Nivolumab (Opdivo) alone or in combination with ipilimumab (Yervoy) produced encouraging responses that were maintained over time in patients with recurrent or metastatic cervical cancer, according to updated findings from the phase 1/2 CheckMate-358 trial (NCT02488759).

At a minimum follow-up of 24 months, the investigator-assessed objective response rate (ORR) was 26% (95% CI, 9%-51%) with nivolumab alone (n = 19), 31% (95% CI, 18%-47%) with 3 mg/kg of nivolumab plus 1 mg/kg of ipilimumab (n = 45; N3+I1), and 38% (95% CI, 29%-48%) with 1 mg/kg of nivolumab plus 3 mg/kg of ipilimumab (n = 112; N1+I3).

“These data indicate that chemotherapy-free immunotherapy with nivolumab alone or in combination with ipilimumab can provide durable tumor regression with manageable toxicity in patients with recurrent/metastatic cervical cancer, regardless of tumor PD-L1 expression,” Ana Oaknin, MD, PhD, lead study author and head of the Gynaecological Tumour Unit at the Vall d’Hebron Institute of Oncology in Barcelona, Spain, said in a presentation of the data at the 2022 ESMO Congress.

In earlier findings, nivolumab demonstrated clinically meaningful antitumor activity as a single agent and in the N3I1 and N1I3 dosing schedules, with ORRs of 26%, 27%, and 41%, respectively.

To be eligible for enrollment, patients had to have histologically confirmed, recurrent/metastatic squamous cell carcinoma of the cervix and have received no more than 2 prior therapies for recurrent/metastatic disease. They were also required to have at least 1 target lesion, an ECOG performance status of 0 or 1, and positive or unknown human papillomavirus status.

Patients were treated with 1 of 3 regimens: 240 mg of nivolumab every 2 weeks (n = 19); 3 mg/kg of nivolumab every 2 weeks plus 1 mg/kg of ipilimumab every 6 weeks (n = 45; N3+I1); or 1 mg/kg of nivolumab every 2 weeks plus 3 mg/kg of ipilimumab every 3 weeks for 4 cycles followed by 240 mg of nivolumab every 2 weeks (n = 45; N1+I3).

Based on an early efficacy signal in the N1+I3 arm, the study protocol was amended in July 2018 to include an N1+I3 expansion arm, in which 44 patients received 1 mg/kg of nivolumab and 3 mg/kg of ipilimumab in the first line and 23 patients received the combination in the second line.

Treatment was continued until disease progression or maximum of 24 months, unacceptable toxicity, or withdrawal of consent.

Imaging assessments were performed every 8 weeks for the first year of treatment and every 12 weeks thereafter.

The primary end point is investigator-assessed ORR. Secondary end points include duration of response (DOR), investigator-assessed progression-free survival (PFS), and overall survival (OS).

Baseline characteristics indicated that most patients were enrolled in Europe, had a PD-L1 expression of at least 1%, and received prior radiotherapy. Notably, 21%, 40%, and 64% of patients in the nivolumab, N3+I1, and N1+I3 arms, respectively, did not receive any prior systemic therapy in the metastatic setting. 

Further findings indicated that N3+I1 and N1+I3 led to an “expectedly” higher ORR in the first line compared with the second line, at 39% (95% CI, 17%-64%) vs 26% (95% CI, 11%-46%) and 41% (95% CI, 29%-53%) vs 35% (95% CI, 21%-51%), respectively.

“N1+I3 showed a higher response rate than N3+I1 in the first- and second- or later-line setting,” Oaknin added.

The median DOR was not reached (NR; 95% CI, 35.3-NR) with nivolumab alone, 24.4 months (95% CI, 8.7-NR) with N3+I1, and 34.1 months (95% CI, 11.5-NR) with N1+I3.

Additionally, the median PFS was 5.1 months (95% CI, 1.9-9.1), 3.8 months (95% CI, 2.1-10.3), and 5.8 months (95% CI, 3.8-9.3) with nivolumab, N3+N1, and N1+N3, respectively.

The minimum follow-up for OS was 67.4 months, 36.9 months, and 17.9 months for the nivolumab, N3+I1, and N1+I3 arms, respectively. The median OS was 21.6 months (95% CI, 8.3-46.9), 15.2 months (95% CI, 9.0-36.2), and 20.9 months (95% CI, 14.4-32.8), respectively.

