Patients with relapsed/refractory large B-cell lymphoma (LBCL) experienced a clinically meaningful improvement in quality of life (QoL) after 100 days of treatment with axicabtagene ciloleucel (axi-cel; Yescarta). Complete findings on the use of the autologous anti-CD19 CAR T-cell therapy as a second-line treatment were recently presented in an analysis of the phase 3 ZUMA-7 trial (NCT03391466) during the 2021 ASH Annual Meeting and Exposition.

Using the patient-reported outcome (PRO) instruments EORTC QLQ-C30, EQ-5D-5L, and Work Productivity and Activity Impairment: General Health (WPAI), investigators reported patients treated with axi-cel (n = 165) in the QoL analysis set assessed at day 100 achieved a statistically significant difference in mean change of scores from baseline in favor of axi-cel vs SOC (n = 131). Patients had a change from baseline in favor of axi-cel at day 100 in the prespecified PRO end points for EORTC QLQ-C30 physical functioning (

 < .0001), EORTC QLQ-C30 global health status/QoL (

 < .0001), and EQ-5D-5L visual analog scale (VAS; 

“Sensitivity analyses controlling for covariates and patterns of missingness showed similar results with retained significance at day 100,” said Mahmoud Elsawy, MD, MSc, an assistant professor in the Division of Hematology at Dalhousie University in Halifax, Nova Scotia. “[Furthermore] the mean estimated scores for the axi-cel arm returned to or exceeded the scores at baseline by day 100 to day 150 vs month 9 or later in the SOC arm.”

EORTC QLQ-C30 is a cancer-specific 30-item questionnaire that includes global health status and functional and symptom scales. The questionnaire has functional scales for physical, role, emotional, cognitive, and social functioning. Symptom scales include fatigue, nausea and vomiting, pain, dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial difficulties.

EQ-5D-5L is a general questionnaire with 5 QoL domains plus a global assessment. The domains include mobility, self-care, usual activities, pain/discomfort, and anxiety and depression. The VAS provides a rating of global assessment of the patient’s state of health on the day of assessment.

WPAI measures work productivity and activity impairment. The instrument has scales for absenteeism, presenteeism, overall work impairment, and activity impairment.

Eligible adult patients underwent an initial disease assessment prior to treatment and were reassessed at day 50, 100, 150, and month 9, then every 3 months thereafter from randomization up to 24 months or at the time of an event-free survival (EFS) event, whichever occurred first. Prespecified hypotheses for 3 PRO domains (EORTC QLQ-C30 physical functioning, EORTC QLQ-C30 global health status/QoL, and EQ-5D-5L VAS) were tested using a mixed-effect model with repeated measures at day 100 and subsequent time points if previous time points were found to be statistically insignificant.

Investigators defined clinically meaningful change as 10 points for each EORTC QLQ-C30 score, 7 points for the EQ-5D-5L VAS score, and 0.06 for the EQ-5D-5L index. Exploratory analyses on other domains of EORTC QLQ-C30 and EQ-5D-5L were also performed.

Axi-cel showed a favorable statistically significant change from baseline (

 < .05) at day 100 in the EORTC QLQ-C30 scales for nausea and vomiting, diarrhea, insomnia, and appetite loss. Statistically significant changes from baseline were also seen in role functioning at days 100 and 150. Social functioning, fatigue, and dyspnea measures all moved favorably in a statistically significant manner for axi-cel at day 100, day 150, and month 9.

Regarding the WPAI PRO instrument, investigators reported that patients treated with axi-cel had statistically significant (

 < .05) lower mean absenteeism, and lower mean activities impairment at day 100 compared with those receiving SOC treatment.

ZUMA-7 enrolled a total of 359 adult across 77 sites in the United States, Canada, Europe, and Israel. Patients were randomized 1:1 to receive either conditioning chemotherapy plus axi-cel or SOC investigator-selected platinum-based chemotherapy for at least 2 cycles. Responding patients in the SOC arm proceeded to high-dose chemotherapy followed by autologous stem cell transplantation (HDT-ASCT) and nonresponding patients were given additional treatment off of study protocol.

