Ariana Pelosci 

A distinguishable number of HER2-low advanced gastric cancer were seen and discernable from HER2-negative and positive disease in patients. This warrants the development of future treatment options for this subgroup of patients.

According to data from a single-institution study presented at the 2022 Gastrointestinal Cancers Symposium, 21% of patients had HER2-low inoperable or recurrent advanced gastric cancer, and had immediately identifiable clinicopathological features in sex, histology, and metastatic site serum levels between those with HER2-negative and HER2-positive disease.

The aim of the retrospective analysis was to determine if HER2-low in gastric cancer can be distinguishable from HER2-positive or HER2-negative disease. Between 2011 and 2018, 750 patients with advanced gastric cancer were treated with fluoropyrimidine and platinum-containing chemotherapy. For this analysis, the researchers excluded 16 patients because a lack of available data on HER2 or FISH testing .

As a result, the study authors reviewed the findings from 734 patients, of which 410 had HER2-negative disease, 154 were HER2-low, and 170 had HER2-positive disease. The investigators defined HER2 disease as the following: HER2-negative with an immunohistochemistry (IHC) score of 0; HER2-low with IHC 1+ or 2+; and HER2-positive with IHC of 2+ or 3+. The data cutoff was August 2022.

The median age in the HER2-negative group was 64, 63 in HER2-low, and 64 in HER2-positive, with a majority of patients being male across all 3 groups (

 = .193). The stomach was the most common location of the primary tumor with others including esophagogastric junction or the cardia (

 = .029), with most being metastatic upon diagnosis (

Most patients did not receive a gastrectomy prior to treatment (

 = .008), and it was common for patients to have 2 or more metastases (

The metastatic sites were split between either the liver (18.3% vs 24.8% vs 46.5%), distant lymph node (29.5% vs 37.0% vs 37.6%), or peritoneum (56.3% vs 44.8% vs 21.8%) in patients with HER2-negative, HER2-low, or HER2-positive disease, respectively.

The median overall survival among the HER2-negative group was 15.7 months (95% CI, 14.2-17.3), 15.7 months for patients with HER2-low disease (HR, 1.01; 95% CI, 0.82-1.23; 

 = .843), and 21.7 months (95% CI, 17.1-24.7) for those with HER2-positive advanced gastric cancer (HR, 0.73; 95% CI, 0.59-0.89; 

Progression-free survival (PFS) was evaluated if patients received subsequent chemotherapies. In those receiving taxane therapy, the PFS was 3.3 months, 3.5 months, and 4.1 months, across all arms respectively. The PFS for the 3 groups receiving irinotecan was 2.6 months, 2.4 months, and 2.5 months. For those receiving nivolumab (Opdivo), the PFS was 1.9 months, 2.1 months, and 2.7 months. Across all 3 regimens, there was no statistical difference in PFS.

To be eligible for the retrospective analysis, patients must have been aged 18 years or older, had histologically confirmed adenocarcinoma of the stomach or esophagogastric junction, and have had previously been untreated, inoperable, or recurrent advanced disease. Additionally, patients must have been treated with a platinum-containing regimen in the first-line setting and have confirmed HER2 status.

Exclusion criteria included having been previously treated at another hospital or being recurrent 6 months or more after the last therapy treatment.

The investigators concluded that the findings of the analysis confirm that the development of an effective treatment targeting HER2-low advanced gastric cancer is warranted.

Nakayama I, Takahari D, Chin K, et al. Clinicopathological features of HER2-low expressed advanced gastric cancers. J Clin Oncol. 2023; 41(suppl 4):459. doi:10.1200/JCO.2023.41.3_suppl.459

Articles

Findings presented at the 2022 Gastrointestinal Cancers Symposium warrant the need for new treatments that attack HER2-low advanced gastric cancer. 

Abundant Number of HER2-Low Cases Detected in Patients With Advanced Gastric Cancer 

Results from the phase 2 ELARA trial (NCT03568461) show that tisagenlecleucel (Kymriah) continued to induce high rates of durable responses in patients with relapsed/refractory follicular lymphoma after 2 years of follow-up, according to presented at the 

2022 American Society of Hematology (ASH) Annual Meeting

A complete response (CR) rate was observed in 68% (95% CI, 58%-77%) of patients, and there was an overall response rate (ORR) of 86% (95% CI, 78%-92%). Of all patients, baseline disease characteristics were observed in 63% of those who had progression of disease within 2 years (POD24), high metabolic tumor volume in 21%, bulky disease in 64%, double refractory disease in 67%, and a high Follicular Lymphoma International Prognostic Index (FLIPI) score of 3 or more in 59%.

