Abstract
BACKGROUND
Diffuse large B-cell lymphoma (DLBCL) is typically treated with rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP). However, only 60% of patients are cured with R-CHOP. Polatuzumab vedotin is an antibody–drug conjugate targeting CD79b, which is ubiquitously expressed on the surface of malignant B cells. We replaced vincristine with polatuzumab vedotin and compared the new regimen with R-CHOP.
METHODS
In this double-blind, placebo-controlled, international phase 3 study, patients aged 18–80 years with previously untreated intermediate- and high-risk DLBCL were randomized 1:1 to receive six cycles of pola-R-CHP or R-CHOP, plus two cycles of rituximab alone. The primary endpoint was investigator-assessed progression-free survival. Secondary endpoints included overall survival and safety.
RESULTS
Overall, 879 patients were enrolled (pola-R-CHP: n = 440; R-CHOP: n = 439). After a median follow-up of 28.2 months, the 2-year progression-free survival rate was 76.7% (95% CI, 72.7 to 80.8) versus 70.2% (95% CI, 65.8 to 74.6); progression-free survival was superior with pola-R-CHP versus R-CHOP (HR, 0.73 by Cox analysis; 95% CI, 0.57 to 0.95; P < 0.02). No difference was seen in overall survival between treatment arms; 2-year overall survival rate was 88.7% (95% CI, 85.7 to 91.6) in the pola-R-CHP arm, and 88.6% (95% CI, 85.7 to 91.6) in the R-CHOP arm (HR, 0.94; 95% CI, 0.65 to 1.37; P = 0.75). The safety profile was comparable for pola-R-CHP versus R-CHOP.
CONCLUSIONS
In patients with previously untreated intermediate- and high-risk DLBCL, pola-R-CHP reduces the risk of disease progression, relapse, or death by 27% compared with R-CHOP, with a similar safety profile.
CLINICAL TRIAL INFORMATION
This study is registered at ClinicalTrials.Gov as: NCT03274492.
INTRODUCTION
Diffuse large B-cell lymphoma (DLBCL) is the most common lymphoma.1 Addition of rituximab, an anti-CD20 monoclonal antibody, to the CHOP regimen (cyclophosphamide, doxorubicin, vincristine, and prednisone) yielded significant improvement in patient outcomes.2,3 While most patients, depending on prognostic factors, can be cured by this treatment, up to 40% of patients remain refractory to R-CHOP, or relapse after an initial response.4,5 Numerous approaches have attempted to improve treatment outcomes with R-CHOP in randomized trials, including intensification of chemotherapy6–8 or rituximab,9 addition of maintenance therapy,10,11 a second-generation anti-CD20 monoclonal antibody,12 or incorporation of novel agents.13,14 These studies have not demonstrated a meaningful improvement in outcomes, and R-CHOP remains the standard first-line treatment for DLBCL.4,15
CD79b is a subunit of a heterodimer transmembrane component of the B-cell antigen receptor involved in cell signaling, and is ubiquitously expressed on the surface of mature B-cell lymphomas, including DLBCL.16,17 Polatuzumab vedotin is an antibody–drug conjugate comprising an anti-CD79b monoclonal antibody18 conjugated by a protease cleavable linker to a potent microtubule inhibitor, monomethyl auristatin E.16,19 Polatuzumab vedotin has shown efficacy in relapsed/refractory DLBCL, both as a single agent, with an overall response rate of 52%,20 and in combination with rituximab.21 A randomized study evaluating the addition of polatuzumab vedotin to bendamustine and rituximab in relapsed/refractory DLBCL showed an improvement of overall survival.22
Polatuzumab vedotin with rituximab, cyclophosphamide, doxorubicin, and prednisone (pola-R-CHP) was investigated as first-line therapy for DLBCL in a phase 1b/2 trial and demonstrated an overall response rate of 89% with 77% complete responses. Vincristine was excluded from the regimen due to the risk of overlapping neurological toxicity with polatuzumab vedotin.23 We conducted the phase 3 POLARIX trial to compare the efficacy and safety of pola-R-CHP versus R-CHOP in patients with previously untreated DLBCL.
METHODS
TRIAL CONDUCT
POLARIX is a randomized, double-blind, placebo-controlled, international phase 3 study. The study protocol was approved by institutional review boards or ethics committees at participating institutions in accordance with the International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use guidelines, including Good Clinical Practice, and the Declaration of Helsinki.24 All patients provided informed consent. The study was sponsored by Genentech, Inc. and F. Hoffmann-La Roche Ltd, and designed by the sponsor in collaboration with LYSA (Lymphoma Study Association). An independent monitoring committee reviewed safety data regularly during the conduct of the study. The first draft was written primarily by authors Hervé Tilly and Calvin Lee; third-party medical writing assistance was funded by the Sponsor. All authors reviewed the data, confirmed the completeness and accuracy of the results and the trial’s fidelity to the protocol and statistical analysis plan, and contributed to the writing of the manuscript.