Patients with relapsed/refractory LBCL who a maximum of 1 year removed from their first-line therapy were eligible for the trial. Eligible patients also needed to intend to proceed to HDT-ASCT. Optional steroid-bridging therapy was permitted.

The primary end point of the trial was EFS by blinded central review. The key secondary end points were objective response rate and overall survival. Additional secondary end points included progression-free survival, safety, and PROs.

Baseline patient demographics for patients included in the QoL analysis set were comparable. Among the 165-patient axi-cel group, 28% were at least 65 years old vs 32% in the SOC group (n = 131). Most patients in both arms were primary refractory (72% vs 68%, respectively) and were negative for double/triple hit status per investigator (62% vs 58%, respectively). Investigators noted a second-line age-adjusted International Prognostic Index score of 2 or 3 in 42% of the axi-cel arm and 43% of the SOC arm.

“Score comparisons at later timepoints warrant cautious interpretation because attrition due to disease progression, new lymphoma therapy, or death was disproportionately higher on the SOC arm and may select patients with the best outcomes,” Elsawy said. “[Nonetheless] the superior clinical outcomes and patient experience with axi-cel over SOC should help inform treatment choices in second-line relapsed/refractory LBCL.”

Elsawy M, Chavez JC, Avivi I, et al. Patient-reported outcomes in a phase 3, randomized, open-label study evaluating the efficacy of axicabtagene ciloleucel (axi-cel) versus standard of care therapy in patients with relapsed/refractory large b-cell lymphoma (ZUMA-7). Paper presented at: 2021 ASH Annual Meeting and Exposition; December 11-14, 2021; Atlanta, GA. Abstract 430.

Articles

Axicabtagene ciloleucel improved the quality of life in patients with relapsed/refractory large B-cell lymphoma receiving the agent as a second-line therapy.

Patients with LBCL Experience Improved Quality of Life Following Axi-Cel Treatment 

A long-term follow-up analysis of a phase 1b/2 study found that patients with previously treated, advanced endometrial cancer experienced durable responses with a manageable safety profile after receiving the combination of lenvatinib (Lenvima) plus pembrolizumab (Keytruda). Vicky Makker, MD, preented the updated findings from the trial (NCT02501096) during the 2021 Society for Immunotherapy of Cancer (SITC) Annual Meeting.

“With extended follow-up, this updated analysis continued to show durable responses, as well as [survival] benefits in patients with challenging to treat, advanced endometrial cancer who received lenvatinib plus pembrolizumab,” said Makker, MD, a medical oncologist at Memorial Sloan Kettering Cancer Center in New York, New York. “The safety profile [for the combination] was generally consistent with that of the individual monotherapies.”

At the August 18, 2020, data cutoff, the total population of the analysis included 108 patients. The objective response rate (ORR) was 39.8% (95% CI, 30.5%-49.7%), including 9 (8.3%) complete responses (CRs). The median progression-free survival (PFS) was 7.4 months (95% CI, 5.2-8.7) and the median overall survival (OS) was 17.7 months (95% CI, 15.5-25.8). The median duration of response (DOR) was 22.9 months (95% CI, 10.2-not evaluable [NE]).

To be eligible for the open-label, single-arm trial, patients needed to have histologically confirmed and metastatic endometrial carcinoma measurable by immune-related RECIST. A maximum of 2 prior systemic therapies were permitted and patients needed to have an ECOG performance status of 1 or less. The study required patients have a minimum life expectancy of at least 12 weeks.

Investigators administered oral lenvatinib at a dose of 20 mg per day; 200 mg pembrolizumab was administered intravenously every 3 weeks. Pembrolizumab could be given for a maximum of 35 cycles and lenvatinib could continue beyond this point as long as benefit was observed. The primary end point of the trial was ORR at week 24. Key secondary end points included overall ORR, disease control rate (DCR), DOR, and progression-free survival (PFS).