“Tisagenlecleucel was found to be well-tolerated and feasible for outpatient administration. The extended follow-up of 2 years or more from the ELARA trial continues to demonstrate durable efficacy and a favorable safety profile following tisagenlecleucel in patients with relapsed/refractory follicular lymphoma,” Martin Dreyling, MD, lead study author and associate professor at the University of Munich, said during the presentation.

The study design included an initial screening, apheresis, and cryopreservation; enrollment with optional bridging chemotherapy and tisagenlecleucel manufacturing; followed by a restaging of lymphodepletion; tisagenlecleucel infusion; first efficacy assessment at month 3; and concluded with a long-term follow-up. Patients received a single intravenous infusion of tisagenlecleucel with a dose range from 0.6 to 6x108 CAR-positive viable T cells. Tisagenlecleucel was received by 18% of those in the outpatient setting,

In the long-term analysis, there were no new safety signals observed. However, Dreyling did point out that all-grade cytokine release syndrome occurred in 49% (n = 47/97) of patients, and 0% had grade 3 or higher events. Additionally, all-grade immune effector cell neurotoxicity syndrome was observed in 4% (n = 4/97) of patients, and 1% (n = 1/97) had a grade 3 or higher event. Grade 3 or higher neurological events occurred in 2% (n = 2/97)of patients. Of those who received outpatient treatment, none required intensive care unit treatment, and one-third did not need hospitalization to manage effects.

After a median follow-up of 29 months, the secondary end points of median duration of response (DOR), progression-free survival (PFS), overall survival (OS), and time to next treatment (TTNT) were not reached.

The median DOR for all patients and those with a CR were not estimable (NE). However, those with a partial response (PR) had a median DOR of 3 months (95% CI, 2-4). The event-free probability in all patients at 12 months was 74% (95% CI, 62%-82%) and 66% (95% CI, 54%-76%) at 24 months. Additionally, the event-free probability for patients in CR at 12 and 24 months, was 87% (95% CI, 76%-93%) and 78% (95% CI, 65%-87%), respectively.

The median PFS for all patients and those who had CR were not met, but the median for those in PR was 6 months (95% CI, 5-6). The event-free probability in all patients was 67% (95% CI, 56%-76%) at 12 months and 57% (95% CI, 46%-67%) at 24 months. For patients with CR, the event-free probability was 87% (95% CI, 76%-93%) at 12 months and 75% (95% CI, 62%-84%) at 24 months.

Additionally, the median OS in all patients was NR, but was 35 months (95% CI, 35-NE) for those in CR and 26 months (95% CI, 24-NE) for those in PR. The 12-month event-free probability in all patients was 95% (95% CI, 88%-98%), and the 24-month rate was 88% (95% CI, 78%-93%). For patients with a CR, the 12-month event-free probability was 98% (95% CI, 89%-100%), and the 24-month rate was 95% (95% CI, 85% -98%).

The median TTNT was not reached for all patients and for those with a CR. However, for those who had a PR, the median TTNT was 10 months (95% CI, 6-NE). The event-free probability for all patients at 12 months was 80% (95% CI, 70%-87%) and 70% (95% CI, 59%-78%) at 24 months. In patients who had a CR, the event-free probability was 95% (95% CI, 86%-98%) at 12 months and 83% (95% CI, 71%-91%) at 24 months.

Patients with higher baseline tumor burden had shorter PFS, which included metabolic tumor volume by PFS (

In the exploratory analysis at POD24, the nodal area involvement, tumor volume, and lymphocyte activation gene (LAG) T cells in the tumor microenvironment (TME) were prognostic for PFS separation. Additionally, lower LAG-positive T cells were more favorable towards TME and were associated with a longer DOR (

Additionally, lower tumor necrosis factor (

 = .031) were less inflammatory and showed a prolonged PFS.

Dreyling M, Dickinson M, Martinez-Lopez J, et al. Long-term clinical outcomes and correlative efficacy analyses in patients with relapsed/refractory follicular lymphoma treated with tisagenlecleucel in the ELARA trial. Presented at the 2022 American Society of Hematology Annual Meeting; December 10-13; New Orleans, LA. Abstract 608.

