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Phase II study of the safety and efficacy of the anti-PD-1 antibody balstilimab in patients with recurrent and/or metastatic cervical cancer

Open AccessPublished:August 25, 2021DOI:https://doi.org/10.1016/j.ygyno.2021.08.018

      Highlights

      • Balstilimab elicited promising and durable clinical activity in patients with recurrent/metastatic cervical cancer.
      • Tumor responses occurred irrespective of tumor PD-L1 status or histology.
      • Balstilimab is well tolerated, with a safety profile consistent with other PD-1 inhibitors.
      • These findings highlight balstilimab as an attractive candidate for both single-agent and combination-based immunotherapy.

      Abstract

      Objective

      This phase II clinical trial evaluated the safety and antitumor activity of balstilimab, an anti-PD-1 antibody, in patients with previously-treated, recurrent/metastatic cervical cancer.

      Methods

      Eligible patients were 18 years or older with recurrent and/or metastatic cervical cancer and who had relapsed after a prior platinum-based treatment regimen for advanced disease. Balstilimab was administered intravenously at 3 mg/kg once every two weeks, for up to 24 months. The primary endpoint was objective response rate (ORR, RECIST v1.1) as assessed by an independent review committee.

      Results

      At data cutoff, 161 women (median age, 53 years [range 25–81]) were enrolled and treated with balstilimab. Of these, 140 had measurable disease at baseline and one prior line of platinum-based therapy in the metastatic, persistent, or recurrent setting; these patients were included in the efficacy analyses. The ORR was 15% (95% CI, 10.0%–21.8%) and included 5 patients with a complete response and 16 with a partial response. The median duration of response was 15.4 months. In patients with PD-L1-positive tumors the ORR was 20%, however patients with PD-L1-negative tumors also responded to balstilimab (ORR, 7.9%). Responses were not restricted to tumors of squamous cell histology, and an ORR of 12.5% was seen in the subset of patients with cervical adenocarcinoma. The disease control rate was 49.3% (95% CI, 41.1%–57.5%). Immune-mediated enterocolitis (3.1%) and diarrhea (1.9%) were the most common grade 3 or higher treatment-related adverse events.

      Conclusion

      Balstilimab demonstrated meaningful and durable clinical activity, with manageable safety, in patients with previously-treated, recurrent/metastatic cervical cancer.

      Keywords

      1. Introduction

      Cervical cancer is the most common female genital tract malignancy and fourth leading cause of cancer mortality in women worldwide [
      • Arbyn M.
      • Weiderpass E.
      • Bruni L.
      • de Sanjose S.
      • Saraiya M.
      • Ferlay J.
      • et al.
      Estimates of incidence and mortality of cervical cancer in 2018: a worldwide analysis.
      ], responsible for more than 311,000 deaths annually. The prognosis for patients diagnosed with recurrent and/or metastatic disease is particularly poor, as evidenced by a 5-year overall survival (OS) rate of 17% [
      • NCI Surveillance E, and End Results Program
      Cancer Stat Facts: Cervical Cancer.
      ]. Beyond palliative platinum-based chemotherapy, treatment options for these patients are limited and typically administered without expectation of cure. Further, optimal second-line and later regimens for the management of advanced, relapsed disease are yet to be established [
      • Boussios S.
      • Seraj E.
      • Zarkavelis G.
      • Petrakis D.
      • Kollas A.
      • Kafantari A.
      • et al.
      Management of patients with recurrent/advanced cervical cancer beyond first line platinum regimens: where do we stand? A literature review.
      ].
      In this regard, agents that target the programmed death 1 (PD-1)/programmed death ligand 1 (PD-L1) immune checkpoint pathway have emerged as promising candidates for altering the cervical cancer therapeutic landscape [
      • Crusz S.M.
      • Miller R.E.
      Targeted therapies in gynaecological cancers.
      ,
      • Liu Y.
      • Wu L.
      • Tong R.
      • Yang F.
      • Yin L.
      • Li M.
      • et al.
      PD-1/PD-L1 inhibitors in cervical Cancer.
      ,
      • Kagabu M.
      • Nagasawa T.
      • Fukagawa D.
      • Tomabechi H.
      • Sato S.
      • Shoji T.
      • et al.
      Immunotherapy for uterine cervical cancer.
      ]. Since 2015, multiple clinical trials evaluating the potential utility of PD-1/PD-L1 antibodies for cervical cancer treatment have been conducted, and numerous others are ongoing [
      • Kagabu M.
      • Nagasawa T.
      • Fukagawa D.
      • Tomabechi H.
      • Sato S.
      • Shoji T.
      • et al.
      Immunotherapy for uterine cervical cancer.
      ]. To date, only the anti-PD-1 antibody pembrolizumab has received accelerated approval by the US Food and Drug Administration for the treatment of patients with PD-L1-positive, recurrent/metastatic cervical cancer following disease progression on or after chemotherapy. Approval was based on the results of the phase 2 KEYNOTE-158 study, in which pembrolizumab monotherapy yielded an objective response rate (ORR) of 14.3% with the median duration of response not reached (median follow-up of 10.2 months) in a PD-L1-positive cohort of 77 patients with previously treated cervical cancer [
      • Chung H.C.
      • Ros W.
      • Delord J.P.
      • Perets R.
      • Italiano A.
      • Shapira-Frommer R.
      • et al.
      Efficacy and safety of Pembrolizumab in previously treated advanced cervical Cancer: results from the phase II KEYNOTE-158 study.
      ]. While these efficacy outcomes appear relatively modest, both parameters were similar or superior to those observed with other available treatment options in the same setting [
      • Boussios S.
      • Seraj E.
      • Zarkavelis G.
      • Petrakis D.
      • Kollas A.
      • Kafantari A.
      • et al.
      Management of patients with recurrent/advanced cervical cancer beyond first line platinum regimens: where do we stand? A literature review.
      ]. This observation underscores the significant unmet clinical need for this group of patients, for whom alternative and effective treatments are urgently needed.
      Balstilimab (AGEN2034) is an investigational, fully human monoclonal antibody that binds with high affinity to PD-1, designed to prevent the interaction between this receptor and its ligands PD-L1 and PD-L2 [
      • Moore K.N.
      • Dresher C.
      • Liu J.
      • O’Malley D.M.
      • Wang E.W.
      • Wang J.S.-Z.
      • et al.
      Phase 1/2 open-label, multiple ascending dose trial of AGEN2034, an anti-PD-1 monoclonal antibody, in advanced solid malignancies: results of dose escalation.
      ]. By functioning as a PD-1 antagonist, balstilimab enhances T-cell receptor (TCR) signaling and T-cell responsiveness under conditions of TCR stimulation. Here we present results of a phase II single-arm trial designed to assess the safety and efficacy of balstilimab monotherapy for patients with recurrent and/or metastatic cervical cancer who had relapsed after a prior platinum-based treatment regimen.