The 1- and 2-year OS rates with nivolumab alone were 73% (95% CI, 46%-88%) and 43% (95% CI, 20%-64%), respectively. With N3+I1, the 1- and 2-year OS rates were 54% (95% CI, 38%-68%) and 37% (95% CI, 23%-51%), respectively. N1+I3 led to 1- and 2-year OS rates of 69% (95% CI, 60%-77%) and 48% (95% CI, 38%-57%), respectively.

“Durable responses were observed regardless of tumor PD-L1 status across all treatment arms, [although] fewer responses [were] seen in patients with PD-L1 <1% treated with nivolumab monotherapy compared with patients with PD-L1 <1% treated with nivolumab and ipilimumab,” Oaknin said.

Regarding safety, no new signals were identified, and the frequency of adverse effects (AEs) was higher with N1+I3 vs either N3+I1 or nivolumab alone.

Specifically, treatment-related AEs (TRAEs) were highest with N1+I3 (any grade, 88%; grade 3/4, 46%), followed by N3+I1 (any grade, 80%; grade 3/4, 29%), and nivolumab alone (any grade, 63%; grade 3/4, 21%).

Similarly, TRAEs leading to discontinuation were highest with N1+I3 (any grade, 24%; grade 3/4, 19%), followed by N3+I1 (any grade, 18%; grade 3/4, 9%), and nivolumab alone (any grade, 11%; grade 3/4, 5%).

Regarding nonendocrine immune-mediated AEs, hepatitis and diarrhea/colitis did not occur in any patients in the nivolumab alone arm compared with the N3+I1 (hepatitis: grade 3/4, 7%; diarrhea/colitis: any grade, 4%; grade 3/4, 2%) and N1+I3 (hepatitis: any grade, 18%; grade 3/4, 16%; diarrhea/colitis: any grade, 16%; grade 3/4, 5%) arms.

“Safety profiles seen in this study were similar to those reported in previous clinical trials,” Oaknin concluded.

Oaknin A, Moore KN, Meyer T, et al. Safety and efficacy of nivolumab (NIVO) ± ipilimumab (IPI) in patients (pts) with recurrent/metastatic cervical cancer (R/M Cx Ca) in checkmate 358. 

. 2022;33(suppl 7):S782. doi:10.1016/j.annonc.2022.07.648

Naumann RW, Hollebecque A, Meyer T, et al. Safety and efficacy of nivolumab monotherapy in recurrent or metastatic cervical, vaginal, or vulvar carcinoma: results from the phase I/II CheckMate 358 trial. 

. 2019;37(31):2825-2834. doi:10.1200/JCO.19.00739

Naumann RW, Oaknin A, Meyer T, et al. Efficacy and safety of nivolumab (nivo) + ipilimumab (ipi) in patients (pts) with recurrent/metastatic (R/M) cervical cancer: results from CheckMate 358. 

. 2019;30(suppl 5):V898-V899. doi:10.1093/annonc/mdz394.059

Articles

Nivolumab alone or in combination with ipilimumab produced encouraging responses that were maintained over time in patients with recurrent or metastatic cervical cancer.

Nivolumab-Based Therapy Drives Durable Responses in Recurrent/Metastatic Cervical Cancer

The addition of CBM588, a live probiotic comprised primarily of 

, to the combination of nivolumab (Opdivo) and ipilimumab (Yervoy) produced superior response rates and a progression-free survival (PFS) benefit vs nivolumab plus ipilimumab alone in previously untreated patients with metastatic renal cell carcinoma (RCC), according to findings from a phase 1b trial (NCT03829111).

Data presented at the 2022 International Kidney Cancer Symposium showed that patients treated with CBM588 plus nivolumab/ipilimumab (n = 19) achieved an objective response rate (ORR) of 58% compared with 20% for those given nivolumab/ipilimumab alone (n = 10; 

 = .06). In the CBM588 arm, all responders achieved partial responses (PRs), 21% of patients had stable disease, and 21% of patients had progressive disease. In the nivolumab/ipilimumab arm, both responders experienced a PR, 20% of patients had stable disease, and 60% experienced disease progression. The disease control rate was 79% in the CBM588 arm compared with 20% in the nivolumab/ipilimumab arm (

“Although limited by the sample size, the combination of nivolumab, ipilimumab, and CBM588 demonstrated superior clinical outcomes over nivolumab/ipilimumab. PFS and ORR with nivolumab, ipilimumab, and CBM588 also exceeded those observed with nivolumab/ipilimumab in historical datasets,” lead study author Nazli Dizman, MD, a hospital resident at the Yale School of Medicine, said in a presentation.