The phase 2 ELARA trial achieved durable responses in patients with relapsed/refractory follicular lymphoma who were treated with tisagenlecleucel. 

Tisagenlecleucel Sustains Responses After 2 Years in R/R Follicular Lymphoma

Five-year follow-up found that rituximab (Rituxan) plus lenalidomide (Revlimid) elicited superior progression-free survival (PFS) for patients with relapsed/refractory indolent non-Hodgkin lymphoma, according to results from the phase 3 AUGMENT study (NCT01938001), which were presented at the 2022 American Society of Hematology (ASH) Annual Meeting.

In the rituximab plus lenalidomide arm, the median PFS — which was the primary endpoint of the study — was 27.6 months (95% CI, 22.1-60.5) compared with 14.3 months (95% CI, 12.4-17.7) in the placebo arm (HR, 0.50; 95% CI, 0.38-0.66; 

The overall survival (OS) in both the combination and placebo arms was not estimable (NE; HR, 0.59; 95% CI, 0.37-0.95; 

 = .0285). However, the 5-year OS rates were 83.2% vs 77.3% for the rituximab plus lenalidomide arm and placebo arms, respectively.

“The updated results for OS are consistent with the improvement observed in PFS. These results, including OS data, further support the use of the regimen as a standard of care for patients with relapsed/refractory indolent non-Hodgkin lymphoma,” John P. Leonard, MD, Richard T. Silver Distinguished Professor of Hematology and Medical Oncology at Weill Cornell Medicine, and lead author of this study, said during the presentation.

The study involved a total of 358 patients who were randomly assigned 1:1 to either the rituximab plus lenalidomide arm (n = 178) or the placebo arm (n = 180). In the combination arm, patients were given 20 mg of lenalidomide on days 1 to 21 of cycles 1 to 12, and rituximab was given at 375 mg/m2 on days 1, 8, 15, and 22 during cycle 1 and day 1 during cycles 2 to 5. Matched dose of placebo was given in the control arm.

Secondary endpoints included overall response rate, complete response, duration of response, OS, and time to next lymphoma treatment.

In the total population, the median age was 63 years; 48% were male; and 68% had an ECOG performance score of 0. In the combination arm, most patients had histology of follicular lymphoma (83%) vs marginal zone lymphoma (17%), with comparable rates in the placebo arm (82% vs 18%).

Between both arms, a majority of patients had 1 prior line of therapy (57% vs 54%). Prior rituximab treatment occurred in 85% of patients in the combination arm and 83% in the placebo arm, while 17% vs 14% were refractory to their last treatment regimen.

Overall, 70% of patients completed treatment in the rituximab plus lenalidomide arm vs 61% in the placebo arm; and 37% vs 43% discontinued the study. Reasons for study discontinuation included the withdrawal of consent (19% vs 12%), death (15% vs 26%), loss to follow-up (2% vs 4%), and other (1% vs 1%) in the combination and placebo arms, respectively. Of note, the final data cutoff date was January 26, 2022, and the median follow-up was 65.9 months.

The median time to next lymphoma treatment was 73.1 months (95% CI, 43.0-NE) in the rituximab plus lenalidomide arm vs 31.8 months (95% CI, 22.2-39.4) in the placebo arm (HR, 0.53; 95% CI, 0.39-0.71; 

 < .0001). Leonard pointed out that fewer patients in the combination arm received 1 or more lines of subsequent therapy (41%) compared with the placebo arm (61%).

Treatment-emergent adverse effects (TEAEs) that were grade 3/4 and which were observed in 69% of patients in the combination arm and 32% in the placebo arm, were related to lenalidomide or placebo in 57% vs 21%, or were related to rituximab occurred in 32% vs 11% of patients. Grade 5 TEAEs occurred in 2 patients each between both arms. Additionally, serious TEAEs occurred in 26% vs 14% of patients in the combination and placebo arms, respectively.

Of note, the overall safety profile remained consistent with the primary analysis, and investigators did not find any new signals.

Patients who received lenalidomide were more likely to receive a dose reduction (26%) than those receiving placebo (3%). Additionally, there was a higher interruption in lenalidomide treatment (64%) compared with placebo or rituximab (26%).