PATIENTS
Patients aged 18–80 years with CD20-positive DLBCL,25 who had not received previous lymphoma treatment, had an Eastern Cooperative Oncology Group performance status of 0–2 (a 5-point scale where higher numbers reflect greater disability), Ann Arbor Stage I–IV, a baseline International Prognostic Index (IPI)26 score of 2–5 (a 5-level prognostic scale where higher numbers reflect poorer prognosis), and had adequate hematologic, renal, hepatic and cardiac function were eligible for inclusion, regardless of cell-of-origin or presence of MYC, BCL2, and/or BCL6 rearrangements. Key exclusion criteria included a history of indolent lymphoma, contraindications to any component of R-CHOP, prior receipt of anthracyclines, and known central nervous system (CNS) involvement. Detailed eligibility criteria and trial methods are provided in the Supplementary Appendix.
RANDOMIZATION AND MASKING
Eligible patients were randomized 1:1 to pola-R-CHP or R-CHOP (details of doses and schedules are provided in the protocol, available at NEJM.org). Randomization was stratified according to IPI score (2 vs. 3–5), bulky disease (presence of one lesion ≥7.5 cm vs. absence) and geographical region (Western Europe, United States, Canada, and Australia vs. Asia vs. rest of world). The investigator, sponsor, and patients were blinded to treatment assignment. Details of the randomization procedure and blinding are given in the protocol.
TREATMENT
Eight 21-day cycles of treatment were planned. The first six cycles were pola-R-CHP or R-CHOP, with either intravenous polatuzumab vedotin 1.8 mg/kg and a placebo of intravenous vincristine (pola-R-CHP), or vincristine 1.4 mg/m2 (maximum 2 mg) and a placebo of polatuzumab vedotin (R-CHOP) administered on Day 1, plus intravenous rituximab 375 mg/m2, cyclophosphamide 750 mg/m2, and doxorubicin 50 mg/m2 on Day 1, and oral prednisone 100 mg once daily on Days 1–5. Cycles 7–8 comprised rituximab 375 mg/m2 monotherapy in both arms.
Central nervous system prophylaxis with intrathecal chemotherapy, according to institutional practice, was permitted. Granulocyte-colony stimulating factor administration was required during the first six cycles of treatment as primary prophylaxis of neutropenia. Consolidative radiotherapy administered to initial sites of bulky disease or extranodal sites was permitted at the discretion of the investigator. In these cases, radiotherapy had to be planned before randomization and was given after end-of-treatment assessments (Supplementary Appendix).
Management of dose interruptions, modifications, discontinuations of polatuzumab vedotin and vincristine, and any other permitted treatments are detailed in the protocol.
ENDPOINTS AND ASSESSMENTS
The primary efficacy endpoint was investigator-assessed progression-free survival, defined as the time from the date of randomization until the first occurrence of disease progression, relapse, or death from any cause. Key secondary endpoints, examined hierarchically,27 were investigator-assessed event-free survival (i.e., time from randomization to the earliest occurrence of disease progression/relapse, death due to any cause, initiation of any non-protocol specified anti-lymphoma treatment, or biopsy-confirmed residual disease after treatment completion), positron emission tomography (PET)-based CR rate at the end of treatment by blinded independent central review, overall survival, and safety. Details regarding the hierarchical testing are described further in the Supplementary Appendix. Additional secondary endpoints, not subject to hypothesis testing, included investigator-assessed disease-free survival, defined as the time from the date of first documented CR to the date of relapse or death from any cause. Disease-free survival analyses were conditional on patients achieving response and were therefore based on a group of patients defined post-randomization. Methods regarding additional secondary and exploratory endpoints are detailed in the protocol. The primary safety objective was to evaluate the safety of pola-R-CHP compared with R-CHOP; adverse events were reported according to Medical Dictionary for Regulatory Activities and graded according to National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0.
Lugano Classification lymphoma response criteria28 were used by investigators to perform tumor assessments, and by the independent review committee to evaluate PET-computed tomography [CT]-based end-of-treatment response. CT and PET-CT were mandatory at baseline and at treatment completion; CT and/or PET-CT were planned after Cycle 4 and during surveillance (i.e., every 6 months for the next 24 months, then every 12 months for the next 36 months). Cell-of-origin assessment, immunohistochemistry of BCL2 and MYC, and fluorescence in situ hybridization of MYC, BCL2 and BCL6 were performed at central laboratories (Supplementary Appendix).
STATISTICAL ANALYSIS
Efficacy analyses were conducted using the intention-to-treat (ITT) population, defined as all randomized patients; the safety analysis population included all patients who received at least one dose of any study drug, and specifically for the pola-R-CHP arm, any exposure to polatuzumab vedotin treatment.
The primary analysis occurred when 228 progression events were observed and all patients had been on study for at least 24 months. This represents the primary analysis for progression-free and event-free survival, and complete response rate, and the interim analysis for overall survival. For the primary endpoint of progression-free survival, assuming a hazard ratio (HR) of 0.69, 875 planned patients and 228 progression events were required to provide the trial with 80% power at a one-sided 2.5% (or equivalently, a two-sided 5.0%) significance level to detect a minimum reduction of 23% (the minimum detectable difference: HR 0.77) in the risk of disease progression, relapse, or death with pola-R-CHP over R-CHOP. The null hypothesis was rejected if the one-sided P value from the log rank test was <0.025, with the conclusion that pola-R-CHP prolongs progression-free survival relative to R-CHOP. The Kaplan–Meier method was used to estimate the progression-free survival distribution for each treatment arm. Estimates of the treatment effect were expressed as HRs using a stratified Cox proportional-hazards analysis, including 95% confidence intervals (CIs). In patients who were progression-free at data cut-off, progression-free survival was censored on the date of the last disease assessment. For patients with missing or unevaluable tumor assessments beyond the baseline assessment, progression-free survival was censored on the date of randomization. All P values presented are two-sided and are only presented for hierarchically tested endpoints. The proportional hazard assumption for progression-free survival was evaluated using the method proposed by Grambsch et al.,29 and there was no evidence suggesting the violation of proportionality.
Detailed statistical methods are described in the statistical analysis plan in the Supplementary Material.
RESULTS
PATIENTS
Overall, 1063 patients were screened. Between 14 November 2017 and 27 June 2019, 879 patients were randomized, 440 to pola-R-CHP and 439 to R-CHOP (ITT population) (Fig. 1). The safety-evaluable population comprised 435 and 438 patients for pola-R-CHP and R-CHOP, respectively. Baseline patient demographics and clinical characteristics were similar between treatment arms (Tables 1 and S1). The median age (range) in the overall patient population was 65 years (19–80). Stratification factors (IPI score, bulky disease, and geographic region) and centrally tested subtypes were balanced between treatment arms. The median interval between diagnosis, defined by the date of biopsy, and initiation of treatment was similar in the two treatment groups (26 and 27 days in pola-R-CHP and R-CHOP arms, respectively; Table 1).
Figure 1.
Patient Disposition.
*Most common criteria patients did not meet: IPI 2–5 (n = 23), availability of archival or freshly collected tumor tissue before study enrollment (n = 22), signed written informed consent form (n = 19), previously untreated CD20-positive DLBCL (n = 19).
†Reasons for not receiving treatment: physician decision (n = 2), patient withdrawal (n = 1), exclusion criteria identified (n = 1).
‡Reasons for not receiving treatment: patient withdrawal (n = 1), other malignancy identified (n = 1). Pola-R-CHP, polatuzumab vedotin + rituximab + cyclophosphamide, doxorubicin, and prednisone; R-CHOP, rituximab + cyclophosphamide, doxorubicin, vincristine, and prednisone.
Table 1.
Baseline Patient Demographics and Clinical Characteristics (ITT population).
| Pola-R-CHP N = 440 |
R-CHOP N = 439 |
|
|---|---|---|
| Median age (range), years | 65.0 (19–80) | 66.0 (19–80) |
| Age ≤60/>60 years, n (%) | 140 (31.8)/300 (68.2) | 131 (29.8)/308 (70.2) |
| Female/male sex, n (%) | 201 (45.7)/239 (54.3) | 205 (46.7)/234 (53.3) |
| Geographic region, n * | ||
| Western Europe, United States, Canada, and Australia | 302 (68.6) | 301 (68.6) |
| Asia | 81 (18.4) | 79 (18.0) |
| Rest of world | 57 (13.0) | 59 (13.4) |
| Ann Arbor Stage I-II/III-IV, n (%) | 47 (10.7)/393 (89.3) | 52 (11.8)/387 (88.2) |
| Extranodal sites 0–1/≥2, n (%) | 227 (51.6)/213 (48.4) | 226 (51.5)/213 (48.5) |
| Bulky disease <7.5 cm/≥7.5 cm, n (%)* | 247 (56.1)/193 (43.9) | 247 (56.3)/192 (43.7) |
| ECOG performance status 0–1/2, n (%)†‡ | 374 (85.0)/66 (15.0) | 363 (82.7)/75 (17.1) |
| LDH level normal/elevated, n (%)‡ | 146 (33.2)/291 (66.1) | 154 (35.1)/284 (64.7) |
| IPI score 2/3–5, n (%)*§ | 167 (38.0)/273 (62.0) | 167 (38.0)/272 (62.0) |
| Median time from initial diagnosis to treatment initiation (IQR), days | 26 (16.0–37.5) | 27 (19.0–41.0) |
| Cell-of-origin, n (%)¶ | (n = 330) | (n = 338) |
| GCB/ABC/unclassified | 184 (55.8)/ 102 (30.9)/44 (13.3) | 168 (49.7)/119 (35.2)/51 (15.1) |
| Double expressor lymphoma, n (%)¶ | (n = 362) | (n = 366) |
| DEL/non-DEL | 139 (38.4)/223 (61.6) | 151 (41.3)/215 (58.7) |
| Double-/triple-hit lymphoma, n (%)¶ | (n = 331) | (n = 334) |
| Yes/no | 26 (7.9)/305 (92.1) | 19 (5.7)/315 (94.3) |
The full table of baseline characteristics is available in the Supplementary Appendix (Table S8).
According to stratification.
ECOG performance status of 0–2 (a 5-point scale where higher numbers reflect greater disability).
ECOG performance status and LDH level were not reported for 1 patient and 4 patients, respectively.
IPI score indicates low (0 or 1), low-intermediate (2), high-intermediate (3), or high (4 or 5) risk on the basis of a scoring system that gives one point for each of the following risk factors: age >60 years, ≥1 extranodal area of disease, an ECOG performance status of 2 or higher, a lactate dehydrogenase level above the upper limit of normal, and Ann Arbor stage III or IV disease.
Centrally performed tests: cell-of-origin was performed by NanoString Lymph 2Cx, MYC and BCL2 immunohistochemistry were performed for DEL; MYC and BCL2, and/or BCL6 rearrangements were performed for double- and triple-hit lymphoma; percentages are calculated from the evaluable population. Baseline tumor tissue samples were not received from 63 patients in the ITT population, the remainder of unknown results represent test failures; together, these account for the difference between ITT and biomarker-evaluable population.
ABC, activated B-cell subtype; DEL, double expressor lymphoma; ECOG, Eastern Cooperative Oncology Group; GCB, germinal center B-cell subtype; IPI, International Prognostic Index; IQR, interquartile range; ITT, intent-to-treat; LDH, lactate dehydrogenase; Pola-R-CHP, polatuzumab vedotin + rituximab + cyclophosphamide, doxorubicin, and prednisone; R-CHOP, rituximab + cyclophosphamide, doxorubicin, vincristine, and prednisone.
TREATMENT EXPOSURE
Most patients received all six doses of the active blinded agents, polatuzumab vedotin or vincristine (91.7% and 88.5%, in pola-R-CHP and R-CHOP arms, respectively); 89.2% and 86.3% of patients treated with pola-R-CHP and R-CHOP, respectively, received all eight cycles of treatment (Fig. 1). Median relative dose intensities of rituximab, doxorubicin, and cyclophosphamide were >99% in both treatment arms.
As allowed by the protocol, 11 (2.5%) patients in the pola-R-CHP arm and 18 (4.1%) in the R-CHOP arm received pre-planned radiotherapy after completion of study treatment. Seventy-two (16.4%) and 86 (19.6%) patients received any CNS prophylaxis in pola-R-CHP and R-CHOP arms, respectively (Table S2).
EFFICACY
Primary Endpoint
At data cut-off (28 June 2021), after a median follow-up 28.2 months (range: 0.1–43.4), a significant improvement in investigator-assessed progression-free survival was observed with pola-R-CHP versus R-CHOP. Milestone analysis showed an absolute improvement of 6.5% in the progression-free survival rate at 2 years with pola-R-CHP versus R-CHOP (76.7% [95% CI, 72.7 to 80.8] vs. 70.2% [95% CI, 65.8 to 74.6]) (stratified HR, 0.73; 95% CI, 0.57 to 0.95; P < 0.02; Fig. 2A). Exploratory subgroup analyses comparing progression-free survival across treatments varied by patient and disease characteristics; notable subgroups without a clear benefit include those under age 60 years, those with germinal center gene expression, those with bulky disease, and those with lower IPI risk scores (Fig. S1).
Figure 2.
Kaplan–Meier Plots of (A) Investigator-assessed PFS, (B) Investigator-assessed EFS, (C) Investigator-assessed DFS, and (D) OS in the ITT Population.
Data cut-off date: June 28, 2021
CI, confidence interval; DFS, disease-free survival; EFS, event-free survival for efficacy causes; HR, hazard ratio; ITT, intention-to-treat; NE, not evaluable; OS, overall survival; PFS, progression-free survival; Pola-R-CHP, polatuzumab vedotin + rituximab + cyclophosphamide, doxorubicin, and prednisone; R-CHOP, rituximab + cyclophosphamide, doxorubicin, vincristine, and prednisone.
Secondary Endpoints
Investigator-assessed event-free survival (ITT population) was statistically improved with pola-R-CHP versus R-CHOP; 2-year event-free survival was higher with pola-R-CHP versus R-CHOP (Table 2) (HR, 0.75; 95% CI, 0.58 to 0.96; P = 0.02; Fig. 2B). End-of-treatment blinded committee-assessed CR rate did not differ between pola-R-CHP versus R-CHOP (78.0% vs. 74.0%; P = 0.16); analysis of investigator-assessed disease-free survival indicated that patients who achieved a best response of CR with pola-R-CHP (Table S3) were more likely to maintain remission than those who achieved a CR with R-CHOP (75.6% at 2 years [95% CI 71.5–79.7] for pola-R-CHP; 69.4% at 2 years [95% CI 65–73.8] for R-CHOP; HR, 0.70; 95% CI, 0.50 to 0.98; Table 2 and Fig. 2C). No difference was noted in overall survival between treatment arms (Table 2 and Fig. 2D). Thirteen (3.0%) patients in the pola-R-CHP arm and 12 (2.7%) in the R-CHOP group experienced disease progression or relapse with CNS involvement (Table S2).
Table 2.
Efficacy Outcomes (ITT Population).
| Pola-R-CHP N = 439 |
R-CHOP N = 440 |
|
|---|---|---|
| Progression-free survival, number of events (%)* | 107 (24.3) | 134 (30.5) |
| Earliest event death/progression or relapse, n | 19/88 | 20/114 |
| HR (95% CI); P value | 0.73 (0.57 to 0.95); 0.02 | |
| 1-year rate (95% CI) | 83.9 (80.4 to 87.4) | 79.8 (75.9 to 83.6) |
| 2-year rate (95% CI) | 76.7 (72.7 to 80.8) | 70.2 (65.8 to 74.6) |
| Event-free survival, number of events (%)* | 112 (25.5) | 138 (31.4) |
| Earliest event death/progression or relapse/other†, n | 18/86/8 | 20/106/12 |
| HR (95% CI); P value | 0.75 (0.58 to 0.96); 0.02 | |
| 2-year rate (95% CI) | 75.6 (71.5 to 79.7) | 69.4 (65.0 to 73.8) |
| Overall response rate at treatment completion, n (%)‡ | 376 (85.5) | 368 (83.8) |
| Complete response | 343 (78.0) | 325 (74.0) |
| Partial response | 33 (7.5) | 43 (9.8) |
| Stable disease | 8 (1.8) | 6 (1.4) |
| Progressive disease | 22 (5.0) | 28 (6.4) |
| Not evaluable/missing | 34 (7.7) | 37 (8.4) |
| Overall survival events, n (%) | 53 (12.0) | 57 (13.0) |
| HR (95% CI); P value | 0.94 (0.65 to 1.37); 0.75 | |
| 2-year rate (95% CI), % | 88.7 (85.7 to 91.6) | 88.6 (85.6 to 91.6) |
| Number of patients evaluable for disease-free survival¶ | 381 | 363 |
| Disease-free survival events, n (%)* | 62 (16.3) | 79 (21.8) |
| Earliest event death/relapse | 8/54 | 13/66 |
| HR (95% CI) | 0.70 (0.50 to 0.98) | |
As assessed by the investigator.
Other refers to subsequent anti-lymphoma therapy or positive biopsy after treatment.
As assessed by independent central review.
Patients with a best response of complete response at any time during the study were evaluable for disease-free survival; see Table S3.
CI, confidence interval; HR, hazard ratio; ITT, intent-to-treat; Pola-R-CHP, polatuzumab vedotin + rituximab + cyclophosphamide, doxorubicin, and prednisone; R-CHOP, rituximab + cyclophosphamide, doxorubicin, vincristine, and prednisone.
Next Anti-Lymphoma Therapy
At time of data cut-off, 99/440 patients (22.5%) and 133/439 patients (30.3%) in the pola-R-CHP and R-CHOP arms, respectively, received at least one subsequent anti-lymphoma therapy (Table S4). The proportions of patients receiving radiotherapy (9.3% vs. 13.0%), and systemic therapy (17.0% vs. 23.5%; including stem cell transplantation [3.9% vs. 7.1%] and chimeric antigen receptor [CAR] T-cell therapy [2.0% vs. 3.6%]), were lower with pola-R-CHP than with R-CHOP. After disease progression, unblinding was permitted for individual patients and eight patients (all in the R-CHOP arm) received polatuzumab vedotin as part of a subsequent therapy.
SAFETY
The overall safety profile was comparable for pola-R-CHP and R-CHOP, with types and rates of adverse events and Grade ≥3 adverse events similar between treatment arms (Table 3). No new safety signals were detected, and the safety profile of pola-R-CHP was consistent with the known safety of the individual drugs.
Table 3.