      2. Methods

      2.1 Patients

      Eligible patients had a pathologically confirmed diagnosis of squamous cell carcinoma, adenosquamous carcinoma, or adenocarcinoma of the cervix, with metastatic, persistent, or recurrent disease at the time of enrollment. Patients were required to have at least one lesion measurable by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 [
      • Eisenhauer E.A.
      • Therasse P.
      • Bogaerts J.
      • Schwartz L.H.
      • Sargent D.
      • Ford R.
      • et al.
      New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1).
      ], and disease that had relapsed after a first line, platinum-based treatment regimen (subjects who received chemotherapy concurrently with primary radiation, or adjuvant chemotherapy following completion of radiation therapy and progressed within 6 months, were permitted to enroll). Patients were included regardless of PD-L1 expression status at baseline, which was analyzed in archival tumor biopsy specimens using the validated PD-L1 IHC 22C3 pharmDx assay at a central laboratory. Patients were additionally required to be ≥18 years of age; have an Eastern Cooperative Oncology Group performance status score of 0 or 1; and have adequate hematologic, renal, and hepatic function. Key exclusion criteria included prior immune checkpoint inhibitor therapy; known hypersensitivity to humanized monoclonal antibodies; or >1 systemic treatment regimen for advanced cervical cancer. All patients provided written informed consent in accordance with federal, local, and institutional guidelines.

      2.2 Study design and treatment

      This was an open-label, single-arm, global phase II clinical trial conducted at 60 sites throughout the United States, Europe, South America, and Australia. Patients were enrolled from November 20, 2017 to April 16, 2020 and received intravenous balstilimab at a dose of 3 mg/kg once every two weeks, given as a 60-min infusion. This dose was the recommended phase II dose determined by a run-in, phase I dose-escalation stage [
      • Drescher C.
      • Moore K.N.
      • Liu J.F.
      • O’Malley D.M.
      • Wang E.W.
      • Wang J.S.Z.
      • et al.
      Phase I/II, open-label, multiple ascending dose trial of AGEN2034, an anti-PD-1 monoclonal antibody, in advanced solid malignancies: Results of dose escalation in advanced cancer and expansion cohorts in subjects with relapsed/refractory cervical cancer.
      ]. Treatment was permitted for up to 24 months, or until disease progression, intolerable toxicity, or investigator/patient decision. The study was conducted in accordance with the International Conference on Harmonisation Guidelines for Good Clinical Practice and the Declaration of Helsinki. The trial is registered at ClinicalTrials.gov (NCT03104699).

