Lisa Astor is the Associate Editorial Director for Targeted Oncology. Astor received her Bachelor of Arts in English Literature from New York University.

Lisa Astor

A genetic subtyoe-guided approach to giving immunochemotherapy for patients with diffuse large B-cell lymphoma (DLBCL) showed encouraging rate of complete response (CR) in first reports from the phase 2 Guidance-01 trial (NCT04025593).

According to findings presented at the 2021 International Conference on Malignant Lymphoma, 5 of the regimens using R-CHOP (rituximab [Rituxan] plus cyclophosphamide, doxorubicin, vincristine, and prednisone) plus a genetic subtype–related treatment led to durable remissions and manageable toxicity. Presenter Mu-Chen Zhang, MD, reminded that DLBCL is associated with a degree of heterogeneity in terms of clinical and biological features. R-CHOP immunochemotherapy, the standard of care for patients with newly diagnosed DLBCL, leads to CRs in about 60% of patients.

“Genetic subtypes of DLBCL have distinct oncogenic pathway features, gene expression profiles, and variable clinical outcomes. Thismay explain why these patients are varied from the standard R-CHOP regimen,” said Zhang, of the Department of Hematology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine in Shanghai, China.

The investigators sought to determine if adding novel targeted agents to R-CHOP (R-CHOP-X) based on the genetic subtype of each patient’s disease could lead to improved clinical efficacy in the frontline setting.

All patients received at least 1 cycle of standard R-CHOP prior to randomization and stratification. Then, patients randomized to the R-CHOP-X arm were classified into 1 of 6 genetic subtypes by targeted sequencing and fluorescence in situ hybridization testing into classification groups defined in 2018 in the New England Journal of Medicine.2 The subtypes were MCD-like, BN2-like, N1-like, EZB-like, 

In the MCD-like and BN2-like groups, patients received ibrutinib (Imbruvica) 420 mg twice daily; the N1-like and other subtype groups received lenalidomide (Revlimid) 25 mg once daily for days 1 to 10; those with EZB-like disease received tucidinostat, an HDAC inhibitor, at 20 mg on days 1, 4, 8, and 11; and the group with TP53-mutant disease received decitabine at 10 mg/m2 on days 1 through 5. All patients also received R-CHOP and treatment was given for 5 cycles. Granulocyte colony-stimulating factor prophylaxis was given in the case of grade 3 or higher neutropenia.

The primary end point was CR rate, and secondary end points included progression- free survival (PFS), overall survival, objective response rate, and safety. The study assumed that 65% of patients in the R-CHOP control group and 85% of patients in the R-CHOP-X group would achieve a CR.

All patients had to have newly diagnosed disease, be aged 18-80 years, and have an International Prognostic Index (IPI) score of 2 or higher, ECOG performance status of 0 to 2, ejection fraction greater than 50%, and preserved organ and bone marrow function. Those with primary central nervous system lymphoma; uncontrollable cardio-cerebral vascular, coagulation, autoimmune, or infectious disease; active hepatitis B virus; or a history of HIV were excluded from the trial.

Patients were required to have absolute neutrophil count levels greater than 1500/mL and platelet levels greater than 75,000/mL at the time of retreatment, or immunochemotherapy would be delayed. If delayed by 8 to 14 days because of thrombocytopenia or neutropenia, the dose of cyclophosphamide and doxorubicin would be reduced. Targeted therapies were not held and doses were not modified midcycle.

Baseline characteristics were similar between the 2 arms. Among all 128 patients, the median age was 64 years (range, 25-74), and the majority were male (52%), had stage III-IV disease (77%), at least 2 extranodal sites (52%), an ECOG performance status of 0 or 1 (83%), and an IPI score of 3 to 5 (65%). Zhang noted that this indicated that this was a high-risk population.


Thirty-eight percent of patients had germinal center B-cell like disease, and 36% had MYC/BCL2 double expression.

The primary end point was met with 87% (95% CI, 79%-96%) of patients in the R-CHOP-X arm and 66% (95% CI, 54%-78%) in the R-CHOP control arm achieving CR (P = .003). Partial responses were observed in 5% of patients in the R-CHOP-X arm and in 9% of the R-CHOP arm, stable disease was reached in 5% and 8% of patients, respectively, and 3% and 17% of patients had progressive disease.

Patients were followed for survival for a median of 16.1 months. At 1 year, the PFS rate was 93% (95% CI, 81%-97%) in the R-CHOP-X arm and 73% (95% CI, 60%-83%) in the R-CHOP arm.