Secondary primary malignancies occurred in 7% of patients in the combination arm and 12% in the placebo arm, and included solid tumors (4% vs 8%), noninvasive non-melanoma skin cancer (3% vs 3%), and hematological malignancy (1% vs 2%).

In patients who died, secondary primary malignancies occurred in 2% in the combination arm and 3% in the placebo arm. The incidence rate of secondary primary malignancies per 100 patients-years was 1.62% (95% CI, 0.94%-2.78%) in the rituximab plus lenalidomide arm and 2.66% (95% CI, 1.73-4.07%) in the placebo arm.

Fewer patients with histologic transformations were observed in the combination arm (6%) compared with the placebo arm (8%). Additionally, the incidence rate per 100 patient-years was 1.24% (95% CI, 0.66%-2.30%) in the combination arm vs 1.85% (95% CI, 1.12%-3.07%) in the placebo arm.

Overall, 15% of patients in the combination arm died compared with 26% in the placebo arm. Causes of death included disease progression or disease complication (5% vs 14%), secondary primary malignancy or complication (2% vs 2%), AEs (2% vs 1%), other (5% vs 6%), or unknown (2% vs 4%) in the combination and placebo arms, respectively.

Leonard JP, Treny M, Offner F, et al. Five-year results and overall survival update from the phase 3 randomized study AUGMENT: lenalidomide plus rituximab versus rituximab plus placebo in patients with relapsed/refractory indolent non-Hodgkin lymphoma. Presented at the 2022 American Society of Hematology (ASH) Annual Meeting; December 10-13, 2022; New Orleans, LA. Abstract 230.

Five-year follow up results from the phase 3 AUGMENT trial show that lenalidomide plus rituximab produced enhanced progression-free survival in patients with relapsed/refractory indolent non-Hodgkin lymphoma. 

Lenalidomide/ Rituximab Extends 5-Year PFS on R/R Indolent Non-Hodgkin Lymphoma

A significant improvement in progression-free survival was shown with the combination of capivasertib plus fulvestrant in patients with hormone-receptor–positive/HER2-negative advanced breast cancer and those who have AKT pathway-altered tumors, according to results from the phase 3 CAPItello-291 trial (NCT04305496) presented during a press conference at the 

The median PFS was 7.2 months in those receiving capivasertib plus fulvestrant vs 3.6 months in the placebo arm (HR, 0.60; 95% CI, 0.51-0.71; 2-sided 

 < .001). Patients had an objective response rate (ORR) of 22.9% in the capivasertib arm vs 12.2% in the placebo arm. In patients who had AKT pathway mutations, the median PFS was 7.3 months in the capivasertib arm and 3.1 months in the placebo arm (HR, 0.50; 95% CI, 0.38-0.65; 2-sided 

 < .001). Additionally, the ORR was 28.8% vs 9.7% in the capivasertib and placebo arms, respectively.

“The improvement in progression-free survival with relatively well-tolerated [adverse] effects is extremely encouraging,” Nicholas Turner, MD, PhD, lead author of the study said. “We are hopeful that capivasertib will become a new treatment option for patients whose cancer has progressed on a regimen containing an endocrine therapy.”

A total of 708 patients were randomly assigned 1:1 in the overall population to either the capivasertib plus fulvestrant (n = 355) arm or the placebo plus fulvestrant arm (n = 353). Those who had AKT pathway-altered tumors were also randomly assigned to either the capivasertib arm (n = 155) or the placebo arm (n = 134). Patients received 400 mg twice daily of capivasertib for 4 days on and 3 days off; 500 mg of fulvestrant during cycle 1 days 1 and 15 then every 4 weeks; with the placebo arm being matched.

The primary end points were PFS by investigator assessment both in the overall population and those with AKT pathway tumors, while the secondary end points included overall survival (OS) and ORR.

In the overall population, a majority of patients received 1 prior line of endocrine therapy (80.6% vs 71.4%) compared with the AKT altered-pathway tumors (83.9% vs 71.6%), additionally, previous CDK4/6 inhibitors were given between both the overall (69.0% vs 69.1%) and the AKT altered pathways (72.9% vs 67.9%), as well as previous adjuvant/neoadjuvant therapy in the overall population (50.7% vs 48.2%) and the AKT altered pathway (51.0% vs 50.0%) in the capivasertib vs placebo arms, respectively.