      2.3 Endpoints and assessments

      The primary efficacy endpoint was objective response rate (ORR), assessed by an independent endpoint review committee, according to RECIST version 1.1. To evaluate tumor response, computerized tomography or magnetic resonance imaging was performed at baseline and every 6 weeks on-study. Secondary efficacy outcomes included duration of response (DOR) and disease control rate (DCR). The additional secondary end points of progression-free survival (PFS) and overall survival (OS) will be reported elsewhere. The association of PD-L1 expression (positivity defined by a combined positive score [CPS] ≥1%) with clinical response was an exploratory endpoint.
      Safety and tolerability were primary safety endpoints. Adverse events (AEs) were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.03 and monitored continuously from the time of the first study dose until 28 days after the last dose of study drug or 10 weeks after the last dose if an adverse event was present. Immune-related adverse events (irAEs) were adverse events of special interest considered to have immune-mediated mechanisms of action, including infusion-related reactions.

      2.4 Statistical considerations

      The aim of this phase II study was to detect preliminary evidence of clinical activity for balstilimab in patients with metastatic cervical cancer. For this analysis, the data cutoff date was February 11, 2021. The primary end point of ORR was estimated as the binomial proportion of best overall response of a confirmed partial response (PR) or complete response (CR) and reported with two sided, 95% Wilson score confidence interval (CI). Trial enrollment was planned for approximately 150 subjects; at this sample size, the power to exclude an ORR of 5% by the lower limit of the 95% Wilson score interval was 92.2% and 96.2%, assuming a true ORR of 12% and 13%, respectively. The sample size also provided ≥77% probability to observe an AE with an underlying rate of ≥1%. Descriptive statistics were used to summarize trial results, i.e., statistics for continuous variables included medians and ranges and categorical variables were summarized by counts and percentages. DOR and duration of stable disease were analyzed using Kaplan-Meier estimates.

      3. Results

      3.1 Patients

      Between November 20, 2017 and April 16, 2020, a total of 161 patients were enrolled and received treatment with balstilimab, thus comprising the safety population (Fig. 1). Baseline demographic and disease characteristics are summarized in Table 1. The median age was 53 years (range, 25–81) and over half had an ECOG performance status of 1 (52.2%). The distribution of cervical cancer histology was squamous cell carcinoma (62.7%), adenocarcinoma (32.3%), and adenosquamous carcinoma (4.3%). All individuals had prior platinum exposure and 47 (29.2%) had received bevacizumab as part of a previous therapeutic regimen. Ninety-nine patients (61.5%) had PD-L1-positive tumors (CPS ≥1%) and 43 (26.7%) were determined to be PD-L1-negative; the remainder of cases (11.8%) were either not evaluable or tissue was not available. Of the patients deemed PD-L1-positive, 23 (23.2%) had prior bevacizumab treatment. The median duration of follow-up (time on study from first dose to data cutoff) was 14.6 months (range, 9.9–38.8).
      Fig. 1
      Fig. 1Patient enrollment and disposition. a Patients who received ≥1 dose of study treatment, with measurable disease at baseline, and had prior line of platinum-based treatment in the metastatic, persistent, or recurrent setting (per Independent Review Committee).
      Table 1Patient demographics and baseline characteristics.
      Characteristicn = 161
      Age, years
      Median (range)53 (25–81)
      ECOG PS, n (%)
      076 (47.2)
      184 (52.2)
      21 (0.6)
      Tumor histology, n (%)
      Squamous101 (62.7)
      Adenocarcinoma52 (32.3)
      Adenosquamous7 (4.3)
      Other
      Poorly differentiated carcinoma with extensive necrosis.
      1 (0.6)
      PD-L1 tumor expression status, n (%)
      Positive (CPS ≥1%)99 (61.5)
      Negative (CPS <1%)43 (26.7)
      Unknown
      PD-L1 status not determined due to missing/insufficient biopsy tissue for analysis or samples were non-evaluable.
      19 (11.8)
      Prior therapy exposure, n (%)
      Platinum161 (100.0)
      Bevacizumab47 (29.2)
      CPS, combined positive score; ECOG PS, Eastern Cooperative Oncology Group performance status; PD-L1, programmed death ligand 1.
      a Poorly differentiated carcinoma with extensive necrosis.
      b PD-L1 status not determined due to missing/insufficient biopsy tissue for analysis or samples were non-evaluable.

