in previously untreated DLBCL. Overall, patient characteristics were similar for CAVALLI and GOYA, except CAVALLI enrolled more patients with Ann Arbor stage IV and BCL2 immunohistochemistry–positive patients. The end-of-therapy complete response rate in all patients did not differ significantly between CAVALLI and GOYA (69.2% vs 62.8%, respectively) but was improved in BCL2-positive subgroups.

When compared with GOYA and adjusted for baseline covariates, improvement in progression-free survival in CAVALLI was observed in BCL2 immunohistochemistry–positive patients (HR = 0.53; 95% CI = 0.30–0.93), including within both activated B-cell and germinal center B-cell origin subgroups. No progression-free survival benefit was observed in patients with BCL2 immunohistochemistry–negative germinal-center B-cell–like disease (n = 47); the BCL2 immunohistochemistry–negative activated B-cell subgroup was too small for evaluation. Grade 3 to 4 adverse events occurred in 85% of patients in CAVALLI vs 66% in GOYA; the majority were cytopenias, infections, and febrile neutropenia.

Clinical Implications: Front-line R-CHOP with venetoclax in BCL-2 positive, high-risk DLBCL resulted in improved efficacy at a cost of increased toxicity when compared with selected patients treated on the GOYA trial. These data support the continued exploration of this regimen in specific subgroups of patients with BCL2-positive DLBCL.

ABSTRACT 783: R-CHOP in previously untreated DLBCL: Phase III GOYA study4,5

“Results from the international phase III GOYA study suggest that 6 cycles (not 8 cycles) of R-CHOP every 3 weeks should be the standard of care in patients with DLBCL.”
— Syed Ali Abutalib, MD, and Matthew Lunning, DO

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Key Findings: In this exploratory analysis of 712 previously untreated patients with DLBCL in the GOYA study, no additional progression-free survival benefit was observed with 8 cycles of R-CHOP (n = 186) compared with 6 cycles of R-CHOP plus 2 cycles of rituximab (n = 526), even after adjusting for baseline differences, including cell of origin and IPI score. The 3-year progression-free survival rates were comparable: 68.7% with 6 cycles vs 66.8% with 8 cycles (HR = 0.92; 95% CI = 0.69–1.23). The 3-year overall survival rates appeared higher with 6 cycles than with 8 cycles (83.2% vs 76.2%; HR = 0.65; 95% CI = 0.46– 0.91). The incidence of grade 3 to 5 adverse events was lower with 6 cycles than with 8 cycles (17.8% vs 38.9%, respectively). In support of these findings, similar results were achieved after repeating the same efficacy analysis in patients who received six or eight cycles of R-CHOP in combination with eight cycles of obinutuzumab.

Clinical Implications: Results from the international phase III GOYA study suggest that 6 cycles (not 8 cycles) of R-CHOP every 3 weeks should be the standard of care in patients with DLBCL.

ABSTRACT 784: Ibrutinib plus R-CHOP (prespecified 6–8 cycles) in previously untreated non–germinal-center B-cell–like DLBCL6

Endpoints: Primary endpoint was event-free survival defined as the time from randomization to progression, relapse from complete response, initiation of treatment for PET-positive or biopsy-proven residual disease after ≥ 6 cycles of R-CHOP, or death, in the intent-to-treat or activated B-cell population. Secondary endpoints included progression-free survival, complete response rate, overall survival, and safety.

Key Findings: In this randomized, placebo-controlled phase III trial, the median follow-up was 34.8 months, and the median age was 62 years (with 58.5% < 65 years); 67.7% had activated B-cell subtype. In the ibrutinib plus R-CHOP and placebo plus R-CHOP arms, 80.8% and 90.7% of patients received at least 6 cycles of R-CHOP; 22.4% and 13.6% discontinued treatment (all drugs), with adverse events being the most common reason.

Ibrutinib plus R-CHOP did not improve event-free survival in patients with non–germinal-center B-cell–like (by immunohistochemistry) or activated B-cell (by gene-expressing profiling) DLBCL. The hazard ratio for event-free survival was 0.934 (95% CI = 0.726–1.200) for the intent-to-treat and 0.949 (95% CI = 0.704–1.279) for the activated B-cell subset. Multivariate analysis showed a significant interaction between treatment effect and age as a continuous or categorical variable. Efficacy was a function of age: stable benefit was seen in younger patients, with less benefit seen with increasing age. There was no longer a favorable benefit in those 65 years or age or older.