The mean age of the total population was 65.1. Most patients (50.9%) had an endometroid carcinoma and 32.4% had a serous adenocarcinoma. The vast majority of the population (98.1%) had previously been treated for endometrial cancer with a platinum plus taxane combination and 49.1% of patients were PD-L1 positive.

The end points of the follow-up analysis included ORR, PFS, DOR, OS, and safety. The median follow-up duration was 34.7 months (95% CI, 30.9-41.2). The analysis population included 94 patients who were MMR proficient (pMMR) and 11 patients who were MMR deficient (dMMR).

In the pMMR cohort, the mean age was 65.4 and 48.9% of patients were PD-L1-positive. An even number (50%) of patients received 1 or 2 prior treatments for endometrial cancer. Common histological subtypes included endometrioid adenocarcinoma (48.9%), serous adenocarcinoma (35.1%), and clear cell adenocarcinoma (5.3%). Nearly all (98.1%) had been previously treated for endometrial cancer with a platinum plus taxane combination.

In the dMMR group, the mean age was 62.4 and most patients were PD-L1-positive (63.6%). All patients had been previously treated for endometrial cancer with a platinum plus taxane combination and 36.4% had undergone 2 prior treatment regimens. The most common histological subtype was endometrioid carcinoma (72.7%), of which 36.4% of patients were FIGO grade 2.

Among the patients who were pMMR, the ORR was 38.3% (95% CI, 28.5%-48.9%) and 8 patients achieved a CR. The median DOR was 25.0 months (95% CI, 8.5-NE) and the mean time to response was 3.2 months. The median PFS was 7.4 months (95% CI, 4.4-7.6) and the median OS was 17.2 months (95% CI, 15.0-28.5).

In the dMMR cohort, the ORR was 63.6% (95% CI, 30.8%-89.1%). The median DOR was 21.2 months (95% CI, 7.33-NE). Notably, the median OS was NE (95% CI, 7.4-NE) and the median PFS was 26.4 months (95% CI, 4.0-NE).

In terms of safety, 96.3% of the total population experienced any treatment-related treatment-emergent adverse events (TEAEs). Most patients (74.1%) experienced a TEAE that lead to study-drug interruption and 21.3% had a TEAE that lead to study-drug discontinuation. TEAEs of grade 3 or higher were reported in 71.3% of patients.

Common TEAEs of any grade included hypertension (60.2%), diarrhea, fatigue (both 53.7%), decreased appetite (50%), and hypothyroidism (46.3%). Grade 3 or higher TEAEs included hypertension (33.3%), fatigue (8.3%), and diarrhea (7.4%).

“Study 309/KEYNOTE-775 (NCT03517449), a confirmatory study of lenvatinib plus pembrolizumab vs treatment of physician’s choice in advanced endometrial cancer, further supports the lasting clinical benefits observed in this follow-up study,” concluded Makker.

On July 21, 2021, the FDA granted a full approval to lenvatinib plus pembrolizumab for the treatment of patients with advanced endometrial carcinoma that is not microsatellite instability-high or dMMR, who have disease progression after previous systemic therapy in any setting, and who are not candidates for curative surgery or radiation based on data from the KEYNOTE-775 trial.

Makker V, Aghajanian C, Cohn AL, et al. Lenvatinib and pembrolizumab in advanced endometrial carcinoma: long-term efficacy and safety update from a phase 1b/2 study. Presented at: 2021 Society for Immunotherapy of Cancer (SITC) Annual Meeting; November 10-14, 2021; Washington, DC. Abstract 354.

FDA grants regular approval to pembrolizumab and lenvatinib for advanced endometrial carcinoma. News release. FDA. July 22, 2021. Accessed September 6, 2021. https://bit.ly/3wRB9Sw

This article was originally published on OncLive as “Lenvatinib Plus Pembrolizumab Displays Strong Efficacy in Advanced Endometrial Cancer”

A presentation at the 2021 Society for Immunotherapy of Cancer (SITC) Annual Meeting shared updated findings on the efficacy of lenvatinib plus pembrolizumab in patients with advanced endometrial cancer. 