In the non-altered population, the investigator-assessed PFS was 7.2 months in the capivasertib arm vs 3.7 months in the placebo arm (HR, 0.70; 95% CI, 0.56-0.88). When PFS was assessed via the prespecified subgroup analysis, there was a consistent benefit seen in all groups.

The planned OS analysis, which was requested, showed a benefit between both groups in the overall population (HR, 0.74; 95% CI, 0.56-0.98) and the AKT altered-pathway group (HR, 0.69; 95% CI, 0.45-1.05).

Adverse effects of grade 3 or higher that were most common in those receiving capivasertib vs placebo included diarrhea (9.3% vs 0.3%), rash that was maculopapular (6.2% vs 0%), rash (5.4% vs 0.6%), hyperglycemia (2.3% vs 0.3%), and stomatitis (2.0% vs 0%). Discontinuation because of AEs occurred in 2.3% of patients in both the capivasertib and placebo arms.

Turner N, Oliveria M, Howell SJ, et al. Capivasertib and fulvestrant for patients with aromatase inhibitor-resistant hormone receptor-positive/human epidermal growth factor receptor 2-negative advanced breast cancer: results from the Phase III CAPItello-291 trial. Presented at the 2022 San Antonio Breast Cancer Symposium; December 6-10, 2022; San Antonio, TX. Abstract GS3-04.

Findings from the phase 3 CAPItello-291 trial show that the combination of capivasertib plus fulvestrant achieved improvement in progression-free survival among patients with hormone-receptor–positive/HER2-negative advanced breast cancer. 

Capivasertib Plus Fulvestrant Reduces Risk of Disease Progression or Death in HR+/HER2– Breast Cancer

Results from the phase 3 ECHELON-1 trial determined brentuximab vedotin plus doxorubicin, vinblastine, and dacarbazine should be used as first-line treatment in patients with stage III or IV classical Hodgkin lymphoma.

The use of brentuximab vedotin (Adcetris) was analyzed in the phase 3 ECHELON-1 trial (NCT01712490) for patients with Hodgkin lymphoma.

 In March 2018, the FDA approved brentuximab vedotin for patients with stage III or IV classical Hodgkin lymphoma in combination with chemotherapy.

At the National Comprehensive Cancer Network 2022 Annual Congress: Hematologic Malignancies, David J. Straus, MD, medical oncologist at Memorial Sloan Kettering Cancer Center in New York, New York, presented the most updated findings of the trial, and debated if this was the best course of action for treating Hodgkin lymphoma. The presentation focused on results from the trial, and how to implement the findings into treatment plans.

A total of 1334 patients were enrolled and randomized 1:1 to either the brentuximab vedotin plus doxorubicin, vinblastine, and dacarbazine (A+AVD) group or brentuximab vedotin plus bleomycin, doxorubicin, vinblastine, and dacarbazine (ABVD) group. In the A+AVD group (n = 664), patients were given 1.2 mg/kg of brentuximab vedotin intravenously on days 1 and 15 compared with the ABVD group (n = 670) where patients received matched dosing. Patients then continued to end-of-treatment CT/PET scans with follow-up every 3 months for 36 months then every 6 months until the study ended.

The primary end point of the trial was modified progression-free survival (PFS) and the key secondary end point was alpha-controlled event-driven analysis of overall survival (OS). Long-term follow-up assessments included exploratory analysis of OS in patients who were PET2-positive and PET2-negative, PFS per investigator, subsequent treatment use, and safety.

In the A+AVD arm, the 5-year PFS was 84.9% (95% CI, 81.7%-87.6%) compared with 78.9% (95% CI, 75.2%-82.1%) in the ABVD group (HR, 0.66; 95% CI, 0.50-0.88; 

 = .0035). In those who were PET2-positive, PFS was inferior (HR, 0.70; 95% CI, 10.39-1.26 ; log-rank 

 = .2) compared with those who were PET2-negative (HR, 0.66; 95% CI, 0.50-0.88; log-rank 

 = .0035). Straus noted that only about a third of the patients who were PET2-positive relapsed.

At 6 years, the estimated PFS rates for the A+AVD group was 82.3% (95% CI, 79.1%-85.0%) vs 74.5% (95% CI, 70.8%-77.7%) in the ABVD group (HR, 0.68; 95% CI, 0.53-0.86; log-rank 

 = .002). The median follow-up was 73 months.