      3.2 Clinical activity

      Of the 160 patients enrolled with measurable disease at baseline, 20 subjects had received only front-line chemoradiotherapy (CRT) for locally advanced cervical cancer (with or without neoadjuvant/adjuvant chemotherapy) and progressed within 6 months prior to enrollment. Baseline characteristics and outcomes for this patient subset are listed in Supplementary Tables S1 and S2. The remaining 140 patients had received one prior line of platinum-based therapy for the metastatic, persistent, or recurrent disease (Fig. 1). This defined population of patients who had relapsed after a platinum-based treatment regimen in the recurrent/metastatic disease setting was evaluated as part of the efficacy analyses.
      The confirmed ORR in these patients, as assessed by RECIST v1.1 per independent central review, was 15% (95% CI, 10.0–21.8) and included 5 complete responses (3.6%) and 16 partial responses (11.4%) (Table 2). A summary of histological breakdown, treatment history, target lesion site, and PD-L1 status in patients with a best overall response of CR or PR is provided in Supplementary Table S3. Fig. 2A plots changes in target lesion burden for these patients as a function of time, with individuals grouped according to confirmed tumor response. Responses were durable, with an observed median duration of response of 15.4 months (95% CI, 5.7 months, not reached). In patients who responded, the median time to response was 2.7 months (95% CI, 2.0–3.9). Overall, the disease control rate (defined as proportion of patients with a confirmed complete or partial response, or stable disease without progression for at least 12 weeks) was 49.3% (95% CI, 41.1–57.5). Fig. 2B plots the best percentage change from baseline in target lesion size for all patients in the efficacy evaluable population. At the time of analyses, 21 patients remained on treatment (Fig. 1).
      Table 2Objective response rate, disease control, and durability.
      Characteristicn = 140
      Confirmed objective response rate, n (%)21 (15.0)
      95% CI(10.0–21.8)
      Best overall response, n (%)
      Complete response5 (3.6)
      Partial response16 (11.4)
      Stable disease51 (36.4)
      Progressive disease56 (40.0)
      Not available/evaluable
      Post-baseline imaging data not available or tumor measurements not adequate for best overall response evaluation.
      12 (8.6)
      Disease control rate, n (%)
      Defined as proportion of patients with a confirmed complete or partial response, or stable disease without progression for at least 12 weeks.
      69 (49.3)
      95% CI(41.1–57.5)
      Duration of response, (median) months
      Provided for responders only (n = 21).
      15.4
      95% CI(5.7 – NR)
      Estimated rate of response duration, %
      Provided for responders only (n = 21).
      Presented as % ongoing responses (number of patients at risk).
      ≥6 mo73.7 (12)
      ≥9 mo54.6 (8)
      ≥12 mo54.6 (6)
      Objective response rate by PD-L1 status, n (%)
      Positive (n = 85)17 (20.0)
      Negative (n = 38)3 (7.9)
      Unknown (n = 17)
      PD-L1 status not determined due to missing/insufficient biopsy tissue for analysis or samples were non-evaluable.
      1 (5.9)
      Objective response rate by histology, n (%)
      Squamous (n = 85)15 (17.6)
      Adenocarcinoma (n = 48)6 (12.5)
      NR, not reached.
      a Post-baseline imaging data not available or tumor measurements not adequate for best overall response evaluation.
      b Defined as proportion of patients with a confirmed complete or partial response, or stable disease without progression for at least 12 weeks.
      c Provided for responders only (n = 21).
      d Presented as % ongoing responses (number of patients at risk).
      e PD-L1 status not determined due to missing/insufficient biopsy tissue for analysis or samples were non-evaluable.
      Fig. 2
      Fig. 2(A) Percentage change in target lesion RECIST sum over time in patients with confirmed responses to balstilimab treatment. Dashed red line corresponds to 30% decrease in tumor size. (B) Best percentage change in target lesion size from baseline in the efficacy-evaluable patient population; PD-L1 status is indicated by color coding of bars. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)
      In the subset of patients with PD-L1-positive tumors (n = 85) the ORR was 20.0% (95% CI, 12.9–29.7, with duration of response not reached), and confirmed responses to balstilimab were also seen in subjects who were PD-L1-negative (3/38, 7.9%) (Table 2). Responses were observed across histologic subtypes, including tumor responses that occurred in 12.5% of patients with cervical adenocarcinomas (6/48). Of note, twenty adenocarcinoma patients (41.7%) were PD-L1 positive; this compared to 62/85 (72.9%) patients with PD-L1-positive, squamous cell carcinoma tumors. Forty-seven efficacy-evaluable patients (33.6%) had received prior bevacizumab treatment; responses were seen in five of these subjects (one complete and four partial responders) for an ORR of 10.6% (Supplementary Table S4).