By genetic subtype groupings, the CR rate was higher in the R-CHOP-X arm than in the R-CHOP arm (

). Significant increases in CR were observed in the MCDlike (85% with R-CHOP and ibrutinib vs 54% with R-CHOP), BN2-like (91% with R-CHOP and ibrutinib vs 67% with R-CHOP), and 

-mutant (82% with R-CHOP and decitabine vs 60% with R-CHOP) groups where the patient populations were larger and able to show a difference. In the “others” group, the rate was similar, at 88% with R-CHOP plus lenalidomide (n = 25) compared with 80% with R-CHOP alone (n = 25).

Zhang noted that grade 3 or 4 hematologic adverse events were common in the 2 arms. Neutropenia was observed in 81% of patients in the R-CHOP-X arm vs in 75% of the R-CHOP arm; thrombocytopenia in 31% and 11%, respectively; anemia in 25% and 20%; and febrile neutropenia in 20% and 11%. Cytopenia and thrombocytopenia were manageable with supportive care and without treatmentrelated mortality. No grade 4 non-hematologic adverse events were reported.

Despite the increased rate of AEs, the dose intensity of chemotherapy was maintained at similar levels between the 2 arms, Zhang said. She highlighted that this was the first study of genetic subtype–guided therapy in DLBCL.

1. Zhang MC, Xu PP, Wang L, Cheng S, Zhao WL. Genetic subtype guided rituximab-based immunochemotherapy improves outcome in newly diagnosed diffuse large B-cell lymphoma: first report of a randomized phase 2 study (Guidance-01). Presented at: 16th International Conference on Malignant Lymphoma; June 19-22, 2021; virtual. Abstract 026.

2. Schmitz R, Wright GW, Huang DW, et al. Genetics and pathogenesis of diffuse large B-cell lymphoma. N Engl J Med. 2018;378(15):1396- 1407. doi:10.1056/NEJMoa1801445

Articles

Encouraging results have been reported from the phase 2 Guidance-01 clinical trial.








R-CHOP With Added Genetic Subtype-Based Targeted Therapy Improves CR Rates in Newly Diagnosed DLBCL

The triplet regimen of rituximab (Rituxan), venetoclax (Venclexta), and lenalidomide (Revlimid) was shown to be a safe frontline regimen in patients with mantle cell lymphoma (MCL) and showed early signs of efficacy.

“Early preliminary data [indicate] that the regimen was effective in patients with  several high-risk features…as indicated by complete remission [CR] rate and negative MRD [minimal residual disease] testing,” Tycel Jovelle Phillips, MD, clinical associate professor in the Department of Medicine at University of Michigan Health Rogel Cancer Center in Ann Arbor, Michigan, said in a presentation during the 2021 International Conference on Malignant Lymphoma.

Rituximab plus lenalidomide (R2) has previously demonstrated efficacy in MCL treatment, and venetoclax, has demonstrated preclinical synergy with lenalidomide. The investigators believed that the triplet regimen would be safe and would improve objective response rate, time to best response, and potentially induce MRD negativity vs R2 alone.

The trial enrolled patients with untreated MCL who required treatment. They were treated with lenalidomide 20 mg daily on days 1 through 21 every 28 days plus venetoclax starting at 50 mg and escalating weekly up to 400 mg daily and rituximab 375 mg/m

 on days 1, 8, 15, and 22 of cycle 1 as induction therapy for 12 planned cycles that was later amended to 6 cycles. Patients were then assessed by positron emission tomography (PET)/CT scan and with MRD testing every 3 cycles during induction and yearly during maintenance. Those who achieved a CR and MRD negativity who were ineligible for transplant went on to maintenance therapy with lenalidomide 10 mg daily on days 1 through 21 every 28 days plus venetoclax 400 mg daily and rituximab 375 mg/m

 only on even cycles. With maintenance therapy, venetoclax was given for 12 months, lenalidomide for 24 months, and rituximab for 36 months.

Immunoglobulin next-generating sequencing was used to identify and quantify disease- associated sequence rearrangements to 10-6 in peripheral blood samples.

A total of 30 patients were enrolled, 28 were treated, and 82% remained on treatment at data cutoff.

Of the 28 treated patients, 64% were male, all were Caucasian and had stage III or IV disease, 79% had an ECOG performance status of 0 or 1, 93% had bone marrow involvement, and 88% had high-risk disease. Patients had a median age of 65 years (range, 46-72). Additionally, 14% had blastoid disease, 7% had pleomorphic disease, 18% had mutated TP53 status, and 29% had abnormal cytogenetics.

All patients underwent PET/CT scan at 3 months, and 67% of these patients showed a CR, 29% had a partial response (PR), and 3% had progressive disease (PD). At 6 months, 27 patients were scanned, and 78% had a CR, 19% had a PR, and 3% had PD. Sixteen patients were scanned at 9 months, and 94% had a CR while the remainder had PD. At 12 months, all 12 patients who underwent PET/CT had a CR.

The duration of clinical response ranged from 2.8+ months to 24.4+ months as of data cutoff. Five patients are no longer on the trial, 3 due to disease progression and 2 for other reasons. All patients who progressed had 

The majority of patients who had positive MRD at the first assessment changed to MRD negative in subsequent assessments. Concordance was seen in most patients and assessments between flow cytometry and next-generation sequencing.

Progression-free survival rates were 96.4% (95% CI, 89.8%-100%) at 3 months, 92.0% (95% CI, 82.0%-100%) at 6 months, 92.0% (95% CI, 82.0%-100%) at 9 months, and 85.5% (95% CI, 71.0%-100%) at 12 months 

The median duration of treatment was 308 days (range, 237-636). Dose reductions or delays were reported in 53% of patients, and dose discontinuations due to adverse events (AEs) were reported in 21%.

The period for dose-limiting toxicities (DLTs) was 42 days from the initiation of venetoclax. All patients were safely able to escalate venetoclax up to the 400-mg daily dose, and no DLTs were reported.

The most common AEs of any grade were neutrophil count decrease (89%), platelet count decrease (72%), diarrhea (41%), anemia (36%), fatigue (25%), lymphocyte count decrease (25%), dyspnea (23%), and white blood cell decrease (21%).

There were several grade 3 or higher AEs, the most common of which were neutrophil count increase (62%), platelet count decrease (50%), and diarrhea (14%). Two secondary cancers were reported on the study— 1 adenocarcinoma of unknown primary and 1 cutaneous squamous cell carcinoma—and 4 deaths were reported on the study, 2 from lymphoma and 2 from other causes.

Phillips noted that the investigators plan to expand the study with 50 patients without a 

 mutation. They are also looking to modify the regimen to target patients with high-risk features, including 

Phillips TJ, Danilov A, Bond DA, et al. The combination of venetoclax, lenalidomide and rituximab in patients with newly diagnosed mantle cell lymphoma induces high response rates and MRD undetectability. Presented at: 16th International Conference on Malignant Lymphoma; June 19-22, 2021; virtual. Abstract 061.

According to Tycel Jovelle Phillips, MD, the study of venetoclax in combination with the R2 regimen will be expanded to include 50 patients with mantle cell lymphoma without a TP53 mutation.

Venetoclax Plus R2 Is Safe and Effective in Frontline MC

A large number of responses were observed in patients with advanced-stage follicular lymphoma who were treated with frontline nivolumab (Opdivo) plus rituximab (Rituxan), according to results from the phase 2 1st FLOR trial (NCT03245021).

Additionally, the combination showed a manageable safety profile, according to Eliza A. Hawkes, MD, who presented the results during the 2021 International Conference on Malignant Lymphoma.

Hawkes, a senior clinical research fellow and medical lead in lymphoma at the Olivia Newton- John Cancer Research Institute in Heidelberg, Australia, noted that standard frontline combination therapies have high response rates (75%-89%) but also high toxicity rates.

“Noting that these roughly compare to some chemotherapy combinations, the high efficacy compared [with] similar checkpoint inhibitor combinations in relapsed [disease] suggests adequate immune function is crucial to the success of these agents,” Hawkes said.

She suggested that due to the tumor microenvironment composition in follicular lymphoma, there is a possible role for immune manipulation with checkpoint inhibition. However, prior trials of PD-1/PD-L1 inhibitors have shown limited efficacy in heavily pretreated follicular lymphoma. In the phase 2 Check-Mate 140 trial (NCT02038946), nivolumab monotherapy led to an objective response rate (ORR) of 4% and a median progression-free survival (PFS) of 2.2 months in patients with relapsed/refractory disease.

Combination pembrolizumab (Keytruda) and rituximab led to an ORR of 65% and a complete response (CR) rate of 50% in patients with relapsed/refractory follicular lymphoma, suggesting that there is synergy between the 2 agents.