CBM588 is a live bacterial product that contains 

, a butyrate-producing anaerobic spore-forming bacterium that is commonly used and studied in gastrointestinal conditions in Japan.

A retrospective analysis of 118 patients with non–small cell lung cancer showed that those who received CBM588 before and/or after immune checkpoint inhibitors experienced an ORR of 48%, including a complete response rate (CR) of 8% compared with an ORR of 25% and no CRs for patients given immune checkpoint inhibitors alone.

The phase 1b trial evaluated the efficacy and safety of nivolumab/ipilimumab with or without CBM588 in patients with RCC who had measurable metastatic disease with clear cell and/or sarcomatoid histology. Patients were also required to have no prior systemic treatment for metastatic disease, intermediate- or poor-risk IMDC classification, and an ECOG performance status of 0 or 1.

Patients were randomly assigned 2:1 to receive CBM588 plus nivolumab/ipilimumab or nivolumab/ipilimumab alone. The primary end point of the trial was the change in 

 Secondary end points included ORR, PFS, change in serum cytokine levels, change in immune cell populations, change in stool metabolic pathways, and toxicity.

The median age of patients in the CBM588 arm was 66 years (range, 45-90) compared with 64 years (range, 45-79) in the nivolumab/ipilimumab arm. Most patients had clear cell histology (63% and 70% in the CBM588 and nivolumab/ipilimumab arms, respectively), and had intermediate IMDC prognostic risk (89% and 70%). The minority of patients did not undergo prior nephrectomy (47% and 40%). All patients in both arms had at least 2 metastatic sites. The most common metastatic sites included lung (68% and 60%), lymph node (42% and 70%), bone (37% and 40%), soft tissue (37% and 30%), liver (16% and 20%), and pancreas (16% and 10%).

Additional data showed that patients in the CBM588 arm achieved a median PFS of 36.4 months (95% CI, 9.4-63.5) compared with 2.5 months (95% CI, 2.0-2.9) for those in the nivolumab/ipilimumab arm (HR, 0.10; 95% CI, 0.03-0.33; 

 < .001). The median duration of response in the CBM588 arm was 30.7 months.

The median overall survival was not reached in either arm. In the CBM588 arm, 82.8% of patients were alive at the time of data cutoff.

Regarding safety, at least 1 any-grade adverse effect (AE) was reported in all patients in the CBM588 arm compared with 90% in the nivolumab/ipilimumab arm. Grade 2 or higher AEs occurred in 63% and 50% of patients in the CBM588 and nivolumab/ipilimumab arms, respectively.

Two instances (11%) of grade 3 nephritis were reported in the CBM588 arm, and grade 3 events of adrenal insufficiency, fatigue, maculo-papular rash, arthritis/arthralgia, diarrhea, acute kidney injury, abdominal pain, transaminitis, glucose intolerance, increase alkaline phosphatase pancreatitis, acidosis, and chest wall pain each occurred in 1 patient. One grade 4 instance of decreased neutrophil count was reported in 1 patient in the CBM588 arm. No grade 4 or higher AEs were observed in the nivolumab/ipilimumab arm.

A randomized, double-blind phase 3 study will compare the combination of nivolumab/ipilimumab plus CBM588 or placebo as a frontline treatment for patients with intermediate- or high-risk advanced clear cell RCC.

“Larger efforts investigating the impact of CBM588 on clinical outcomes are underway. We are devoting our efforts to better understand the mechanism of action of CBM588 by studying metabolic samples in patients and in mice,” Dizman concluded.

Dizman N. Clinical outcomes with nivolumab/ipilimumab (nivo/ipi) with or without CBM588 in metastatic renal cell carcinoma (mRCC): long-term follow-up of a randomized phase Ib clinical trial. Presented at: International Kidney Cancer Symposium; November 4-5, 2022. Austin, Texas. Abstract 9.

Tomita Y, Ikeda T, Sakata S, et al. Association of probiotic Clostridium butyricum therapy with survival and response to immune checkpoint blockade in patients with lung cancer. 

. 2020;8(10):1236-1242. doi:10.1158/2326-6066.CIR-20-0051

CBM588, nivolumab, and ipilimumab in treating patients with stage IV or advanced kidney cancer. ClinicalTrials.gov. Updated October 14, 2022. Accessed November 7, 2022. 

https://clinicaltrials.gov/ct2/show/NCT03829111

The addition of CBM588 to the combination of nivolumab and ipilimumab produced superior response rates and a progression-free survival benefit vs nivolumab plus ipilimumab alone in previously untreated patients with metastatic renal cell carcinoma.