Lenvatinib/Pembrolizumab Combo Continues to Show Benefit in Advanced Endometrial Cancer

It has become imperative that patients with cancer receive a full COVID-19 vaccination with 1 of the 3 approved vaccines as soon as they are able, emphasized Steven Ludlow, PharmD, BCOP, BCPS.

“Today, there continues to be an issue with COVID-19,” said Ludlow, a clinical pharmacy specialist at the H. Lee Moffitt Cancer Center in Tampa, Florida, during a presentation at the 

 CFS®. “We just last week crossed the very ominous line of 5 million worldwide deaths. We’re looking pretty good; things are on the mend right now. But we were saying this in June as well, just before we had our brush with [the Delta variant]. We still have a very large pool of [patients with] COVID-19 in the population, and there is also the general unvaccinated status of many undeveloped nations.”

Three COVID-19 vaccines available in the United States: BNT162b2 (Pfizer/BioNTech), mRNA-1273 (Moderna), and JNJ-78436735 (Janssen/Johnson & Johnson). BNT162b2 and mRNA-1273 are mRNA-based vaccines, whereas JNJ-78436735 is an andenovirus vector–based product. Both mRNA-based vaccines are administered in a 2-dose series, approximately 28 days apart; JNJ-78436735 is a single-dose vaccine. BNT162b2 is the only vaccine that has received FDA approval for patients who are at least 16 years or older, and the other 2 have been granted emergency use authorization by the FDA.

According to the most recent National Comprehensive Cancer Network (NCCN) recommendations concerning COVID-19 vaccines for patients with cancer, individuals should receive the vaccine if it is available to them, except for those with solid tumors undergoing major surgery, being treated with hematopoietic cell transplantation (HCT)/cellular therapy, and those with hematologic malignancies receiving intensive cytotoxic chemotherapy.

The NCCN recommends that patients undergoing HCT or cellular therapy wait until at least 3 months after their treatment to receive a COVID-19 vaccine. Patients with hematologic malignancies undergoing intensive cytotoxic chemotherapy are recommended to delay their vaccination until absolute neutrophil count recovery. Patients with solid tumors being treated with major surgery are recommended to separate their date of surgery from vaccination by a few days, at minimum.

“The only reason for [patients who have undergone major surgery to delay the vaccine] is not because of surgery itself, [this is to prevent] confusion with fevers that are an adverse effect related [to a vaccine] with one that may be a complication of a major surgery,” Ludlow said.

In terms of vaccine booster doses, almost all patients with cancer should receive a booster dose 6 months after their second dose of an mRNA vaccine. For patients who received the JNJ-78436735 vaccine, a booster dose is recommended 2 months later. The NCCN does not recommend using antibody titers to determine if patients should receive the third dose, the decision should be made based on the underlying cancer, therapy, and other immunocompromising conditions.

In patients with immunosuppression, a third dose of an mRNA is recommended by the CDC after the standard 2 dose regimen. The third shot is not considered a booster, but rather it is part of a 3-dose series. The third dose should be given 28 days after the initial primary of an mRNA vaccine.

In the moderately to severely immunocompromised, the CDC recommends a booster dose 6-months after the third of the initial series. This primarily concerns patients with hematologic malignancies and patients who receive stem cell transplant. After the fourth dose, if these patients progress to CAR-T cell therapy or stem cell transplant, they should repeat their initial primary series, potentially with a booster dose.

“We cannot do direct comparisons; these vaccines were studied in different places, at different times, and with different variants,” Ludlow said. “We saw the data with the mRNA vaccines which were tested originally against the Alpha strain. We saw the South American and South African strains being tested against the Johnson & Johnson products. It’s unfair to put these [data] right next to each other. I would say that the best vaccine is the one that’s in your patient's arm.”

Ludlow S. COVID-19 vaccine: what the medical oncologist needs to know. Presented at: 39th Annual CFS® Innovative Cancer Therapy for Tomorrow; November 3-5, 2021; New York, NY.

FDA Approves First COVID-19 Vaccine. News release. FDA; August 23, 2021. Accessed November 4, 2021. https://www.fda.gov/news-events/press-announcements/fda-approves-first-covid-19-vaccine

Cancer and COVID-19 vaccination, version 4.0 : recommendations of the National Comprehensive Cancer Network (NCCN) COVID-19 Vaccination Advisory Committee. August 30, 2021. Accessed November 4, 2021. https://www.nccn.org/docs/default-source/covid-19/2021_covid-19_vaccination_guidance_v4-0.pdf?sfvrsn=b483da2b_70

NCCN COVID-19 vaccination guide for people with cancer. National Comprehensive Cancer Network. Accessed November 4, 2021. https://www.nccn.org/docs/default-source/covid-19/covid-vaccine-and-cancer-05.pdf?sfvrsn=45cc3047_2

COVID-19 vaccines for moderately to severely immunocompromised people. CDC. Updated October 18, 2021. Accessed November 4, 2021. https://www.cdc.gov/coronavirus/2019-ncov/vaccines/recommendations/immuno.html

This article was originally published on OncLive as “COVID-19 Vaccination Remains Imperative for Patients with Cancer”

Patients with cancer should receive the entire COVID-19 vaccination as soon as possible, according to an expert at the 39th Annual Chemotherapy Foundation Symposium. 

COVID-19 Vaccination a Must For Patients With Cancer

Impressive response rates, duration of response (DOR) and overall survival were all observed in pretreated patients with recurrent/metastatic cervical cancer who were administered a combination of the anti-PD-1 antibody balstilimab and the anti-CTLA-4 antibody zalifrelimab (AGEN1884) in a single arm phase 2 trial (NCT03495882) recently presented at the 2021 ESMO Annual Congress.

Among the 125-patient efficacy evaluable population, the combination elicited an overall response rate (ORR) of 25.6%. Ten (8.8%) responders experienced a complete response (CR). Among the 67-patients with a positive PD-L1 status, the ORR was 32.8% compared with 9.1% in the PD-L1-negative subgroup (n = 33).

Notably, the median duration of response (DOR) was not reached (range, 9.3 months-not reached). The 6-month DOR rate was 86.4% and the 12-month rate was 66.7%.

“There remains a significant unmet medical need for patients with recurrent or metastatic cervical cancer who progress after platinum-containing chemotherapy,” explained David O'Malley, MD, the director of the Division of Gynecologic Oncology at The Ohio State University Comprehensive Cancer Center–Arthur G. James Cancer Hospital and Richard J. Solove Research Institute and a professor in the Department of Obstetrics and Gynecology at The Ohio State University College of Medicine in Columbus.

“We know that single agent PD-1 activity is modest while CTLA-4 inhibition demonstrates limited to no activity in patients with cervical cancer,” he added. “Combining anti-PD1 and anti-CTLA-4 [agents] is now an established treatment paradigm across a broad spectrum of solid tumors. In this phase 2 study design, we report the largest trial to date combining PD-1 and CTLA-4 in patients with cervical cancer.”

In order to be eligible for the trial, patients needed to have histologically confirmed squamous cell carcinoma, adenosquamous carcinoma, or adenocarcinoma of the cervix that relapsed after platinum-based treatment. Patients also had to have measurable disease and an ECOG performance status of 0 or 1.

The primary end point of the trial was ORR by RECIST v1.1 per an independent review committee. Secondary end points included OS, DOR, and progression-free survival. The trial enrolled a total of 155 patients in Europe, Australia, South America, and the United States.