      3.3 Safety

      The most common treatment-related AEs (TRAEs) of any grade were asthenia (23%), diarrhea (12.4%), pruritis (11.8%), and fatigue (10.6%) (Table 3), the majority of which were grade 1 or 2. The incidence of ≥ grade 3 TRAEs was 11.8%, with immune-mediated enterocolitis the most frequently reported at 3.1% (five patients). A total of 12 patients (7.5%) experienced at least one serious TRAE, and immune-mediated enterocolitis again accounted for the most common event. TRAEs leading to dose interruptions or discontinuations occurred in 23 (14.3%) and 7 (4.3%) patients, respectively. Immune-mediated pneumonitis was the leading cause of treatment discontinuation (3 patients). One death deemed possibly related to treatment occurred on study in a 37-year-old patient who died 41 days after her final dose of balstilimab of an unknown cause as she had been lost to follow-up.
      Table 3Treatment-related adverse events in the safety population.
      Eventn = 161
      Any TRAE, n (%)
      Individual adverse events with incidence ≥10% are reported.
      115 (71.4)
      Asthenia37 (23.0)
      Diarrhea20 (12.4)
      Pruritis19 (11.8)
      Fatigue17 (10.6)
      Grade ≥ 3 TRAE, n (%)
      Individual grade 3/4 adverse events occurring in 2 or more patients are reported.
      19 (11.8)
      Immune-mediated enterocolitis5 (3.1)
      Diarrhea3 (1.9)
      Hypokalemia2 (1.2)
      Anemia2 (1.2)
      Treatment-related SAE, n (%)12 (7.5)
      Treatment-related irAEs, n (%)
      Investigator-assessed events occurring in 3 or more patients are reported.
      53 (32.9)
      Hypothyroidism
      Includes related terms of hypothyroidism and immune-mediated hypothyroidism.
      11 (6.8)
      Hyperthyroidism6 (3.7)
      Diarrhea5 (3.1)
      Immune-mediated pneumonitis
      Includes related terms of pneumonitis, immune-mediated pneumonitis, and interstitial lung disease.
      5 (3.1)
      Immune-mediated enterocolitis5 (3.1)
      Arthralgia3 (1.9)
      Pyrexia3 (1.9)
      TRAE leading to dose interruption, n (%)23 (14.3)
      TRAE leading to dose discontinuation, n (%)7 (4.3)
      irAE, immune-related adverse event; SAE, serious adverse event; TRAE, treatment-related adverse event.
      a Individual adverse events with incidence ≥10% are reported.
      b Individual grade 3/4 adverse events occurring in 2 or more patients are reported.
      c Investigator-assessed events occurring in 3 or more patients are reported.
      d Includes related terms of hypothyroidism and immune-mediated hypothyroidism.
      e Includes related terms of pneumonitis, immune-mediated pneumonitis, and interstitial lung disease.
      Treatment-related irAEs were observed in 53 patients (32.9%), and most frequently included hypothyroidism (11 patients, 6.8%), hyperthyroidism (6 patients, 3.7%), diarrhea, immune-mediated pneumonitis, and immune-mediated enterocolitis (each 5 patients, 3.1%). Other irAEs that occurred in 3 or more patients were arthralgia and pyrexia (1.9%) (Table 3). These adverse events were generally managed with appropriate supportive care (including replacement therapy), corticosteroids, or withholding treatment. The only infusion-related reactions seen were individual cases of grade 1 pyrexia or grade 1 flushing.

      4. Discussion

      Balstilimab monotherapy elicited promising clinical activity in patients with previously-treated, advanced cervical cancer in this study which, to our knowledge, represents the largest phase II trial to date of a PD-1 inhibitor conducted in this high-need patient population. In the full efficacy-evaluable cohort the primary end point of ORR was 15%, including five patients (3.6%) who experienced a confirmed complete response; in the subset of PD-L1-positive patients the ORR was 20%. Responses were durable, as evidenced by a median DOR of 15.4 months. With the caveat that cross-trial comparisons can be challenging, it is informative to consider these outcomes with results for other PD-1 inhibitors in similar patient populations. Accelerated approval of pembrolizumab in the second-line metastatic setting was based on the results of the KEYNOTE-158 trial where an overall ORR of 12.2% was seen; however responses only occurred in subjects with PD-L1-positive tumors, resulting in an ORR in this subpopulation of 14.6% (14.3% in the cohort of patients who had received prior chemotherapy) [
      • Chung H.C.
      • Ros W.
      • Delord J.P.
      • Perets R.
      • Italiano A.
      • Shapira-Frommer R.
      • et al.
      Efficacy and safety of Pembrolizumab in previously treated advanced cervical Cancer: results from the phase II KEYNOTE-158 study.
      ]. In the earlier KEYNOTE-028 phase Ib study that evaluated pembrolizumab in patients of similar eligibility (n = 24, all PD-L1-positive), an ORR of 17% was observed due to four subjects achieving a partial response [
      • Frenel J.S.
      • Le Tourneau C.
      • O’Neil B.
      • Ott P.A.
      • Piha-Paul S.A.
      • Gomez-Roca C.
      • et al.
      Safety and efficacy of pembrolizumab in advanced, programmed death ligand 1-positive cervical Cancer: results from the phase Ib KEYNOTE-028 trial.
      ]. Here we report confirmed responses in patients receiving balstilimab who were PD-L1 negative, suggesting possible functional differentiation from pembrolizumab and potential opportunity to provide clinical benefit to a greater proportion of cervical cancer patients.
      Nivolumab is a fully human immunoglobulin G4 anti-PD-1 antibody, similar to balstilimab, and is approved for the treatment of a variety of cancers including melanoma and non-small cell lung cancer [
      • OPDIVO
      (Nivolumab) [Package Insert].
      ]. Recently, the results of two trials of nivolumab in small number cohorts of patients with recurrent/metastatic cervical cancer have been reported. As part of the CHECKMATE 358 study, an ORR of 26.3% was observed in a cohort of 19 patients with previously treated, recurrent/metastatic disease [
      • Naumann R.W.
      • Hollebecque A.
      • Meyer T.
      • Devlin M.J.
      • Oaknin A.
      • Kerger J.
      • 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.
      ]. At the time of analysis, the DOR had not been reached (median duration of follow up of 19.2 months). However, in a separate phase II study of nivolumab in 24 patients with cervical cancer (NRG-GY002) only one partial response was seen, resulting in an ORR of just 4% [
      • Santin A.D.
      • Deng W.
      • Frumovitz M.
      • Buza N.
      • Bellone S.
      • Huh W.
      • et al.
      Phase II evaluation of nivolumab in the treatment of persistent or recurrent cervical cancer (NCT02257528/NRG-GY002).
      ]. Of note, the patient population of NRG-GY002 was comparable to the current study, with all subjects having received one prior systemic chemotherapeutic regimen for the management of persistent, recurrent, or metastatic disease. The reasons for the marked differences in nivolumab activity between the two trials is unclear. One potential contributing factor may be related to the histological composition of each trial. CHECKMATE 358 evaluated only patients with squamous cell carcinoma (i.e. those patients more likely to respond), while NRG-GY002 enrolled patients with squamous cell carcinoma, adenocarcinoma, and adenosquamous tumors (60%, 24%, 16%, respectively). Similar to the balstilimab study presented here, the NRG-GY002 patient population is more representative of the true distribution of cervical cancer histologies. However, without a prospective randomized comparison, this is hypothesis driven.
      In this regard, an intriguing finding of the present study was that balstilimab treatment induced a 12.5% response rate in patients whose tumors were of adenocarcinoma origin. The reason(s) for the activity of balstilimab in adenocarcinoma remain to be determined, but it is known that differences exist in the immunological microenvironments and tumor escape mechanisms between cervical adenocarcinoma and squamous cell carcinoma [
      • Boussios S.
      • Seraj E.
      • Zarkavelis G.
      • Petrakis D.
      • Kollas A.
      • Kafantari A.
      • et al.
      Management of patients with recurrent/advanced cervical cancer beyond first line platinum regimens: where do we stand? A literature review.
      ]. For example, and as was the case for the patient population evaluated in this study, PD-L1 is more frequently expressed by squamous-type tumors compared with adenocarcinoma [
      • Reddy O.L.
      • Shintaku P.I.
      • Moatamed N.A.
      Programmed death-ligand 1 (PD-L1) is expressed in a significant number of the uterine cervical carcinomas.
      ,
      • Heeren A.M.
      • Punt S.
      • Bleeker M.C.
      • Gaarenstroom K.N.
      • van der Velden J.
      • Kenter G.G.
      • et al.
      Prognostic effect of different PD-L1 expression patterns in squamous cell carcinoma and adenocarcinoma of the cervix.