The OS rates at 6 years was 93.9% (95% CI, 91.6%-95.5%) in the A+AVD group vs 89.4% (95% CI, 86.6%-91.7%) in the ABVD group (HR, 0.59; 95% CI, 0.40-0.88; log-rank 

 = .009). The median OS was not reached at 73 months of follow-up. Additionally, the subgroup analysis showed OS remained consistent. The multivariate analysis was adjusted for baseline characteristics and disease factors (HR, 0.53; 95% CI, 0.34-0.83). The covariates with the greatest association with OS was age, non-White race, ECOG performance status, and PET2 status.

In the A+AVD group, 5.9% of patients died compared with 9.7% in the ABVD group. The main causes of death included Hodgkin lymphoma or complications in 32 patients vs 45 patients, and second malignancies in 1 patient vs 11 patients in the A+AVD and ABVD groups, respectively. In the A+AVD group, other causes of death included accident or suicide (n = 3), unknown cause (n = 1), heart failure (n = 1), and intracranial hemorrhage (n = 1). In the ABVD group, other causes of death included unknown causes (n = 5), COVID-19 (n = 1), heart failure (n = 1), and lower respiratory tract infection (n = 1).

Second malignancies in the A+AVD group included 9% hematologic malignancies and 14% had solid tumors. In the ABVD group, 17% had hematologic malignancies and 14% had solid tumors. Transplants occurred in 2 patients in each arm. In 3 patients in the ABVD arm, prior radiation was received.

Pregnancy and peripheral neuropathy were one of the safety end points assessed. Among the patients enrolled in the trial, 191 pregnancies occurred in patients or their partners.

 There were no still births reported. In the A+AVD group, 67% of patients had peripheral neuropathy at 2-year follow-up vs 43% in the ABVD group.

 At follow-up grade 3 peripheral neuropathy occurred in 2% of patients in the A+AVD group vs less than 1% in the ABVD group, while grade 4 occurred in less than 1% vs 0%.

Strauss concluded the presentation statin OS was improved in the A+AVD arm, with the trial being the first to show it. Additionally, patients experienced fewer secondary malignancies as well as disease-related deaths. These data cement the fact that A+AVD should be used as first-line treatment for patients with stage III or IV classical Hodgkin lymphoma.

1. Straus DJ, Długosz-Danecka M, Connors JM, et al. Brentuximab vedotin with chemotherapy for stage III or IV classical Hodgkin lymphoma (ECHELON-1): 5-year update of an international, open-label, randomised, phase 3 trial.

l. 2021;8(6):e410-e421. doi:10.1016/S2352-3026(21)00102-2. Published Correction appears in Lancet Haematol. 2022 Feb;9(2):e91].

2. Brentuximab vedotin. News Release. FDA. March 20, 2018. Accessed October 16, 2022. https://bit.ly/3yM9gim

3. Connors JM, Jurczak W, Straus DJ, et al. Brentuximab vedotin with chemotherapy for stage III or IV Hodgkin's lymphoma. 

. 2018;378(4):331-344. doi:10.1056/NEJMoa1708984. Published Correction appears in N Engl J Med. 2018 Mar 1;378(9):878].

4. Ansell SM, Radford J, Connors JM, et al. Overall survival with brentuximab vedotin in stage III or IV Hodgkin's lymphoma. 

. 2022;387(4):310-320. doi:10.1056/NEJMoa2206125

At the NCCN Annual Congress:Hematologic Malignancies, David J. Straus, MD debated if this was the best course of action for treating Hodgkin lymphoma. 

Brentuximab Vedotin Shows Promising Activity as First-Line Use in Classical Hodgkin Lymphoma 

Finding the right treatment for patients with mantle cell lymphoma (MCL) in the second-line setting can be difficult, as there currently is no standard of care. If a patient experiences a response from treatment, it may typically last between 5 to 10 years with lower overall response rates (ORR).

During a presentation at the National Comprehensive Cancer Network 2022 Annual Congress: Hematologic Malignancies, Tycel Phillips, MD, clinical associate professor at City of Hope National Medical Center in Durate, California spoke about finding the optimal treatment for patients with MCL.

Phillips reviewed treatment options such as ibrutinib (Imbruvica), acalabrutinib (Calquence), and zanubrutinib (Brukinsa), as well as options post-bruton tyrosine kinase (BTK) inhibitors. Additionally, he spoke about adverse event (AE) profiles observed with each treatment, and which patients would benefit the most from these options.