Efficacy outcomes favored ibrutinib plus R-CHOP–treated patients younger than age 65, with a statistically significant risk reduction in event-free, progression-free, and overall survival. A similar trend was seen in the activated B-cell subset. Multivariate analyses, adjusting for other baseline covariates, confirmed the treatment benefit in younger—but not older—adults.

The rate of grade ≥ 3 adverse events was 89.9% and 87.1% in the ibrutinib plus R-CHOP and placebo plus R-CHOP arms, respectively. There were more serious adverse events with ibrutinib vs placebo (53.1% vs 34.0%).

Clinical Implications: Overall, the addition of ibrutinib to R-CHOP did not improve efficacy in the intent-to-treat population. Interestingly, in patients younger than age 65, the addition of ibrutinib to R-CHOP improved overall survival, with an acceptable safety profile, but this was not the primary endpoint of the study. Among patients 65 years of age and older, an unexpected increase in toxicity associated with ibrutinib resulted in reduced R-CHOP exposure, which may explain, in part, the worse clinical benefit/risk profile in this group vs placebo.

Primary Mediastinal B-Cell Lymphoma

ABSTRACT 228: Pembrolizumab in relapsed or refractory primary mediastinal large B-cell lymphoma: KEYNOTE-013 and KEYNOTE-1707

Rationale: Unlike DLBCL and similar to classical Hodgkin lymphoma, primary mediastinal B-cell lymphoma has frequent genetic abnormalities leading to overexpression of the programmed cell death protein 1 (PD-1) ligands, PD-L1 and PD-L2.

Methods: Updated results of all patients in KEYNOTE-013 (n = 21) and the first full analysis of patients in KEYNOTE-170 (n = 53)

Key Findings: KEYNOTE-013: In 21 patients, the overall response rate (primary endpoint) was 48% (95% CI = 26%–70%), with a complete response rate of 33%. After a median follow-up of 29.1 months, the median duration of response was not reached (range, 1.9+ to 39.8+ months). The median progression-free survival was 10.4 months (95% CI = 3.4 to not reached), with a 12-month progression-free survival rate of 47%; the median overall response was 31.4 months, with a 12-month overall response rate of 65%. No new safety signals were observed compared with prior analyses.

“Together with the longer follow-up of KEYNOTE-013, KEYNOTE-170, the largest prospective clinical trial in relapsed or refractory primary mediastinal B-cell lymphoma, establishes the robust antitumor activity of pembrolizumab in this disease.…”
— Syed Ali Abutalib, MD, and Matthew Lunning, DO

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KEYNOTE-170: In the first full analysis of 53 patients, the overall response rate was 45% (95% CI = 32%–60%), with a complete response rate of 13%. After a median follow-up of 12.5 months, the median duration of response was not reached (range, 1.1+ to 22.0+ months). Thirty patients had a treatment-related adverse event. There were no treatment-related deaths reported.

Clinical Implications: Together with the longer follow-up results of KEYNOTE-013, KEYNOTE-170, the largest prospective clinical trial in relapsed or refractory primary mediastinal B-cell lymphoma, establishes the robust antitumor activity of pembrolizumab in this disease, with durable responses and survival (not cure) in responding patients. These results provided the basis for the U.S. Food and Drug Administration (FDA) accelerated approval of pembrolizumab in patients with relapsed or refractory primary mediastinal B-cell lymphoma.

CD30-Positive Peripheral T-Cell Lymphomas

ABSTRACT 997: Brentuximab vedotin and cyclophosphamide, doxorubicin, and prednisone vs CHOP in the front-line treatment of CD30-expressing peripheral T-cell lymphomas8,9

Primary Endpoint: Progression-free survival

Key Findings: In the randomized, double-blind ECHELON-2 phase III trial, most patients had advanced-stage disease at diagnosis, and 78% had IPI scores ≥ 2. Subtypes of peripheral T-cell lymphoma included systemic anaplastic large cell lymphoma (316 patients), peripheral T-cell lymphomas—not otherwise specified (72 patients), angioimmunoblastic T-cell lymphoma (54 patients), adult T-cell leukemia/lymphoma (7 patients), and enteropathy-associated T-cell lymphoma (3 patients).

Preliminary results by investigator assessment showed an overall blinded pooled objective response rate after completion of front-line treatment of 79% (95% CI = 75.4%–83.1%), with 64% achieving a complete response. The 3-year progression-free and overall survival rates for all patients were 52.9% (95% CI = 47.7%– 57.7%) and 73.1% (95% CI = 68.3%–77.2%).

The incidence of adverse events was consistent with the known safety profiles of brentuximab vedotin and CHOP chemotherapy, including peripheral sensory neuropathy (43%). Grade 3 or higher adverse events reported in at least 10% of patients were neutropenia, febrile neutropenia, and anemia. Treatment was discontinued for adverse events, progressive disease, investigator decision, and patient decision.

Clinical Implications: Blinded pooled data from ECHELON-2 showed that brentuximab vedotin plus CHOP chemotherapy was well tolerated, with encouraging 3-year progression-free and overall survival rates. In November 2018, the FDA approved brentuximab vedotin in combination with chemotherapy for previously untreated systemic anaplastic large cell lymphoma or other CD30-expressing peripheral T-cell lymphomas.

Dr. Abutalib is Associate Director, Hematology and BMT Program; Director, Clinical Apheresis Program, Cancer Treatment Centers of America, Zion, Illinois; Associate Professor of Medicine, Roseland Franklin University of Medicine and Science; as well as Founder and Co-Editor, Advances in Cell and Gene Therapy. Dr. Lunning is Associate Professor, Division of Oncology & Hematology, University of Nebraska, Omaha.

DISCLOSURE: Dr. Abutalib is an advisor for AstraZeneca. Dr. Lunning has received research funding from Celgene, Curis, Janssen Scientific Affairs, Juno Therapeutics, MiRagen, and TG Therapeutics; and is a consultant for AbbVie, Bayer, Celgene, DAVA, Gilead Sciences, Janssen, Juno Therapeutics, Kite, Novartis, OncLive, Portola, Seattle Genetics, Spectrum, TG Therapeutics, VANIUM, and Verastem.

REFERENCES

1. Leonard JP, Trněný M, Izutsu K, et al: AUGMENT: A phase III randomized study of lenalidomide plus rituximab (R2) vs rituximab/placebo in patients with relapsed/refractory indolent non-Hodgkin lymphoma. 2018 ASH Annual Meeting & Exposition. Abstract 445. Presented December 2, 2018.

2. Poeschel V, Held G, Ziepert M, et al: Excellent outcome of young patients (18–60 years) with favourable-prognosis diffuse large B-cell lymphoma treated with 4 cycles CHOP plus 6 applications of rituximab: Results of the 592 patients of the Flyer trial of the Dshnhl/GLA. 2018 ASH Annual Meeting & Exposition. Abstract 781. Presented December 3, 2018.

3. Morschhauser F, Feugier P, Flinn IW, et al: Venetoclax plus rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone improves outcomes in BCL2-positive first-line Diffuse large B-cell lymphoma: First safety, efficacy and biomarker analyses from the phase II CAVALLI study. 2018 ASH Annual Meeting & Exposition. Abstract 782. Presented December 3, 2018.

4. Vitolo U, Trněný M, Belada D, et al: Obinutuzumab or rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone in previously untreated diffuse large B-cell lymphoma. J Clin Oncol 35:3529-3537, 2017.

5. Sehn LH, Congiu AG, Culligan DJ, et al: No added benefit of eight versus six cycles of CHOP when combined with rituximab in previously untreated diffuse large B-cell lymphoma patients: Results from the international phase III GOYA study. 2018 ASH Annual Meeting & Exposition. Abstract 783. Presented December 3, 2018.

6. Younes A, Sehn LH, Johnson, P et al: A global, randomized, placebo-controlled, phase 3 study of ibrutinib plus rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone in patients with previously untreated non–germinal center B-cell-like diffuse large B-cell lymphoma. 2018 ASH Annual Meeting & Exposition. Abstract 784. Presented December 3, 2018.

7. Armand P, Rodig SJ, Melnichenko V, et al: Pembrolizumab in patients with relapsed or refractory primary mediastinal large B-cell lymphoma: Data from the KEYNOTE-013 and KEYNOTE-170 studies. 2018 ASH Annual Meeting & Exposition. Abstract 228. Presented December 1, 2018.

8. Horwitz SM, O’Connor OA, Pro B, et al: The ECHELON-2 trial: Results of a randomized, double-blind, active-controlled phase 3 study of brentuximab vedotin and CHP versus CHOP in the frontline treatment of patients with CD30+ peripheral T-cell lymphomas. 2018 ASH Annual Meeting & Exposition. Abstract 997. Presented December 3, 2018.

9. Horwitz S, O’Connor OA, Pro B, et al: Brentuximab vedotin with chemotherapy for CD30-positive peripheral T-cell lymphoma (ECHELON-2): A global, double-blind, randomised, phase 3 trial. Lancet 393:229-240, 2019.


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