The median age of the total population was 50 (range, 24-76). Most patients (70.3%) had squamous cell carcinoma, 27.1% had adenocarcinoma, and 2.6% had adenosquamous histology.ECOG performance status was well balanced, 57.4% registered a 0 and 42.6% were at 1. A majority of patients (56.8%) had positive PD-L1 tumor expression status, defined as a combined positive score of at least 1%. The most common prior therapy exposures, besides platinum-containing (99.4%), were taxane (78.7%) and bevacizumab (32.9%).

Balstilimab was administered at a dose of 3 mg/kg every 2 weeks. Zalifrelimab 1 mg/kg was given every 6 weeks. Treatment lasted for up to 24 months and follow-up imaging occurred every 6 weeks through 2 years.

At a median follow-up of 21 months, the median PFS was 2.7 months (95% CI, 1.5-3.7). The median OS was 12.8 months (95% CI, 8.8-17.6). In the PD-L1-positive subset, the median OS improved to 15.7 months (95% CI, 7.6-21.1).

“The response rates [for this combination] nearly double currently achieved with approved agents in the second-line setting, including single agent PD-1 antibodies,” noted O’Malley. “Beyond response rate, the distinguishing feature of combining CTLA-4 and PD-1 antibodies are improved depth and durability of responses as well as survival outcomes. Longer follow-up will hopefully confirm this exciting trend and establish long-term survival as an achievable goal in advanced/recurrent cervical cancer.”

In terms of safety, 71.0% of the 155-patient safety population experienced a treatment-related adverse event (TRAE) of any grade. Common TRAEs of any grade included hypothyroidism (16.8%), diarrhea (14.2%), and fatigue (11.6%). TRAEs of at least grade 3 occurred in 20.0% of patients and included increased alanine transaminase (2.6%) and diarrhea (1.9%). TRAEs that lead to dose interruption were reported in 12.3% of patients and TRAEs leading to dose discontinuation occurred in 7.7% of patients.

Immune-mediated AEs were less commonly observed (44.5%), and included hypothyroidism (14.2%), hyperthyroidism (7.1%), diarrhea (7.1%), and puritis (4.5%).

“[This was] the largest study to date evaluating dual PD-1/CTLA-4 checkpoint blockade in patients with recurrent/metastatic cervical cancer,” concluded O’Malley. “With a median follow-up of almost 2 years, the balstilimab and zalifrelimab combination showed high response rates, durable clinical activity, and promising overall survival results. Advocacy outcomes were particularly impressive in the PD-L1 positive patients, but also broadly seen in subgroups with poor risk features. A confirmatory randomized phase 2 study comparing balstilimab and zalifrelimab with balstilimab alone is actively enrolling.”

O’Malley DM, Neffa M, Monk BJ, et al. Balstilimab (anti-PD-1) in combination with zalifrelimab (anti-CTLA-4): Final results from a phase II study in patients (pts) with recurrent/metastatic (R/M) cervical cancer (CC). Presented at: 2021 European Society for Medical Oncology Congress. September 16-21, 2021; virtual. Abstr 724MO.

A phase 2 trial presented at the 2021 ESMO Annual Congress showed that Balstilimab plus Zalifrelimab induced superior response rates, duration of responses, and overall survival in patients with recurrent/metastatic cervical cancer. 

Balstilimab Zalifrelimab Combination Yields Promising Results in Recurrent/Metastatic Cervical Cancer

Copanlisib (Aligopa) plus rituximab (Rituxan) proved to be safe and effective in the treatment of patients with relapsed indolent non-Hodgkin lymphoma (iNHL), compared with rituximab plus placebo, according to an expert from the University of Michigan Rogel Cancer Center.

Tycel J. Phillips, MD,, a clinical associate professor at the University of Michigan Rogel Cancer Center in Ann Arbor, discussed data from the ongoing CHRONOS-3 study (NCT02367040), which examined the combination of copanlisib and rituximab vs placebo plus rituximab in patients with relapsed iNHL, as part of an 

 program. Results from the trial were originally presented at the American Association for Cancer Research Annual Meeting 2021.

