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  • A non-comparative, randomized, phase II trial of atezolizumab or atezolizumab plus tiragolumab for programmed death-ligand 1-positive recurrent cervical cancer (SKYSCRAPER-04)

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Original research
A non-comparative, randomized, phase II trial of atezolizumab or atezolizumab plus tiragolumab for programmed death-ligand 1-positive recurrent cervical cancer (SKYSCRAPER-04)
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  1. Ritu Salani1,
  2. Mary McCormack2,
  3. Yong-Man Kim3,
  4. Sharad Ghamande4,
  5. Shaundra L Hall5,
  6. Domenica Lorusso6,
  7. Lisa Barraclough7,
  8. Lucy Gilbert8,
  9. Adrian Guzman Ramirez9,
  10. Chien-Hsing Lu10,
  11. Renaud Sabatier11,
  12. Nicoletta Colombo12,13,
  13. Youyou Hu14,
  14. Venkatesh Krishnan15,
  15. Luciana Molinero15,
  16. Yuning Feng15,
  17. Nicole Kim15,
  18. Marcela Castro15,
  19. Yvonne G Lin15 and
  20. Bradley J Monk16
    1. 1 Department of Obstetrics and Gynecology, University of California Los Angeles, Los Angeles, California, USA
    2. 2 Department of Oncology, University College London Hospitals, London, UK
    3. 3 Gynecologic Cancer Center, Asan Cancer Institute, Asan Medical Center, University of Ulsan, Seoul, Korea (the Republic of)
    4. 4 Georgia Cancer Center, Augusta University, Augusta, Georgia, USA
    5. 5 National Cervical Cancer Coalition, Research Triangle Park, North Carolina, USA
    6. 6 Gynecologic Oncology Unit, Fondazione Policlinico Gemelli IRCCS and Catholic University of the Sacred Heart, Rome, Italy
    7. 7 Clinical Oncology, The Christie NHS Foundation Trust, Manchester, UK
    8. 8 The Gerald Bronfman Department of Oncology, McGill University Health Centre, McGill University, Montreal, Quebec, Canada
    9. 9 Instituto de Investigación en Ciencias Médicas (ICIMED), San José, Costa Rica
    10. 10 Department of OB/GYN, Taichung Veterans General Hospital, Taichung, Taiwan
    11. 11 Department of Medical Oncology, Aix-Marseille University, CRCM, Inserm, CNRS, Institut Paoli-Calmettes, Marseille, France
    12. 12 Department of Medicine and Surgery, University of Milan-Bicocca, Milan, Italy
    13. 13 Gynecologic Oncology Program, European Institute of Oncology IRCCS, Milan, Italy
    14. 14 F. Hoffmann-La Roche Ltd, Basel, Switzerland
    15. 15 Genentech, Inc, South San Francisco, California, USA
    16. 16 Department of Oncology, HonorHealth University of Arizona College of Medicine and Creighton University School of Medicine, Phoenix, Arizona, USA
    1. Correspondence to Dr Ritu Salani, Department of Obstetrics and Gynecology, University of California Los Angeles, Los Angeles, California, USA; rsalani{at}mednet.ucla.edu

    • Present affiliation The present affiliation of Bradley J Monk is: Florida Cancer Specialists and Research Institute, West Palm Beach, Florida, USA

    Abstract

    Objective To evaluate tiragolumab (anti-TIGIT) and atezolizumab (anti-PD-L1) as second- or third-line therapy for PD-L1-positive persistent/recurrent cervical cancer.

    Methods In the open-label, non-comparative, randomized phase II SKYSCRAPER-04 trial (NCT04300647), patients with PD-L1-positive (SP263 tumor area positivity ≥5%) recurrent/persistent cervical cancer after 1–2 chemotherapy lines (≥1 platinum-based) were randomized 3:1 to atezolizumab 1200 mg with/without tiragolumab 600 mg every 3 weeks until disease progression or unacceptable toxicity. Stratification factors were performance status, prior (chemo)radiotherapy, and disease status. The primary endpoint was independent review committee-assessed confirmed objective response rate per RECIST v1.1 in patients receiving tiragolumab plus atezolizumab. An objective response rate ≥21% (one-sample z-test p≤0.0245) was required for statistical significance versus a historical reference.

    Results Protocol-defined independent review committee-assessed objective response rates were 19.0% (95% CI 12.6 to 27.0) in 126 patients receiving tiragolumab plus atezolizumab (p=0.0787 vs historical reference) and 15.6% (95% CI 6.5 to 29.5) in 45 atezolizumab-treated patients. Response rates were higher in PD-L1high (tumor area positivity ≥10%) than PD-L1low (tumor area positivity 5%–9%) subgroups with both regimens. At 8.5 months’ median follow-up, independent review committee-assessed progression-free survival was 2.8 months (95% CI 1.7 to 4.1) with tiragolumab plus atezolizumab and 1.9 months (95% CI 1.5 to 3.0) with atezolizumab. In post hoc analyses (10.4 months’ median follow-up), median overall survival was 11.1 months (95% CI 9.6 to 14.5) with the combination and 10.6 months (95% CI 6.9 to 13.8) with atezolizumab (crossover permitted). In the combination group, 3% of patients had adverse events requiring treatment discontinuation and 8% had grade ≥3 adverse events of special interest; corresponding values in the single-agent arm were 4% and 11%. There were no treatment-related deaths or new safety findings.

    Conclusion The objective response rate with the tiragolumab-plus-atezolizumab combination was numerically higher than the historical reference but did not reach statistical significance.

    • Cervical Cancer
    • Immunotherapy

    Data availability statement

    Data are available upon reasonable request. Qualified researchers may request access to individual patient-level clinical data through a data request platform. At the time of writing this request platform is Vivli (https://vivli.org/ourmember/roche/). For up-to-date details of Roche’s Global Policy on the Sharing of Clinical Information and how to request access to related clinical study documents, see https://go.roche.com/data_sharing. Anonymized records for individual patients across more than one data source external to Roche cannot, and should not, be linked due to a potential increase in risk of patient re-identification.

    https://doi.org/10.1136/ijgc-2024-005588

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      WHAT IS ALREADY KNOWN ON THIS TOPIC

      • Single-targeted therapy with a PD-1 inhibitor is an effective treatment strategy for persistent/recurrent cervical cancer, but modest objective response rates, even in biomarker-selected populations, leave opportunities for improvement.

      WHAT THIS STUDY ADDS

      • In SKYSCRAPER-04, dual blockade concurrently inhibiting PD-L1 and TIGIT as second- or third-line therapy for PD-L1-positive cervical cancer showed a numerically higher objective response rate than a historical reference, although this did not reach statistical significance. The combination was well tolerated with no new safety signals.

      HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY

      • These data support further research to understand which populations are the most appropriate for enrollment into future clinical trials evaluating TIGIT and PD-(L)1 inhibitors in persistent/recurrent cervical cancer.

      Introduction

      The incidence of cervical cancer has been reduced by cervical cytology and human papillomavirus (HPV) vaccination and the ultimate goal is complete eradication. Nevertheless, cervical cancer is the fourth most common cancer in women globally, with approximately 660 000 new cases and 350 000 deaths in 2022.1 Standard first-line therapy includes chemotherapy (usually a platinum-based doublet) with bevacizumab and/or immunotherapy if eligible.2–6 At relapse, options remain limited and the prognosis is poor.

      Chronic HPV infection increases programmed death-(ligand) 1 (PD-[L]1) expression on cervical cancer cells and is associated with a worse prognosis, but offers a potential therapeutic opportunity.7–10 Single-arm studies evaluating PD-(L)1 inhibitor monotherapy, predominantly after at least one platinum-containing regimen, have shown objective response rates of up to 20%11 12 and the randomized phase III EMPOWER-Cervical 1/GOG-3016/ENGOT-cx9 trial demonstrated improved overall survival versus chemotherapy.13 14 Nevertheless, modest clinical efficacy highlights room for improvement. Combining the PD-1 inhibitor nivolumab with the CTLA-4 inhibitor ipilimumab appeared to improve objective response rates,15 supporting the principles underlying dual immune checkpoint blockade. However, increased toxicity associated with dual blockade reinforces the need to balance tolerability with efficacy.

      TIGIT (T-cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domains) has emerged as a promising target for cancer immunotherapy16–18 due to its overexpression in the tumor microenvironment, co-expression with PD-1 (especially in tumor-infiltrating lymphocytes), and association with impaired T-cell and natural killer cell function and anti-tumor immunity.17–20 Tiragolumab is a novel fully human monoclonal antibody with an intact Fc region that blocks TIGIT and poliovirus receptor binding.21 22 Dual immune blockade with tiragolumab (anti-TIGIT) and atezolizumab (anti-PD-L1) has been hypothesized to potentiate the immune response by restoring or accelerating immunity against human cancers.18 In the first-in-human phase Ib GO30103 study, tiragolumab (with or without atezolizumab) was well tolerated and the combination demonstrated preliminary anti-tumor activity in immunotherapy-naïve patients with metastatic non-small-cell lung or esophageal cancers.23 In the double-blind randomized phase II CITYSCAPE trial in PD-L1-positive recurrent/metastatic non-small cell lung cancer, dual blockade with first-line tiragolumab plus atezolizumab improved efficacy over atezolizumab alone, particularly in patients with PD-L1high tumors.24

      The potent efficacy seen with TIGIT in PD-L1-positive non-small cell lung cancer, coupled with the significant role of the immune system in HPV-associated cervical cancer, provided a compelling rationale for evaluating concurrent TIGIT and PD-L1 blockade in patients with PD-L1-positive pretreated recurrent/persistent cervical cancer.

      Methods

      SKYSCRAPER-04 (NCT04300647) was an open-label, non-comparative, randomized phase II trial assessing the efficacy and safety of atezolizumab alone or combined with tiragolumab as second- or third-line therapy for PD-L1-positive recurrent/persistent cervical cancer. It was conducted at 59 sites across 17 countries in Europe, North and South America, Asia, and Australia (online supplemental table 1). Eligible patients had recurrent or persistent cervical cancer not amenable to curative treatment after one or two prior lines of systemic chemotherapy, including at least one platinum-based chemotherapy (not counting cisplatin administered with radiation), investigator-determined measurable disease, and positive PD-L1 status, defined as ≥5% tumor area positivity in tumor and immune cells assessed centrally by VENTANA PD-L1 (SP263) Investigation Use Only assay (Roche Diagnostics, Rotkreuz, Switzerland). Additional eligibility criteria included Eastern Cooperative Oncology Group performance status ≤1, no history of autoimmune disease or immune deficiency, and no prior CD137 agonist or immune checkpoint blockade therapy. Patients were stratified by performance status (0/1), prior (chemo)radiotherapy (yes/no), and disease status (persistent/recurrent) and randomized by a web-based response system in a 1:3 ratio (permuted-block randomization with block size of 4 then 8) to receive intravenous atezolizumab 1200 mg alone or with intravenous tiragolumab 600 mg, both given on day 1 every 3 weeks. Treatment was continued until disease progression or unacceptable toxicity. Patients randomized to atezolizumab alone were allowed to add tiragolumab to atezolizumab after unequivocal disease progression. All patients provided written informed consent.

      Supplemental material

      The primary objective was to evaluate the efficacy of tiragolumab plus atezolizumab and of single-agent atezolizumab, as measured by independent review committee (IRC)-assessed confirmed objective response rate per Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1. The objective response rate in the combination group was compared with a historical benchmark of 14.6% (based on the PD-L1-positive subgroup in the KEYNOTE-158 trial).11 A one-sample z-test p-value of ≤0.0245 was required for the combination regimen to be deemed statistically significant versus the historical reference. The sample size calculation and interim analysis are described in the online supplemental text. In this non-comparative trial, the atezolizumab-alone group served to generate descriptive data.

      Secondary endpoints included duration of response, disease control rate (IRC-assessed complete or partial response or stable disease per RECIST version 1.1), IRC-assessed progression-free survival, IRC-assessed 6-month progression-free survival rate, overall survival, 6- and 12-month overall survival rates, and safety. Exploratory subgroup analyses by degree of PD-L1 positivity were prespecified, with ≥10% tumor area positivity defined as PD-L1high and 5%–9% tumor area positivity defined as PD-L1low. Post hoc analyses explored the IRC-assessed objective response rate in the subgroup of patients with measurable disease by both investigator and IRC assessment.

      Tumors were assessed at baseline, every 6 weeks for 48 weeks, and then every 9 weeks until unequivocal radiographic disease progression, consent withdrawal, death, or study termination, whichever occurred first. Patients who continued treatment after RECIST-determined disease progression continued tumor assessments until treatment discontinuation. Adverse events were graded according to National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0.

      Efficacy and safety were analyzed in all randomized patients who received at least one dose of study treatment. The primary efficacy analysis took place after all treated patients had been followed for ≥9 months after randomization.

      The protocol and all amendments, informed consent form, and other relevant documents were approved by each site’s institutional review board (UCLA Institutional Review Board IRB#20–0 00 864) before initiating the trial. The trial was conducted in accordance with the ethical principles derived from international guidelines including the Declaration of Helsinki and Council for International Organizations of Medical Sciences International Ethical Guidelines, applicable International Council for Harmonisation Good Clinical Practice Guidelines, and applicable laws and regulations.

      Results

      Patient Population and Treatment Exposure

      Between June 30, 2020 and March 8, 2021, 171 patients were enrolled and treated: 126 with tiragolumab plus atezolizumab and 45 with atezolizumab alone (Figure 1). All patients had PD-L1-positive disease and 61% had PD-L1high tumors (Table 1). Prior therapy included (chemo)radiotherapy in 80%, bevacizumab in 35%, and paclitaxel in 93% of patients. Most patients (>90%) received platinum (either carboplatin or cisplatin) in the first-line setting.

      Figure 1
      Figure 1

      Patient disposition (data cut-off: June 30, 2022; median follow-up 10.4 months). *More than one reason possible. †Radiographic disease progression or symptomatic deterioration. AE, adverse event; ECOG PS, Eastern Cooperative Oncology Group performance status; PD, disease progression; PD-L1, programmed death-ligand 1.

      View this table:
      Table 1

      Baseline characteristics

      In the combination group, the median duration of treatment was 6 (range 1–23) cycles for both atezolizumab and tiragolumab. In the atezolizumab-alone group, the median duration of treatment was 4 (range 1–21) cycles.

      Primary Efficacy Analysis

      The data cut-off for the primary analysis was December 8, 2021 (median follow-up: 8.5 months, IQR 4.8–10.6). The protocol-defined IRC-assessed objective response rate was 19.0% (95% CI 12.6 to 27.0) in the combination group, which was not statistically different from the historical reference (p=0.0787) (Figure 2). The IRC-assessed objective response rate with single-agent atezolizumab was 15.6% (95% CI 6.5 to 29.5). Complete responses were observed in 3.2% (95% CI 0.9 to 7.9) of the combination group and 4.4% (95% CI 0.5 to 15.1) of the atezolizumab-alone group; disease control rates were 31.0% (95% CI 23.0 to 39.8) and 20.0% (95% CI 9.6 to 34.6), respectively. The median IRC-assessed duration of response in 24 responders to combination therapy was 11.8 months (95% CI 6.7 to not estimable; no progression/death in 15 patients). Median duration of response could not be estimated in the single-agent atezolizumab group (no progression/death recorded in five of seven responders).

      Figure 2
      Figure 2

      Primary endpoint: independent review committee-assessed objective response rate (data cut-off: December 8, 2021; median follow-up 8.5 months). Lighter bars represent complete response, darker bars represent partial response. *One-sample z-test p-value not statistically significant. PD-L1high = ≥10% tumor area positivity; PD-L1low = 5%–9% tumor area positivity. IRC, independent review committee; ORR, objective response rate; PD-L1, programmed death-ligand 1.

      Investigator-assessed objective responses were observed in 33 patients (26%; 95% CI 19 to 35) in the combination group and six patients (13%; 95% CI 5 to 27) treated with single-agent atezolizumab. The median duration of response was 9.9 months (95% CI 4.3 to not estimable) in the combination group (no progression/death in 17 patients) and 7.0 months (95% CI 6.5 months to not estimable) in the atezolizumab group (no progression/death in three patients).

      Prespecified subgroup analyses showed that in both treatment groups, objective response rates were higher in the PD-L1high than the PD-L1low subgroup, and all complete responses were in the PD-L1high population (Figure 2).

      After progression-free survival events in approximately 80% of patients, median progression-free survival was 2.8 months (95% CI 1.7 to 4.1) in the combination group and 1.9 months (95% CI 1.5 to 3.0) in the atezolizumab-alone group (Figure 3A). At this time, 19% of patients were still on treatment and 47% had died.

      Figure 3
      Figure 3

      Secondary efficacy endpoints. (A) Progression-free survival (data cut-off: December 8, 2021). (B) Overall survival (data cut-off: June 30, 2022).

      In post hoc analyses restricted to patients with both investigator- and IRC-determined measurable disease at baseline, the objective response rate was 21.6% in 111 patients in the combination group and 15.8% in 38 patients in the atezolizumab-alone group. Consistent with the primary endpoint, both treatment groups had higher objective response rates in the PD-L1high than the PD-L1low subgroups (online supplemental figure 1).

      Updated Overall Survival Analysis

      In a post hoc updated analysis of overall survival with a data cut-off of June 30, 2022, median follow-up was 10.4 months. At that point, 17 patients in the combination group were still receiving study treatment, six initially randomized to atezolizumab alone were still receiving single-agent atezolizumab, and three of 15 patients in whom tiragolumab was added to single-agent atezolizumab at progression were still receiving the combination (Figure 1). The most common reason for treatment discontinuation was disease progression (72% and 73% in the combination and single-agent groups, respectively). Median overall survival was 11.1 months (95% CI 9.6 to 14.5) in the combination group and 10.6 months (95% CI 6.9 to 13.8) in the single-agent group (Figure 3B).

      Safety Analysis

      At the data cut-off for the primary analysis, the median duration of safety follow-up was 4.4 months (range 0.4–15.5 months). Table 2 summarizes the safety of the two regimens. In both treatment groups, more than half of the patients (66% of the combination group, 51% of the single-agent group) experienced treatment-related adverse events but relatively few (13% vs 9%, respectively) were grade 3/4 (online supplemental table 2). Although there were four grade 5 events (one case each of sepsis, acute respiratory failure, and embolism in the combination arm; one case of pneumonia in the atezolizumab arm), there were no grade 5 adverse events of special interest or treatment-related deaths with either treatment. Adverse events led to withdrawal of any treatment in four patients (3%) in the combination group and two patients (4%) in the single-agent group and interruption of any treatment in 29 patients (23%) and eight patients (18%), respectively (online supplemental table 3).

      View this table:
      Table 2

      Summary of safety (data cut-off: December 8, 2021; adverse events during initial treatment before crossover, highest grade reported). Serious adverse events and adverse events of special interest were reported until 90 days after the last dose of study treatment (or until starting new systemic anti-cancer therapy, if earlier, for serious adverse events). Other adverse events were reported until 30 days after the last dose of study treatment or the start of new systemic anti-cancer therapy, whichever occurred first.

      The most common (≥20%) adverse events were anemia (both regimens) and nausea (combination regimen) (online supplemental table 2). In both treatment groups, the only adverse events of special interest in >5% of patients (at any grade) were rash, hepatitis, infusion-related reaction, and hypothyroidism (and hyperthyroidism with combination therapy). Lymphopenia was reported in six patients (5%; three grade 3/4) receiving combination therapy and three patients (7%; all grade 1/2) receiving atezolizumab alone.

      Discussion

      Summary of Main Results

      The combination of tiragolumab and atezolizumab demonstrated an objective response rate numerically higher than the historical control data in this non-comparative, randomized phase II trial, but this did not achieve the prespecified level of statistical significance. In both treatment groups, objective response rates were higher in PD-L1high than PD-L1low populations. Median progression-free survival was <3 months in both treatment groups. In a post hoc analysis with longer follow-up, median overall survival was approximately 11 months in both treatment groups.

      Adding tiragolumab to atezolizumab was well tolerated, reflected by the low treatment discontinuation rate. Grade 3/4 adverse events occurred in 44% of patients receiving the combination, but grade 3/4 adverse events of special interest were infrequent in both treatment groups and there were no grade 5 adverse events of special interest or treatment-related deaths.

      Results in the Context of Published Literature

      When the SKYSCRAPER-04 trial was initiated, the only reported data for single-agent immunotherapy in pretreated recurrent/metastatic PD-L1-positive cervical cancer was the modest 14.3% objective response rate with pembrolizumab, providing proof of concept for PD-(L)1 blockade in cervical cancer.11 Subsequently a single-arm study of another anti-PD-1 agent, balstilimab, demonstrated a 15% objective response rate (20% in the PD-L1-positive subset).12 The only available data for PD-L1 blockade showed no objective responses (two unconfirmed responses; 20%) in 10 patients receiving second-line atezolizumab and bevacizumab.25 The 16% objective response rate with single-agent atezolizumab in SKYSCRAPER-04 is consistent with results for PD-1 inhibitor monotherapy from single-arm studies and from the randomized phase III EMPOWER-Cervical 1 trial, in which cemiplimab demonstrated a 16% objective response rate and significantly improved overall survival versus chemotherapy alone (median 12.0 vs 8.5 months, respectively; HR 0.69),13 leading to regulatory approval in Europe irrespective of PD-L1 status.26 The HR for overall survival was 0.61 (95% CI 0.45 to 0.83) in patients with PD-L1-positive tumors by SP263 and 0.65 (95% CI 0.43 to 0.98) in those with PD-L1-negative tumors.14

      No phase III trials have reported outcomes with dual immune checkpoint blockade. In phase I/II studies, combinations of PD-1 inhibitors and CTLA-4 inhibitors have demonstrated objective response rates of 35% (second-line nivolumab plus ipilimumab in CheckMate 358)27 and 26% (balstilimab plus zalifrelimab; 33% in the PD-L1-positive subset).28 However, high rates of immune-related adverse events and treatment-related adverse events leading to treatment discontinuation underscore the need for better-tolerated regimens. Consistent with studies in lung cancer,24 29 combining tiragolumab with atezolizumab for cervical cancer in SKYSCRAPER-04 did not increase rates of toxicity-related treatment discontinuation.

      Since initiation of this study, elevated levels of TIGIT expression have been reported in cervical cancer tissue.20 Limited preliminary anti-tumor activity has been reported with the combination of vibostolimab (anti-TIGIT) and pembrolizumab in a phase I study.30 More recently, the randomized phase II AdvanTIG-202 trial (NCT04693234) reported an IRC-assessed objective response rate of 23% with ociperlimab (anti-TIGIT) plus tislelizumab (anti-PD-1) (26% in the PD-L1-positive subgroup) and, remarkably, 33% with single-agent tislelizumab regardless of PD-L1 status in the second-line or later recurrent/persistent cervical cancer setting.31 After a median follow-up of 7.4 months, the combination demonstrated median progression-free survival of 3.5 months and median overall survival of 9.0 months (4.2 and 10.4 months, respectively, in the PD-L1-positive subgroup). While acknowledging the limitations of cross-trial comparisons, the efficacy observed with ociperlimab/tislelizumab is encouragingly similar to that observed in SKYSCRAPER-04. However, the activity of tislelizumab monotherapy was much higher than observed with the doublet or single-agent atezolizumab, or with other agents targeting PD-1 (eg, pembrolizumab, cemiplimab, nivolumab). Further work is needed to understand better the structural nuances of these agents, both static and dynamic, on ligand binding, as well as downstream effects of the immune synapse.

      Strengths and Weaknesses

      To the best of our knowledge, SKYSCRAPER-04 is the first trial to report the efficacy and safety of a regimen combining PD-L1 and TIGIT blockade in cervical cancer. Prospective PD-L1 testing and analyses by PD-L1 level (PD-L1high vs PD-L1low) at a central laboratory enable robust interpretation of these biomarker segments. Another strength of this study was the IRC assessment.

      The primary weaknesses of this study are the open-label design and protocol-permitted addition of tiragolumab to atezolizumab in patients with progression on single-agent atezolizumab (ie, crossover). These design features, while pragmatic and well-intentioned, may introduce bias. Additional weaknesses are the limited sample size, the non-comparative design, and the absence of IRC-determined measurable disease at baseline in 22 patients. Although statistical parameters were prespecified, benchmarking the primary objective response rate endpoint against a historical trial is challenged by the limitations of cross-trial comparisons, especially when patient-level data are unknown and the two studies may not be comparable. Formally comparing the two contemporaneously enrolled arms of SKYSCRAPER-04 would have mitigated some of these variables.

      Lastly, the limited information on subsequent therapies and crossover to the combination at progression in 15 patients make it difficult to interpret overall survival, which may be a more appropriate endpoint for evaluating immunotherapies. As both regimens were well tolerated, as indicated by the low treatment discontinuation rates, patients may have been able to receive further lines of active treatment after progression on study treatment.

      Implications for Practice and Future Research

      In the overall population, the activity of this regimen combining TIGIT and PD-L1 inhibition was modest. Activity was higher in the PD-L1high subgroup, but this may reflect a better prognosis rather than an enhanced treatment effect. In patients responding to tiragolumab plus atezolizumab, responses appeared to be durable but identifying those patients who are likely to benefit (or not) from this treatment remains challenging. Ongoing translational research aims to determine whether the combination regimen merits further evaluation in specific biomarker-identifiable subsets of patients.

      At least half of the patients had experienced disease progression before the first scheduled tumor assessment, illustrating the dismal prognosis and the need for better treatment options for these patients. Results in other tumor types suggest that anti-TIGIT agents may offer an effective treatment approach, but it remains to be seen whether this will also apply to cervical cancer or whether alternative targets are required.

      As immune checkpoint inhibitors are increasingly incorporated into earlier treatment settings following positive randomized phase III results,2–4 32 more patients are expected to have been exposed to anti-PD-(L)1 therapy by the second-line setting. The impact of prior therapy on re-exposure to PD-(L)1 blockade is currently unknown. Novel strategies in recurrent/persistent cervical cancer include antibody-drug conjugates, such as tisotumab vedotin, which has demonstrated efficacy and received regulatory approval33 34; however, much room for improvement remains.

      Conclusions

      Combining tiragolumab (anti-TIGIT) and atezolizumab (anti-PD-L1) was well tolerated with low incidences of grade ≥3 adverse events of special interest and adverse events leading to treatment discontinuation, but showed modest anti-tumor activity. This underscores the need for more effective regimens for patients with persistent/recurrent cervical cancer.

      Data availability statement

      Data are available upon reasonable request. Qualified researchers may request access to individual patient-level clinical data through a data request platform. At the time of writing this request platform is Vivli (https://vivli.org/ourmember/roche/). For up-to-date details of Roche’s Global Policy on the Sharing of Clinical Information and how to request access to related clinical study documents, see https://go.roche.com/data_sharing. Anonymized records for individual patients across more than one data source external to Roche cannot, and should not, be linked due to a potential increase in risk of patient re-identification.

      Ethics statements

      Patient consent for publication

      Ethics approval

      This study involves human participants and was approved by each site’s institutional review board (UCLA Institutional Review Board IRB#20-000864) before initiating the trial. Participants gave informed consent to participate in the study before taking part.

      Acknowledgments

      The authors thank all patients and their families, participating study investigators, and healthcare providers and support staff at the participating clinical sites. SKYSCRAPER-04 was sponsored by F. Hoffmann-La Roche Ltd. Medical writing assistance for this publication was provided by Jennifer Kelly, MA (Medi-Kelsey Ltd), funded by F. Hoffmann-La Roche Ltd.

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      Supplementary materials

      • Supplementary Data

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      Footnotes

      • Contributors Study design: RSal, MM, Y-MK, SG, SLH, DL, VK, YGL, BJM. Data collection: RSal, MM, Y-MK, SG, DL, LB, LG, AGR, C-HL, RSab, NC, BJM. Data analysis: YH, VK, LM. All authors participated in data interpretation, review, and approval of the manuscript. RSal acted as guarantor.

      • Funding This study was funded by F. Hoffmann-La Roche Ltd.

      • Competing interests Medical writing support and article processing charges were funded by F. Hoffmann-La Roche Ltd. RSal reports personal consulting fees from Merck, Eisai, Regeneron, GSK, ImmunoGen, Karyopharm, Genentech, Clovis, AstraZeneca, and Mersana. Y-MK reports clinical study grants (to institution) from MSD, AstraZeneca, ImmunoGen, Zentalis, and BeiGene, and unpaid leadership roles for KGOG and EAGOT. SG reports consulting fees from GSK, Eisai, and Seagen; speaker honoraria from GSK; research contracts (with institution) from GSK, Merck, Takeda, BMS, Sutro, Jounce, AstraZeneca, and Eisai; and an unpaid leadership role with the GOG Foundation. DL reports personal fees for consulting from AstraZeneca, Clovis Oncology, Genmab, GSK, ImmunoGen, MSD, PharmaMar, Seagen, and Novartis; speaker honoraria from AstraZeneca, Clovis Oncology, Corcept, Genmab, GSK, ImmunoGen, MSD, Oncoinvest, PharmaMar, Seagen, and Sutro; research grants to institution from AstraZeneca, Clovis Oncology, Genmab, GSK, ImmunoGen, Incyte, MSD, Novartis, PharmaMar, Seagen, and Roche; participation on data safety monitoring or advisory boards for AstraZeneca, Clovis Oncology, Corcept, Genmab, GSK, ImmunoGen, MSD, Oncoinvest, PharmaMar, Seagen, and Sutro; and support for meeting attendance/travel from GSK, AstraZeneca, Clovis Oncology, and MSD. LG reports grants (to institution) from IMV, Pfizer, Sutro Biopharma, MSD, Corcept Therapeutics, ImmunoGen, Shattuck Labs, Roche, Tesaro, K-Group Beta, Inc., GOG Foundation, GSK, AstraZeneca, Oncquest Laboratories, Novocure GmbH, Alkermes Inc., Esperas, and Mersana; consulting fees from GSK and Merck; meeting support/travel from GSK, Merck, Genentech, and Zentalis Pharma; and advisory board participation for GSK, