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.

Articles

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

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

Copanlisib Plus Rituximab May Be ‘Viable Option’ Across Indolent Non-Hodgkin Lymphoma