Treatment-emergent Adverse Events (Safety-evaluable Population).
| n (%) | Pola-R-CHP N = 435 |
R-CHOP N = 438 |
||
|---|---|---|---|---|
| Any-grade adverse events | 426 (97.9) | 431 (98.4) | ||
| Grade ≥3 adverse events | 264 (60.7) | 262 (59.8) | ||
| Serious adverse events | 148 (34.0) | 134 (30.6) | ||
| Grade 5 adverse events | 13 (3.0) | 10 (2.3) | ||
| Most common adverse events* | Any grade | Grade 3–4 | Any grade | Grade 3–4 |
| Peripheral neuropathy† | 230 (52.9) | 7 (1.6) | 236 (53.9) | 5 (1.1) |
| Nausea | 181 (41.6) | 5 (1.1) | 161 (36.8) | 2 (0.5) |
| Neutropenia | 134 (30.8) | 123 (28.3) | 143 (32.6) | 135 (30.8) |
| Diarrhea | 134 (30.8) | 17 (3.9) | 88 (20.1) | 8 (1.8) |
| Anemia | 125 (28.7) | 52 (12.0) | 114 (26.0) | 37 (8.4) |
| Constipation | 125 (28.7) | 5 (1.1) | 127 (29.0) | 1 (0.2) |
| Fatigue | 112 (25.7) | 4 (0.9) | 116 (26.5) | 11 (2.5) |
| Alopecia | 106 (24.4) | 0 | 105 (24.0) | 1 (0.2) |
| Decreased appetite | 71 (16.3) | 5 (1.1) | 62 (14.2) | 3 (0.7) |
| Pyrexia | 68 (15.6) | 6 (1.4) | 55 (12.6) | 0 |
| Vomiting | 65 (14.9) | 5 (1.1) | 63 (14.4) | 3 (0.7) |
| Febrile neutropenia | 62 (14.3) | 60 (13.8) | 35 (8.0) | 35 (8.0) |
| Headache | 56 (12.9) | 1 (0.2) | 57 (13.0) | 4 (0.9) |
| Cough | 56 (12.9) | 0 | 53 (12.1) | 0 |
| Decreased weight | 55 (12.6) | 4 (0.9) | 52 (11.9) | 1 (0.2) |
| Asthenia | 53 (12.2) | 7 (1.6) | 53 (12.1) | 2 (0.5) |
| Dysgeusia | 49 (11.3) | 0 | 57 (13.0) | 0 |
Adverse events are MedDRA version 24.0 preferred terms.
Most common was defined as all-grade AEs occurring in ≥12% of patients in any treatment arm.
Peripheral neuropathy includes preferred terms from the system organ class of peripheral neuropathy, including: peripheral neuropathy, peripheral sensory neuropathy, paresthesia, hypoesthesia, polyneuropathy, peripheral motor neuropathy, dysesthesia, neuralgia, peripheral sensorimotor neuropathy, hypotonia, hyporeflexia, neuromyopathy, ear paresthesia, peroneal nerve palsy, skin burning sensation.
MedDRA, the Medical Dictionary for Regulatory Activities; Pola-R-CHP, polatuzumab vedotin + rituximab + cyclophosphamide, doxorubicin, and prednisone; R-CHOP, rituximab + cyclophosphamide, doxorubicin, vincristine, and prednisone.
The most common Grade ≥3 adverse events were neutropenia (28.3% vs. 30.8%), febrile neutropenia (13.8% vs. 8.0%), and anemia (12.0% vs. 8.4%) with pola-R-CHP and R-CHOP, respectively. While the rate of febrile neutropenia was higher with pola-R-CHP than R-CHOP, the rates of Grade ≥3 infections were comparable (15.2% vs. 12.6%), as were drug discontinuations (2.1% vs. 2.3%), and dose reductions (1.8% vs. 2.5%) due to either infections or neutropenia. G-CSF prophylaxis was reported in 90.1% and 93.2% of patients in the pola-R-CHP and R-CHOP arms, respectively. Serious adverse events were reported in 34.0% of patients treated with pola-R-CHP and 30.6% of patients treated with R-CHOP (Table 3). Grade 5 adverse events were reported in 13 patients treated with pola-R-CHP, and 10 patients treated with R-CHOP (Table S5); these were primarily due to infections, i.e., pneumonia (four and three patients treated with pola-R-CHP and R-CHOP, respectively), and sepsis (one and three patients, respectively).
Overall, 27 patients (6.2%) in the pola-R-CHP arm, and 29 patients (6.6%) in the R-CHOP arm experienced adverse events that led to discontinuation of any study drug. Among these, 19 patients (4.4%) in the pola-R-CHP arm discontinued polatuzumab vedotin due to adverse events, and 22 patients (5.0%) in the R-CHOP arm discontinued vincristine due to adverse events, mainly neurologic toxicity for both agents. Dose reductions of a study drug due to an adverse event occurred in 9.2% of patients treated with pola-R-CHP, and 13.0% with R-CHOP.
Rates of peripheral neuropathy were not significantly different between treatment arms (Table S6). Any-grade peripheral neuropathy events were reported in 52.9% of pola-R-CHP recipients and 53.9% of R-CHOP recipients, and Grade ≥2 events in 13.8% and 16.6%, respectively. Median time to onset of any neuropathy was 2.3 months with pola-R-CHP, and 1.9 months with R-CHOP; median time to resolution of any neuropathy was 4.0 and 4.6 months respectively. Very few patients discontinued any treatment due to peripheral neuropathy (0.2% with pola-R-CHP, and 0.9% with R-CHOP). Fewer patients receiving polatuzumab vedotin experienced peripheral neuropathy events leading to dose reduction than those receiving vincristine (4.4% vs. 8.0%).