The median progression-free survival (PFS) for patients with iNHL treated with copanlisib plus rituximab (n = 307) was 21.5 months (95% CI, 17.8-33.0) compared with 13.8 months (95% CI, 10.2-17.5) for the 151 patients in the rituximab plus placebo cohort (HR, 0.52; 95% CI, 0.39-0.68; P < .0001). The median duration of treatment was 8.3 months (range, 0.2-54.0) and 10.8 months (range, 0.2-46.6) in the copanlisib and rituximab and the rituximab plus placebo groups, respectively.

“Given that this study was mainly done in patients in a second-line setting, it does appear in this situation that copanlisib plus rituximab is a viable option for this patient population,” Phillips explained. “Ideally, the key to if this moves into the mainstream will be the duration of response of this treatment and, [specifically,] how durable some of the complete remissions are in this patient population. As of now, with the data we have, that information has not been extrapolated.”

Copanlisib, a selective, potent, intravenous (IV) pan-class I PI3K inhibitor, is approved as monotherapy for the treatment of patients with relapsed follicular lymphoma (FL) who have received at least 2 systemic therapies.

Copanlisib has predominant on-target activity against the PI3K-α and PI3K-σ isoforms. Rituximab monotherapy is recognized as a standard of care for patients with relapsed iNHL and a long remission after prior rituximab-based therapy, or for those who are unwilling to have or unfit for treatment with chemotherapy.

CHRONOS-3 is a randomized, doubleblinded, placebo-controlled, phase 3 study enrolling a total of 458 adult patients with indolent B-cell lymphoma. Patients included were those with relapsed disease following a previous rituximab, rituximab biosimilar, or anti-CD20 monoclonal antibody–containing regimen. Study participants also had to be progression and treatment free for at least 12 months since the previous rituximab-containing regimen or at least 6 months for patients who were unwilling or unfit to receive chemotherapy.

Patients were randomized 2:1 in favor of the experimental arm. In the copanlisib plus rituximab arm, patients received IV copanlisib at a dose of 60 mg on days 1, 8, and 15 of a 28-day cycle. Rituximab was given at a dose of 375 mg/m2 on days 1, 8, 15, and 22 during cycle 1, and on day 1 of cycles 3, 5, 7 and 9.

The dose scheduled was mirrored in the control arm, with placebo taking the place of copanlisib. Treatment in both arms contin-ued until disease progression or intolerance. Additionally, the investigators conducted a safety follow-up, active follow-up, and survival follow-up in both cohorts.

The primary end point of the study was PFS by central review. Secondary end points included objective response rate (ORR), duration of response (DOR), and safety, and tertiary end points include pharmacokinetics and biomarkers.

In the experimental group, 59.9% of patients presented with FL, 21.5% with marginal zone lymphoma (MZL), 11.4% with small lymphocytic lymphoma (SLL), and 7.2% with lymphoplasmacytic lymphoma (LPL) or Waldenström macroglobulinemia (WM) lymphoma. In the control group, 60.3% had FL, 19.2% had MZL, 9.9% were those with SLL, and 10.6% were those with LPL or WM.

Patients treated with copanlisib plus ritux-imab underwent dose reduction at a rate of 27% compared with 6.8% in the control group. Further, 75.2% and 56.8% of patients expe-rienced dose interruptions or delays in the experimental and control arms, respectively. Treatment discontinuation was reported for 31.9% of patients in the experimental arm vs 8.2% in the control arm because of adverse events.

Subgroup data, stratified by histology, were also presented (

). Patients with FL in the experimental arm had a median PFS of 22.2 months (95% CI, 17.8-33.1) vs 18.7 months (95% CI, 10.2-21.1) in the control arm (HR, 0.58; 95% CI, 0.40-0.83; P = .001). For patients with MZL, the median PFS was 22.1 (95% CI, 13.8-not estimable [NE]) and 11.5 months (95% CI, 5.6-16.3) in the experimental and control groups, respectively (HR, 0.48; 95% CI, 0.25-0.92; P = .012). Patients with SLL in the experimental arm had a PFS of 14.2 months (95% CI, 10.9-20.5), compared with 5.7 months (95% CI, 3.5-11.0) in the control arm (HR, 0.24; 95% CI, 0.11-0.53; P < .0001). The largest difference in PFS was in patients with LPL or WM: 33.4 months (95% CI, 15.5-NE) in the experimental arm vs 7.6 months (95% CI, 1.7-16.6) in the control arm (HR, 0.44; 95% CI, 0.16-1.23; P = .054).