      ]. In addition, and in contrast to squamous cell carcinomas, the presence of PD-L1-positive tumor-associated macrophages in adenocarcinoma tumors is associated with poorer disease-specific survival [
      • Heeren A.M.
      • Punt S.
      • Bleeker M.C.
      • Gaarenstroom K.N.
      • van der Velden J.
      • Kenter G.G.
      • et al.
      Prognostic effect of different PD-L1 expression patterns in squamous cell carcinoma and adenocarcinoma of the cervix.
      ]. The relative incidence of cervical adenocarcinoma has increased over the past few decades, with the advent of long-term and widespread screening leading to the removal of more slow-growing squamous lesions [
      • Siegel R.L.
      • Miller K.D.
      • Jemal A.
      Cancer statistics, 2020.
      ]. Moreover, the stagnant survival rates seen in cervical cancer have been suggested, beyond the lack of major treatment advances, to in part reflect the increasing proportion of adenocarcinoma histology cases [
      • Sherman M.E.
      • Wang S.S.
      • Carreon J.
      • Devesa S.S.
      Mortality trends for cervical squamous and adenocarcinoma in the United States. Relation to incidence and survival.
      ]. In light of these considerations, extending the therapeutic reach of immune checkpoint blockade beyond the squamous cell histotype has potentially broad clinical implications for this disease.
      Balstilimab was well tolerated, with a manageable safety profile that is consistent with that of other approved agents of the PD-1 inhibitor class [
      • Xu C.
      • Chen Y.P.
      • Du X.J.
      • Liu J.Q.
      • Huang C.L.
      • Chen L.
      • et al.
      Comparative safety of immune checkpoint inhibitors in cancer: systematic review and network meta-analysis.
      ]. TRAES of grade 3 or higher occurred in 11.8% of patients, with one patient death considered possibly attributable to treatment although it occurred while the patient was lost to follow-up. The irAEs seen in the study were typical of checkpoint inhibitor therapies, which have also previously been associated with hypothyroidism, diarrhea, pneumonitis, and enterocolitis [
      • Friedman C.F.
      • Proverbs-Singh T.A.
      • Postow M.A.
      Treatment of the immune-related adverse effects of immune checkpoint inhibitors: a review.
      ,
      • Robert C.
      • Schachter J.
      • Long G.V.
      • Arance A.
      • Grob J.J.
      • Mortier L.
      • et al.
      Pembrolizumab versus Ipilimumab in advanced melanoma.
      ,
      • Ferris R.L.
      • Blumenschein Jr., G.
      • Fayette J.
      • Guigay J.
      • Colevas A.D.
      • Licitra L.
      • et al.
      Nivolumab for recurrent squamous-cell carcinoma of the head and neck.
      ,
      • Motzer R.J.
      • Escudier B.
      • McDermott D.F.
      • George S.
      • Hammers H.J.
      • Srinivas S.
      • et al.
      Nivolumab versus Everolimus in advanced renal-cell carcinoma.
      ,
      • Ribas A.
      • Kefford R.
      • Marshall M.A.
      • Punt C.J.
      • Haanen J.B.
      • Marmol M.
      • et al.
      Phase III randomized clinical trial comparing tremelimumab with standard-of-care chemotherapy in patients with advanced melanoma.
      ,
      • Massard C.
      • Gordon M.S.
      • Sharma S.
      • Rafii S.
      • Wainberg Z.A.
      • Luke J.
      • et al.
      Safety and efficacy of Durvalumab (MEDI4736), an anti-programmed cell death Ligand-1 immune checkpoint inhibitor, in patients with advanced urothelial bladder Cancer.
      ,
      • Oaknin A.
      • Tinker A.V.
      • Gilbert L.
      • Samouelian V.
      • Mathews C.
      • Brown J.
      • et al.
      Clinical activity and safety of the anti-programmed death 1 monoclonal antibody Dostarlimab for patients with recurrent or advanced mismatch repair-deficient endometrial Cancer: a nonrandomized phase 1 clinical trial.
      ]. Further, balstilimab administration was characterized by a very low frequency of infusion-related reactions. The adverse event profile of balstilimab is both differentiated from, and compares favorably with, chemotherapies used in this patient population [
      • Boussios S.
      • Seraj E.
      • Zarkavelis G.
      • Petrakis D.
      • Kollas A.
      • Kafantari A.
      • et al.
      Management of patients with recurrent/advanced cervical cancer beyond first line platinum regimens: where do we stand? A literature review.
      ,
      • Monk B.J.
      • Sill M.W.
      • McMeekin D.S.
      • Cohn D.E.
      • Ramondetta L.M.
      • Boardman C.H.
      • et al.
      Phase III trial of four cisplatin-containing doublet combinations in stage IVB, recurrent, or persistent cervical carcinoma: a gynecologic oncology group study.
      ,
      • Moore D.H.
      • Blessing J.A.
      • McQuellon R.P.
      • Thaler H.T.
      • Cella D.
      • Benda J.
      • et al.
      Phase III study of cisplatin with or without paclitaxel in stage IVB, recurrent, or persistent squamous cell carcinoma of the cervix: a gynecologic oncology group study.
      ].
      In conclusion, balstilimab monotherapy was associated with promising, durable clinical activity in patients with advanced cervical cancer who had progressed after prior platinum-based therapy in the setting of recurrent/metastatic disease. Notably, tumor responses occurred irrespective of tumor PD-L1 status or histology. Along with a favorable tolerability profile, balstilimab thus represents an attractive candidate for use as a backbone in combination-based therapeutic approaches. Accordingly, an ongoing phase 2 study of balstilimab in combination with the novel cytotoxic T-lymphocyte-associated protein 4 inhibitor zalifrelimab (NCT03495882) is assessing the feasibility of dual immune checkpoint blockade for further improving outcomes in this patient population.