Investigators believed that PD-1 inhibitors could sensitize patients with relapsed non-Hodgkin lymphoma to subsequent chemotherapy. As such, the study investigators sought to determine if immune priming with nivolumab prior to combination therapy of nivolumab and rituximab could improve outcomes for patients with treatmentnaive follicular lymphoma.

The 1st FLOR study enrolled 39 patients with grade 1 to 3a, stage III/IV follicular lymphoma requiring therapy who were given treatment in an induction and a maintenance phase. Treatment was first given with nivolumab 240 mg/kg intravenously (IV) every 2 weeks for 4 cycles. If patients achieved a CR, they received nivolumab every 2 weeks for 4 cycles then nivolumab at 480 mg/kg IV every 4 weeks for 12 cycles as maintenance. If not, patients received nivolumab 240 mg/kg IV plus rituximab 375 mg/m

 IV every 2 weeks for 4 cycles. If patients achieved a response after induction therapy, they received maintenance with rituximab every 12 weeks for 8 cycles and nivolumab 480 mg/kg every 4 weeks for 12 cycles.

The primary end point was safety in terms of grade 3 or higher adverse events (AEs). Secondary end points included overall toxicity rate, ORR, PFS, and overall survival (OS).

Patients had a median age of 54 years (range, 28-79). The majority were men (51%), had Ann Arbor stage IV disease (67%), an ECOG performance status of 0 (74%), at least 1 extranodal site (74%), grade 1-2 follicular lymphoma (79%), and/or had intermediate-risk disease (56%).

The ORR was 93%, which consisted of CRs in 56% of patients and partial responses in 36%. Twenty-eight percent of patients had a response on nivolumab alone. Sixteen patients had a partial response during the induction phase, and 6 of them converted to a CR during maintenance.


The median duration of response was not reached after a median follow-up of 22 months both in the overall population of patients as well as in the patients who had a response to therapy. The median time to CR was 5 months (range, 1-25).


At 1 year, the OS rate was 97% (95% CI, 85%- 100%) and the failure-free survival rate was 68% (95% CI, 49%-83%). There were 11 progression events and 1 death during the study. The median time to progression was 10 months.

The primary end point of this study was met with only 41% of patients experiencing a grade 3 or higher AE during induction. Grade 3 or higher toxicities were reported in 64% of patients overall. Only 1 case of grade 4 toxicity of lymphopenia was reported during the maintenance phase, and 1 death was reported from transformed disease that was refractory to chemotherapy.

The most common grade 3 AEs observed during induction were lipase/amylase increase (8%), infection (8%), hyperglycemia (5%), and infusion reaction to either agent (5%). Grade 3 or higher AEs overall reported in 2 or more patients were infection (13%), lipase/amylase increase (8%), hyperglycemia (8%), hypotension (5%), infusion reaction (5%), and transaminitis.

Common immune-related AEs were rash, myalgia/arthralgia, dry mouth/eyes/skin, diarrhea, and transaminitis. One patient stopped nivolumab at the end of induction therapy due to grade 3 immune-related AEs. The majority of AEs were reversible.

Hawkes suggested that further studies of immunotherapy-based combinations showed be explored in patients with immunologically intact follicular lymphoma.

1. Hawkes EA, Lee ST, Chong G, et al. Immune priming with nivolumab followed by nivolumab & rituximab in 1st line treatment of follicular lymphoma: the phase II ‘1st FLOR’ study. Presented at: 16th International Conference on Malignant Lymphoma; June 18-22, 2021; virtual. Abstract 081.

2. Armand P, Janssens A, Gritti G, et al. Efficacy and safety results from CheckMate 140, a phase 2 study of nivolumab for relapsed/refractory follicular lymphoma. 

. 2021;137(5):637-645. doi:10.1182/blood.2019004753

3. Nastoupil LJ, Westin J, Fowler N, at al. High response rates with pembrolizumab in combination with rituximab in patients with relapsed follicular lymphoma: interim results of an on open-label, phase II study. 

. 2017;35(S2):120-121. doi:10.1002/hon.2437_108

According to Eliza A. Hawkes, MD, the phase 2 1st FLOR trial showed the positive efficacy of frontline nivolumab in combination with rituximab.

Frontline Nivolumab and Rituximab Shows Efficacy With Manageable Safety in Follicular Lymphoma

Treatment with larotrectinib (Vitrakvi) in patients with various subtypes of salivary gland tumors led to a high rate early and durable responses, according to a presentation during the American Head & Neck Society 10th International Conference on Head and Neck Cancer.