Phillips, a clinical associate professor at the University of Michigan Rogel Cancer Center in Ann Arbor, discussed data from the ongoing CHRONOS-3 study (NCT02367040), which examined the combination of copanlisib and rituximab vs placebo plus rituximab in patients with relapsed iNHL, as part of an 

Primary End Point Results in the CHRONOS-3 Trial

Overall, copanlisib plus rituximab elicited an ORR of 81%, with 34% of responders expe-riencing a complete response (CR). Patients treated with placebo and rituximab had an ORR of 48% and a 15% CR rate. At a median follow-up of 20.0 months, the median DOR was 20.4 months (range, 17.0-30.8) and 17.3 months (range, 11.8-25.3) in the experimental and control groups, respectively.

“A key point to this study, when looking at the benefits, is the safety profile,” Phillips said. “All patients in the [experimental arm of the] study had some treatment-emergent adverse event [TEAE].”

Common TEAEs included hyperglycemia, hypertension, and diarrhea. Hyperglycemia of any grade occurred in 69.4% of patients in the experimental group, with grade 3 occur-ring at a rate of 48.2% and grade 4 at a rate of 8.1%. In the control arm, hyperglycemia was experienced at any grade by 23.3% of patients and at grade 3 in 8.2%, with no patients having grade 4. Hypertension of any grade was seen in 49.2% of the experimental group vs 19.2% in the control group. Diarrhea of any grade occurred at a rate of 33.6% in the experimental cohort, compared with 9.6% in the control arm.

Pneumonitis was an AE of interest in the study. A total of 6.8% of patients in the experimental arm experienced pneumonitis of any grade; 2.0% of these were grade 3 events and 0.7% were grade 4. Patients in the control arm had pneumonitis of any grade at a rate of 1.4%, with 0.7% of these being grade 3 and no patients having grade 4 events.

In terms of TEAEs of any grade that led to discontinuation, 31.3% occurred in the experimental arm and 8.2% were seen in the control arm. Common TEAEs of any grade leading to discontinuation on the exper-imental side were pneumonitis (6.2%), hyperglycemia (2.6%), interstitial lung disease (1.3%), and pneumocystis jirovecii pneumonia (1.3%).

“Overall, this is a very good start,” Phillips said. “We are opening the window for this sort of treatment. As was demonstrated in this study, it does appear that the addition of rituximab did not add any new safety informa-tion or concerns when given with copanlisib. This was something we had not seen with a majority of the delta inhibitors, which have specifically all been given as single agents.”

Matasar MJ, Capra M, Özcan M, et al. Copanlisib plus rituximab versus placebo plus rituximab in patients with relapsed indolent non-Hodgkin lymphoma (CHRONOS-3): a double-blind, randomised, placebo-controlled, phase 3 trial. Lancet Oncol. 2021; 22(5):678-689. doi:10.1016/S1470-2045(21)00145-5

This article was originally published on OncLive as “

Copanlisib/Rituximab Combination Demonstrates Superiority Across iNHL”

More data are needed regarding the duration of response associated with this combination to make it a “mainstream” treatment option for patients, according to an expert from the University of Michigan Rogel Cancer Center. 



Kyle Doherty

Articles

Patients with LBCL Experience Improved Quality of Life Following Axi-Cel Treatment

Lenvatinib/Pembrolizumab Combo Continues to Show Benefit in Advanced Endometrial Cancer

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Balstilimab Zalifrelimab Combination Yields Promising Results in Recurrent/Metastatic Cervical Cancer

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