DISCUSSION
The pola-R-CHP combination led to a statistically significant improvement in progression-free survival compared with standard-of-care R-CHOP in patients with previously untreated DLBCL. This resulted in a 27% reduction in the risk of disease progression, relapse or death, and a 2-year progression-free survival rate favoring pola-R-CHP (76.7% vs. 70.2%) in this intermediate- and high-risk population, in which approximately one-third of patients had activated B-cell subtype DLBCL and almost two-thirds had an IPI score of 3–5. Although this study was not designed or powered to compare progression-free survival in patient subgroups, the observed heterogeneity in the effect of pola-R-CHP needs to be assessed in further studies. As CD79b is ubiquitously expressed on the surface of mature B-cell lymphomas, it may be expected that pola-R-CHP will be active in all DLBCL subtypes, including newly identified genetic subgroups.30–33 Point estimates suggesting pola-R-CHP benefit among different patient groups were observed in patients over 60 years of age, those with an IPI 3–5, those with double-expressor lymphoma, and those with ABC subtype, but not for those aged 60 years and under, with lower IPI or bulky disease, the GCB subgroup, and double- or triple-hit lymphoma. These and other subgroups should be assessed in future studies.
Among key secondary endpoints, pola-R-CHP significantly improved event-free survival versus R-CHOP and, while the difference in CR rate was not statistically significant, remissions appeared to be more durable with pola-R-CHP than with R-CHOP. The median follow-up on this study is 28 months, a period that does not allow the difference in progression-free survival to generate an influence on overall survival. However, some other studies have indicated that progression-free survival and 2-year event-free survival are often surrogates for overall survival in patients with DLBCL.34–36 The lack of difference in overall survival may also be explained by the advent of new, effective treatments for relapsed/refractory DLBCL in recent years.
The relatively short follow up provides no data confirming the expected plateau on the progression-free survival curve. DLBCL is characterized by having an early risk of relapse followed by a remarkable plateau in the survival curve demonstrating the likely cure of disease. Late relapses are unusual. It is expected that the remissions that have lasted at least 2 years will be durable based on past treatment results. The data from this study do not yet confirm that the remissions in response to pola-R-CHP will be durable. That issue can only be addressed with longer follow up.
Importantly, in this double-blinded study, drug delivery was not impeded by the replacement of vincristine with polatuzumab vedotin. Rituximab, doxorubicin, and cyclophosphamide delivery was maintained, with median relative dose intensities >99% in both treatment arms. Moreover, slightly more patients received all planned doses of polatuzumab vedotin than vincristine (91.7% vs. 88.5%) and fewer adverse events led to dose reductions with pola-R-CHP.
The occurrence of peripheral neuropathy is expected in patients treated with antibody–drug conjugates containing MMAE, and has been described in a single-agent polatuzumab vedotin study,20 and in polatuzumab vedotin combination studies.21–23 In this study, the majority of these symptoms were mild to moderate, and resolved after the end of treatment. Moreover, the incidence and severity of peripheral neuropathy was similar between treatment arms. These data are similar to those observed in the ECHELON-2 trial, where another antibody–drug conjugate combination, brentuximab vedotin with CHP, was compared with CHOP in patients with T-cell lymphoma.37 Although the rate of febrile neutropenia was higher with pola-R-CHP versus R-CHOP in the POLARIX study (14.3% vs 8.0%), this did not translate into greater overall rates of infection, treatment discontinuation, or dose reductions, and was similar to the rates (9.0% to 15.2%) reported in recent R-CHOP studies.12–14
Several groups of patients were not included in the study; those with lymphoma arising from previously diagnosed indolent lymphoma, those with a primary mediastinal lymphoma, and those over 80 years of age. A phase 3 trial investigating an age-adapted combination of pola-R-CHP with attenuated chemotherapy doses in the older patient population is ongoing (NCT04332822).
The pola-R-CHP combination demonstrated improved progression-free survival at 2 years, and had a similar safety profile to the R-CHOP regimen in the first-line treatment of patients with DLBCL.
Supplementary Material
ACKNOWLEDGMENTS
We thank the participating patients and their families, and the investigators (Supplementary Appendix), research nurses, study coordinators, and operations staff, as well as the Lymphoma Academic Research Organisation (LYSARC), and Ranjana Advani, M.D. (Chair), Martin Hutchings, M.D., Ph.D., and Raymond J. Carroll, Ph.D. of the Data and Safety Monitoring Committee. Also, Madeleine Ma, M.S., Jiaheng Qiu, Ph.D., Rucha Kothari, M.D., Gabriel Man, M.D., and Matthew Sugidono, Pharm.D. of Genentech, Inc. and Deniz Sahin of F. Hoffmann-La Roche Ltd for contributing to the analysis of the data.
Third-party medical writing assistance, under the direction of the authors, was provided by Andrea Bothwell B.Sc., contract medical writer for Ashfield MedComms, an Ashfield Health company, and Lucinda Sinclair, M.Sc., of Ashfield MedComms, an Ashfield Health company, and was funded by F. Hoffmann-La Roche Ltd.
FUNDING SOURCE
This study was sponsored by Genentech, Inc. and F. Hoffmann-La Roche Ltd.
Contributor Information
Hervé Tilly, Department of Hematology and U1245, Centre Henri Becquerel and University of Rouen, Rouen, France
Franck Morschhauser, Univ. Lille, CHU Lille, ULR 7365 – GRITA – Group de Recherche sur les formes Injectables et les Technologies Associées, Lille, France
Laurie H. Sehn, BC Cancer Centre for Lymphoid Cancer and the University of British Columbia, Vancouver, Canada.
Jonathan W. Friedberg, Wilmot Cancer Institute, University of Rochester, Rochester, NY, USA
Marek Trněný, First Faculty of Medicine, Charles University, General Hospital, Prague, Czech Republic
Jeff P. Sharman, Willamette Valley Cancer Institute/US Oncology, Eugene, OR, USA
Charles Herbaux, CHU de Montpellier, Montpellier, France
John M. Burke, Rocky Mountain Cancer Centers, Aurora, CO, USA
Matthew Matasar, Memorial Sloan Kettering Cancer Center, New York City/Montvale, NY/NJ, USA
Shinya Rai, Department of Hematology and Rheumatology, Kindai University, Faculty of Medicine, Osaka-Sayama City, Japan
Koji Izutsu, National Cancer Center Hospital, Tokyo, Japan
Neha Mehta-Shah, Washington University in St. Louis, St. Louis, MO, USA
Lucie Oberic, Department of Hematology, Institut Universitaire du Cancer, Toulouse-Oncopole, Toulouse, France
Adrien Chauchet, Department of Hematology, CHRU Besançon, Besançon, France
Wojciech Jurczak, Maria Sklodowska – Curie National Research Institute of Oncology, Kraków, Poland
Yuqin Song, Peking University Cancer Hospital, Beijing, China
Richard Greil, 3rd Medical Department, Paracelsus Medical University, Salzburg Cancer Research Institute-CCCIT and Cancer Cluster Salzburg, Austria
Larysa Mykhalska, Clinical Hospital Feofaniya, Kyiv, Ukraine
Juan Miguel Bergua Burgués, Hospital San Pedro de Alcántara, Cáceres, Spain
Matthew C. Cheung, Odette Cancer Centre, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, Canada
Antonio Pinto, Hematology-Oncology & Stem Cell Transplantation Unit, Istituto Nazionale Tumori, Fondazione ‘G. Pascale’, IRCCS, Naples, Italy
Ho-Jin Shin, Division of Hematology-Oncology, Department of Internal Medicine, Medical Research Institute, Pusan National University Hospital, Pusan National University School of Medicine, Busan, Korea
Greg Hapgood, Princess Alexandra Hospital, Brisbane, QLD, Australia
Eduardo Munhoz, Hospital Erasto Gaertner, Curitiba, Brazil
Pau Abrisqueta, Department of Hematology, Hospital Vall d’Hebron, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain
Jyh-Pyng Gau, Taipei Veterans General Hospital, Taipei, Taiwan
Jamie Hirata, Genentech, Inc., South San Francisco, CA, USA.
Yanwen Jiang, Genentech, Inc., South San Francisco, CA, USA
Mark Yan, Hoffmann-La Roche Ltd, Mississauga, ON, Canada
Calvin Lee, Genentech, Inc., South San Francisco, CA, USA
Christopher R. Flowers, MD Anderson Cancer Center, Houston, TX, USA.
Gilles Salles, Memorial Sloan Kettering Cancer Center, New York City, NY, USA.
DATA SHARING STATEMENT
Qualified researchers may request access to individual patient-level data through the clinical study data request platform (https://vivli.org/). Further details on Roche's criteria for eligible studies are available here (https://vivli.org/members/ourmembers/). For further details on Roche's Global Policy on the Sharing of Clinical Information and how to request access to related clinical study documents, see here (https://www.roche.com/research_and_development/who_we_are_how_we_work/clinical_trials/our_commitment_to_data_sharing.htm).
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Associated Data
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Supplementary Materials
Data Availability Statement
Qualified researchers may request access to individual patient-level data through the clinical study data request platform (https://vivli.org/). Further details on Roche's criteria for eligible studies are available here (https://vivli.org/members/ourmembers/). For further details on Roche's Global Policy on the Sharing of Clinical Information and how to request access to related clinical study documents, see here (https://www.roche.com/research_and_development/who_we_are_how_we_work/clinical_trials/our_commitment_to_data_sharing.htm).