“Larotrectinib demonstrated robust and durable efficacy in patients with 

 fusion salivary gland tumors with different types of histology,” said Xiuning Le, MD, PhD, assistant professor in the Department of Thoracic/Head and Neck Medical Oncology at The University of Texas MD Anderson Cancer Center in Houston. “These data highlight the clinical importance of identifying NTRK gene fusions in patients with salivary gland tumors, regardless of histology.”

 gene fusions occur in an estimated 5% of cases of salivary gland tumors, including in approximately 80% of secretory carcinomas.

Larotrectinib was approved for the treatment of adult and pediatric patients with solid tumors harboring 

 gene fusions, regardless of tumor type, without a known acquired resistance mutation that are either metastatic or where surgery is not recommended.

 Across a number of clinical trials, the TRK inhibitor induced an objective response rate (ORR) of 75% (95% CI, 61%-85%) in 206 adult and pediatric patients with TRK fusion–positive cancer.

For the analysis of patients with TRK fusion–positive salivary gland tumors, investigators looked at patients from the phase 2 NAVIGATE basket trial (NCT02576431) and a phase 1 trial (NCT02122913) of adult patients, all with advanced solid tumors. Twenty-four patients were treated with 100 mg larotrectinib twice daily, except for 1 patient who received 150 mg twice daily.

The primary end point was ORR by investigator assessment per RECIST v1.1 criteria, and secondary end points included duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety.

TABLE. SURVIVAL RATES OF LAROTRECTINIB IN NTRK-POSITIVE SALIVARY GLAND CANCERS.

Patients had a median age of 58.5 years (range, 28.0-78.0), 75% were male, and half had an ECOG performance status of 0. Almost all patients had undergone surgery (96%) and radiotherapy (83%), and half had received systemic therapy. Twenty-one percent of patients had received 2 or more prior systemic therapies.

Tumor histology was secretory carcinoma in 54%, adenocarcinoma in 21%, and mucoepidermoid in 13%. Also, 1 patient each had adenoid cystic carcinoma, glandular sarcomatoid carcinoma, and not otherwise specified. All patients had an ETV6-NTR K3 gene fusion.

The ORR was 92% (95% CI, 73%-99%), which consisted of complete responses in 13% and partial responses in 79%; progressive disease was reported in the other 8% of patients, 1 of whom had an NTRK3 G623R resistance mutation after prior entrectinib (Rozlytrek) therapy. Responses were observed in all histologies.

The duration of treatment ranged from 0.95 to 60.4+ months. Five of 8 patients who progressed continued treatment beyond progression for 2.8 to 20.5+ months. The median time to response was 1.84 months (range, 0.99-5.98). Le noted that early responses were “consistent with a potent, efficacious, on-target [tyrosine kinase inhibitor].”

The median DOR, PFS, and OS were all not reached as of data cutoff (

). The DOR rate was 72% at 24 months and 60% at 36 months. The PFS rate was 78% at 24 months and 66% at 36 months. The OS rate was 91% at both 24 and 36 months.

Le noted that the treatment was well-tol-erated overall, even for long-term use. Treatment-emergent adverse events (AEs) were mostly grade 1 or 2. No grade 4 events or treatment discontinuations due to treatment-related AEs were reported in the study.

The most common treatment-related AEs were alanine aminotransferase (ALT) increase, dizziness, aspartate aminotransferase (AST) increase, fatigue, constipation, nausea, myalgia, and muscle spasm. Grade 3 treatment-related AEs included ALT increase in 3 patients, AST increase in 2, dizziness in 1, and abnormal hepatic function in 1.

1. Le X, Baik C, Bauman J, et al. Efficacy and safety of larotrectinib in patients with advanced TRK fusion salivary gland cancer. Presented at: American Head & Neck Society 10th International Conference on Head and Neck Cancer; July 22-25, 2021; virtual. Abstract S030.

2. FDA approves larotrectinib for solid tumors with NTRK gene fu-sions. FDA. Updated December 14, 2018. Accessed August 24, 2021. https://bit.ly/3BaseOq

Treatment with larotrectinib in patients with various subtypes of salivary gland tumors led to a high rate early and durable responses. 

Lisa Astor | Authors

Articles

R-CHOP With Added Genetic Subtype-Based Targeted Therapy Improves CR Rates in Newly Diagnosed DLBCL

Venetoclax Plus R2 Is Safe and Effective in Frontline MC

Frontline Nivolumab and Rituximab Shows Efficacy With Manageable Safety in Follicular Lymphoma

Larotrectinib Shows Significant Efficacy in NTRK+ Salivary Gland Tumors