Phillips began by discussing a study (NCT01236391) that first showed the effectiveness of BTK inhibitors in MCL.

 In this trial, patients were broken out into arms of either no prior treatment with bortezomib (Velcade; n = 63), prior treatment with bortezomib (n = 48), and all patients (n = 111). The ORR was 68%, 67%, and 68%; the complete response (CR) was 19%, 23%, and 21%; and the partial response (PR) was 49%, 44%, and 47% in those with no prior treatment, prior treatment, and all patients, respectively.

The median duration of response (DOR) was 15.8 months (95% CI, 5.6-not reached [NR]) in those with no prior treatment, NR in those with prior treatment, and 17.5 months (95% CI, 15.8-NR) in all patients. The median progression-free survival (PFS) was 7.4 months (95% CI, 5.3-19.2), 16.6 months (95% CI, 8.3-NR), and 13.9 months (95% CI, 7.0-NR) in those with no prior treatment, prior treatment, and all patients, respectively. Finally, the median overall survival (OS) was not reached across all 3 treatment arms.

A compilation study looked at multiple BTK inhibitor studies to determine when the best time to use these treatments.

 In those with 1 prior line of therapy, the median PFS was 33.6 months (95% CI, 19.4-42.1), and the median OS was NR. The median DOR was 4.5 years for patients who achieved a CR, and those with 1 prior line of therapy had 2 times longer DOR than those with more than 1 previous line. This study showed it’s best to use BTK inhibitors in earlier lines of therapy vs later.

In a study assessing the ORR of acalabrutinib (NCT02213926), in the investigator-assessed group the ORR was 81% vs the independent review committee (IRC) of 80%.

 The CR was 40% vs 40%, and the PR was 41% vs 40% in the investigator-assessed and IRC groups, respectively.

Dose reductions occurred in 1.6% of patients, and 6.5% discontinued treatments because of AEs. Regarding AEs, atrial fibrillation was not observed, with the most common AEs being headaches (36%) and diarrhea (38%), of which were mostly grade 1 and 2. Hematologic AEs were mostly grade 1 and 2 and included bruising and petechiae. Additionally, there was 1 grade 3 gastrointestinal hemorrhage. Phillips noted that recent reports have raised concerns about the cardiac related AEs with this treatment, but that more time and study is needed with this new class to fully assess their AE outcomes.

Phillips also spoke about zanubrutinib with a study again assessing ORR (NCT02343120).

 In the investigator-assessed group the ORR was 90.6% (95% CI, 75.0%-98.0%) vs 84.4% (95% CI, 67.2%-94.7%) in the IRC group. The CR was 31.3% vs 25.0% and the PR was 59.4% vs 59.4% between both groups, respectively. The median PFS was 21.1 months, and the DOR was 18.5 months.

AEs that were grade 3 or higher included major hemorrhage (9.4%), atrial fibrillation or flutter (3.1%), hypertension (3.1%), and infection (18.8%).

Of note, Phillips mentioned that there is no main difference between ibrutinib, acalabrutinib, and zanuburtinib efficacy-wise. The reason they are separated is based on their AE profiles differing.

Phillips first discussed the phase 2 PHILEMON study (NCT02460276) that looked at the combination of ibrutinib, lenalidomide (Revlimid), and rituximab (Rituxan) in relapsed or refractory patients.

This study focused on patients who either had 

 mutations in their disease or did not. The ORR was 76% (95% CI, 63%-86%) in all patients, 79% (95% CI, 64%-89%) in 

 unmutated, and 73% (95% CI, 43%-90%) in 

 mutated. The CR rate was 28% (95% CI, 42%-69%), 21% (95% CI, 40%-70%), and 64% (95% CI, 35%-85%), while PR was seen in 20% (95% CI, 11%-33%), 24% (95% CI, 13%-39%), and 9% (95% CI, 2%-38%) in all patients, patients with 

 mutated disease, respectively. However, Phillips explained that this was not the right combination for patients with MCL in the second-line setting.

In the phase 3 SYMPATICO investigation (NCT03112174) of ibrutinib plus venetoclax (Venclexta) patients were evenly split between those without a PET scan and those with.