      Author contributions

      Conceptualization: DMO, AO, BJM, KNM, LMR, IRC.
      Data curation: DMO, AO, FS, CR, LG, DB, AL, KNM, MDPED, ACHB, JA, CPO, CRdA, LMR, IRC.
      Formal analysis: WOF, MA.
      Investigation: DMO, AO, BJM, FS, CR, LG, DB, AL, KNM, MDPED, ACHB, JA, CPO,CRdA, LMR,IRQ.
      Supervision: DMO, WOF, IRQ.
      Writing - original draft: DMO, BJM, WOF.
      Writing - review & editing: All authors.

      Funding

      This study was funded by Agenus Inc.

      Declaration of Competing Interest

      DMO reports personal fees and institutional grants from AstraZeneca, GSK/Tesaro, ImmunoGen, Janssen/Johnson & Johnson, Abbvie, Regeneron, Amgen, Clovis Oncology, Novocure, Genentech/Roche, Iovance, Eisai, Agenus, Merck, SeaGen, Novartis, Mersana; personal fees from Ambry, GOG Foundation, Myriad Genetics, Tarveda, Rubis, and Elevar; additional institutional funding from VentiRx Array Biopharma, EMD Serono, Ergomed, Ajinomoto Inc., Ludwig Cancer Research Stemcentrx, Inc., CERULEAN Pharma, Bristol-Myers Squibb, Serono, TRACON Pharmaceuticals, INC Research, Inc., inVentiv Health Clinical, PRA Intl and GenMab.
      AO reports personal fees from AstraZeneca, PharmaMar, Roche, Clinical Care Options, Clovis Oncology, Deciphera Pharmaceuticals, ImmunoGen, GenMab, Mersana, prIME Oncology, GlaxoSmithKline, and Tesaro; funding from AstraZeneca, Daiichi Sankyo, Eli Lilly and Company, Genentech, Immunomedics, Macrogenics, Merck Sharp & Dohme, Novartis, Pfizer, Piqur Therapeutics, Roche, Synthon, and Zenith Pharmaceuticals.
      BJM reports personal fees from Agenus, Akeso Bio, AstraZeneca, Genmab/Seattle Genetics, Iovance, Merck, Puma, Roche/Genentech, GOG Foundation, and GSK/Tesaro.
      FS reports personal fees and travel support from AstraZeneca, GSK/Tesaro, Merck Sharp & Dohme, Sandoz (Novartis), and Clovis Oncology, and Roche.
      CR reports personal fees from Merck, BMS, Roche, AstraZeneca, and Pfizer.
      LG reports personal fees from AstraZeneca, Clovis Oncology, GlaxoSmithKline, Merck Sharp & Dohme, and Roche; travel support from AstraZeneca and PharmaMar.
      AL reports personal fees from AstraZeneca, Tesaro, Clovis Oncology, Merck Sharp & Dohme, BIOCAD, AbilityPharma, Seattle Genetics, and Zentalis; institutional fees, grant and travel support from GlaxoSmithKline and Merck Serono.
      KNM reports personal fees from Aravive, AstraZeneca, Bristol Myers Squibb, Eisai, Elevar, GSK/Tesaro, Genentech/Roche, ImmunoGen, Merck, Mersana, Myriad, OncXerna, Sorrento, and VBL Therapeutics; funding from PTC Therapeutics, Lilly, and Merck.
      ACHB reports personal fees from AstraZeneca, Clovis Oncology, GlaxoSmithKline, Novartis, Pfizer, Roche, and Seagen.
      JA reports personal fees from AstraZeneca, GlaxoSmithKline, Roche, Merck Sharp & Dohme, PharmaMar; funding from Janssen and Merck Sharp & Dohme; travel support from Janssen, GlaxoSmithKline, and Novartis.
      CPO reports personal fees from Abbvie, AstraZeneca, Bristol Myers Squibb, Clovis Oncology, Genmab, GlaxoSmithKline, Tesaro, Mersana, PharmaMar; funding from Lilly, Roche, and Sanofi.
      CRdA reports personal fees from Merck Sharp & Dohme.
      LMR reports personal fees from AstraZeneca, Clovis Oncology, Eisai, EMD Serono, Genentech/Roche, GlaxoSmithKline, GOG Foundation, Mersana Therapeutics, Merck, Myriad Genetics, OnTarget, Rubius, BluPrint Oncology, Products in Knowledge; grant funding from Akeso Bio, Genentech, and Merck; travel support from GlaxoSmithKline.
      WOF reports employment by, and stock ownership in, Agenus Inc.
      MA reports employment by Agenus Inc.
      IRC reports personal fees from Abbvie, AstraZeneca, Bristol Myers Squibb, Clovis Oncology, Genmab, GlaxoSmithKline, Tesaro, Mersana, PharmaMar, and Roche; research funding from Bristol Myers Squibb, GlaxoSmithKline, and Merck Sharp & Dohme.
      All remaining authors have declared no conflicts of interest.

      Acknowledgments

      We wish to thank all the patients who participated and their families, as well as co-investigators, nurses, study coordinators, and operations staff at each of the clinical sites. We also thank Richard Bates, Director of Scientific Communications at Agenus, who provided drafts and editorial assistance during the production of the manuscript.

      Appendix A. Supplementary data

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