Nivolumab/Ipilimumab Plus CBM588 Generates Superior Efficacy in Metastatic RCC

SRF388, a first-in-class antibody targeting IL-27, elicited responses in pretreated patients with locally advanced or metastatic non–small cell lung cancer (NSCLC), according to data from an ongoing phase 1/1b trial (NCT04374877).

Among 9 patients who received SRF388 monotherapy at or above the recommended phase 2 dose (RP2D), 2 patients achieved a confirmed partial response (PR) for an overall response rate (ORR) of 22%. Notably, the confirmed PRs were observed in the only 2 evaluable patients with squamous NSCLC. Additionally, 1 patient with adenocarcinoma experienced durable stable disease that was ongoing for more than 56 weeks as of the August 24, 2022, data cutoff. All 3 patients had received prior treatment with chemotherapy and anti–PD-(L)1 agents.

Detailed clinical results from ongoing studies of SRF388 are expected to be shared in the first half of 2023.

“We are excited by the monotherapy activity seen with SRF388 in relapsed NSCLC, an area of high unmet need globally,” Rob Ross, MD, chief executive officer of Surface Oncology, stated in a press release. “Based on these promising results in relapsed NSCLC, we have opened the second stage of our trial investigating SRF388 as a monotherapy, and we have treated our first patients in a new cohort to investigate SRF388 in combination with pembrolizumab in second- to fourth-line NSCLC.”

SRF388 is a fully human anti–IL-27 antibody designed to inhibit the activity of the immunosuppressive cytokine.

 IL-27 appears to play an important role in the immunosuppressive tumor microenvironment and may contribute to resistance to treatment with checkpoint inhibitors in patients with liver, kidney, and lung cancer.

Preclinical studies have shown that treatment with SRF388 blocks the immunosuppressive biologic effects of IL-27, leading to immune cell activation in combination with other cancer therapies, including anti–PD-1 therapy, and potent antitumor effects as a monotherapy.

Part B of the phase 1 trial is evaluating SRF388 monotherapy at the RP2D in up to 40 patients with NSCLC and up to 40 patients with hepatocellular carcinoma (HCC).

 Notably, the trial also planned to enroll up to 40 patients with renal cell carcinoma (RCC); however, Surface Oncology announced that it has stopped enrollment for the RCC cohort to focus efforts on NSCLC and HCC, based on encouraging data in those patients.

Patients with NSCLC are required to have histologically confirmed locally advanced or metastatic stage IV disease that has progressed during or after standard therapy, and for whom no available therapies are appropriate. Other key inclusion criteria include at least 1 measurable lesion per RECIST v1.1 criteria, an ECOG performance status of 0 or 1, and adequate hematologic function.

Key exclusion criteria include previous treatment with an anti–IL-27 antibody or anti–IL-27 targeted therapy, a history of grade 4 allergic or anaphylactic reaction to any monoclonal antibody therapy or any excipient in the study drugs, major surgery within 4 weeks prior to screening, or an unstable or severe uncontrolled medical condition.

ORR is serving as the primary end point of part B of the study. Secondary end points include duration of response, disease control rate, progression-free survival, pharmacokinetics, pharmacodynamics, and safety.

SRF388 will also be evaluated in combination with pembrolizumab (Keytruda) in patients with NSCLC who have progressed after 1 to 3 prior lines of therapy, including chemotherapy and anti–PD-1 agents. The study is anticipated to enroll up to 40 patients with NSCLC.

Surface Oncology announces promising SRF388 monotherapy data in non-small cell lung cancer (NSCLC), opening second stage of monotherapy trial and NSCLC pembrolizumab combination cohort. News release. Surface Oncology. November 2, 2022. Accessed November 3, 2022. 

Surface Oncology announces initiation of phase 2 studies evaluating SRF388 in patients with hepatocellular carcinoma and non-small-cell lung cancer. News release. Surface Oncology. April 14, 2022. Accessed November 3, 2022. 

Study of SRF388 in patients with advanced solid tumors. ClinicalTrials.gov. Updated August 18, 2022. Accessed November 3, 2022. 

https://clinicaltrials.gov/ct2/show/NCT04374877

SRF388 elicited responses in pretreated patients with locally advanced or metastatic non–small cell lung cancer.

Pipeline Report: November 2022

Articles

Nivolumab-Based Therapy Drives Durable Responses in Recurrent/Metastatic Cervical Cancer

Nivolumab/Ipilimumab Plus CBM588 Generates Superior Efficacy in Metastatic RCC