 Looking at response at 4 weeks there was none recorded for those who had a PET scan, but when looking at best response, the CR was 67% for those without a PET scan vs 71% for those with a PET scan. PR was 4% vs 0%. Phillips noted that certain patients in this trial had a 

 mutation, and at follow-up, they relapsed quickly. However, this combination may still be effective in those without 

When venetoclax was first analyzed in humans (NCT01328626), the PFS and OS determined it was an effective agent for the treatment in MCL.

 However, the study consisted of patients who were BTK-naive and may not be reflective of what is seen in the real-world setting, according to Phillips. He then deemed the question for clinicians to think about was how effective is venetoclax as a single agent or even in combination with rituximab post-exposure to a covalent BTK inhibitor

In the phase 2 ZUMA-2 trial (NCT02601313) brexucabtagene autoleucel (brexi-cel; Tecartus) was analyzed in patients with MCL.

 The efficacy of this study was promising. After 12.3 months of follow-up, the median PFS and OS, and DOR had not been reached, but overall, 57% of patients and 78% who obtained a CR are still in remission. While he acknowledged longer follow up was needed for this therapy, results suggest a promising treatment for patients that fail BTK inhibitors.

Cytokine release syndrome (CRS) and neurotoxicity were observed in this population. Grade 3 or higher CRS occurred in 15% of patients, and the most common symptoms were pyrexia (91%), hypotension (51%0, and hypoxia (34%). Tocilizumab (Actemra) was given to 59% of patients and corticosteroids to 22% to help manage symptoms.

Grade 3 or higher neurologic AEs occurred in 31% of patients, with the most common symptoms being tremors (35%), encephalopathy (31%), and confusional state (21%). Patients were given either tocilizumab (26%) or corticosteroids (38%) to help mitigate symptoms, with the majority of patients having resolution of their symptoms. 

Additional treatments for MCL were discussed including glofitamab.

 A trial conducted found it produced a high response rate in patients with relapsed/refractory MCL. In the fixed dosing group of 1000 mg (n = 3), the complete metabolic response (CMR) was 67%, 71% in those receiving step-up dosing plus 1000 mg of glofitamab (n = 7), 64% CMR and 27% partial metabolic response (PMR) in those receiving step up dosing plus 2000 mg of glofitamab (n = 11), and 67% CMR and 14% PMR for all patients. In those receiving prior BTK inhibitor therapy, the CMR was 65% and the PMR was 18% compared with 75% for no prior therapy.

Pirtobrutinib was discussed with patients either being pre-treated with BTK inhibitors, or BTK-naïve.

 The ORR was 51% (95% CI, 41%-61%) in those who were pretreated, with a CR of 25%, and a PR of 26%. In those who were BTK-naive, the ORR was 82% (95% CI, 48%-98%), with a CR of 18% and a PR of 64%. The median follow-up was 8.3 months for patients who responded, and 60% of responses are ongoing.

Phillips concluded that it may be difficult to treat patients with MCL who have previously received a BTK inhibitor, but efficacy was improved with the use of CAR T cells. Moving forward, there are other agents that show positive outcomes, but they are currently limited to clinical trials.

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4. Wang M, Rule S, Zinzani PL, et al. Acalabrutinib in relapsed or refractory mantle cell lymphoma (ACE-LY-004): a single-arm, multicentre, phase 2 trial. Lancet. 2018;391(10121):659-667. doi:10.1016/S0140-6736(17)33108-2

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9. Wang M, Munoz J, Goy A, et al. KTE-X19 CAR T-cell therapy in relapsed or refractory mantle-cell lymphoma. N Engl J Med. 2020;382(14):1331-1342. doi:10.1056/NEJMoa1914347

10. Cheson BD, Fisher RI, Barrington SF, et al. Recommendations for initial evaluation, staging, and response assessment of Hodgkin and non-Hodgkin lymphoma: the Lugano classification. J Clin Oncol. 2014;32(27):3059-3068. doi:10.1200/JCO.2013.54.8800

11. Wang M, Shah NN, Alencar AJ, et al. Pirtobrutinib, a next generation, highly selective, non-covalent BTK inhibitor in previously treated mantle cell lymphoma: updated results from the phase 1/2 BRUIN study. Blood. 2021;138(suppl 1):381. doi:10.1182/blood-2021-149138

At the 2022 NCCN annual congress, Tycel Phillips, MD, discussed different strategies that can be effective as second-line treatments in various patients who have relapsed/refractory mantle cell lymphoma. 