Phase 2 GUIDANCE Trial of R-CHOP-X Meets Primary End Point in DLBCL

Red blood cells: © vipman4 - stock.adobe.com

Rituximab (Rituxan), cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) alone or combined with targeted agents (R-CHOP-X) demonstrated efficacy and safety in patients with newly diagnosed, intermediate-risk, or high-risk diffuse large B-cell lymphoma (DLBCL), according to findings published in Cancer Cell.¹

In the randomized, phase 2 GUIDANCE-01 trial (NCT04025593), patients were randomized 1:1 to receive R-CHOP-X or R-CHOP.² A higher response rate was observed with R-CHOP-X vs R-CHOP arm, meeting the primary end point of the study, (88% vs 66%; P =.003), with an overall response rate (ORR) of 92% (95% CI, 85-99) in the R-CHOP-X arm vs 73% (95% CI, 62-85) in the R-CHOP arm (P =.005).¹ 

With R-CHOP-X vs R-CHOP, 2-year progression-free survival (PFS) rates were 88% vs 63% (P <.001). For overall survival (OS), 2-year OS rates were 94% compared with 77% (P =.001). Additionally, the safety profile of R-CHOP-X was manageable, and no new clinically significant or unexpected toxicities were observed.

“Our findings demonstrate efficacy and safety of R-CHOP-X, a mechanism-based tailored therapy, which dually targets genetic and microenvironmental alterations in patients with newly diagnosed DLBCL,” wrote the study authors led by Mu-Chen Zhang, MD, Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.¹

A total of 134 patients were screened and treated between July, 2019 and December, 2020, and 128 ended up being randomly assigned 1:1 to receive R-CHOP-X (n = 64) or R-CHOP (n = 64). The primary end point of the study was complete response (CR) rate.² Secondary end points were PFS, OS, ORR, and number of patients with adverse events (AEs).

Between arms, baseline clinical and pathological characteristics were similar.¹ The median age of those enrolled was 64 years (range, 25-74), most patients presented with relatively high-risk disease (77%), and 80% of patients had an elevated serum LDH level. Additionally, 52% of patients had 2 or more extranodal involvement sites, and 65% had international prognostic index 3-5. A total of 36% of patients presented with MYC/BCL2 double expression and 1 presented with MYC/BCL6 rearrangement lymphoma. No patients had MYC/BCL2 rearrangement.

To characterize patients, simplified 20-gene algorithm was established to include MCD-like (20% of patients), BN2-like (18%), N1-like (4%), EZB-like (2%), TP53 mutations (16%), and not otherwise specified (39%).

At the end of treatment, the CR rate was 88% (95% CI, 79-96) with R-CHOP-X vs 66% (95% CI, 54-78) with R-CHOP arm. For genetic subtypes, CR rates were 85% (95% CI, 62-100) for MCD-like, 91% (95% CI, 71-100) for BN2-like, 100% for N1-like, 100% for EZB-like, 82% (95% CI, 55-100) for TP53mut, and 88% (95% CI, 74-100) for NOS in the R-CHOP-X arm. In the R-CHOP arm, these rates were 54% (95% CI, 23-85), 67% (95% CI, 35-98), 50%, 100%, 60% (95% CI, 23-97), and 80% (95% CI, 63-97), respectively.

With a median follow-up of 36 months, the median PFS and OS were not reached. With R-CHOP-X, 3 patients had a partial response (PR), 2 of whom received radiotherapy of the residual lesion revealed by final positron emission tomography-computed tomography evaluation. The other underwent a splenectomy and was pathologically confirmed with DLBCL. Three patients had stable disease (SD). Two of these patients received chimeric antigen receptor (CAR) T-cell therapy and achieved CR, and the other died from disease progression. Further, 2 patients had progressive disease (PD) and were salvaged with second-line chemotherapy. These patients died from disease progression.

In the R-CHOP arm, 5 patients had a PR with 3 receiving radiotherapy and 2 given second-line treatment. Four of the 7 patients with SD received second-line treatment followed by autologous hematopoietic stem cell transplantation and achieved CR, and the other 3 died from disease progression, including 1 patient who was treated with CAR T-cell therapy. Additionally, 10 patients had PD. Three of the patients with PD were given CAR T-cell therapy and died from disease progression, and the other 7 received second-line therapy. Six of the 7 patients died from disease progression.

Looking at safety, grade 3-4 neutropenia was the most common AE observed in both treatment arms (81% with R-CHOP-X v 75% with R-CHOP). In the R-CHOP-X vs R-CHOP arms, grade 3-4 thrombocytopenia was seen in 31% vs 11% of patients, grade 3 anemia in 25% vs 20%, and febrile neutropenia that was a maximum of grade 3 in 20% vs 11%.

No grade 4 anemia was reported. While there were increased rates of cytopenia and thrombocytopenia with R-CHOP-X, this did not lead to an increase in grade 3 pulmonary infection (6% v 5%) or gastrointestinal bleeding complications (2% v 3%) compared with R-CHOP. Moreover, any grade infections were seen in 22% vs 20%, respectively, and no treatment-related mortality was seen.

The study authors concluded, “genetic subtype-guided targeted agents combined with R-CHOP are effective, safe, and clinically feasible in newly diagnosed DLBCL. With the encouraging results of the POLARIX trial [NCT03274492], this genetic subtype-guided treatment of targeted agents combined with Pola-R-CHP [polatuzumab vedotin-piiq (Polivy), rituximab, cyclophosphamide, doxorubicin, and prednisone] may further improve the clinical outcomes for [patients with] intermediate-risk or high-risk DLBCL.”¹

REFERENCES:

1. Zhang MC, Tian S, Fu D, et al. Genetic subtype-guided immunochemotherapy in diffuse large B cell lymphoma: The randomized GUIDANCE-01 trial. Cancer Cell. 2023;41(10):1705-1716.e5. doi:10.1016/j.ccell.2023.09.004

2. Biomarker guided treatment in DLBCL. ClinicalTrials.gov. Updated November 19, 2020. Accessed October 25, 2023. https://tinyurl.com/2t5u8s7a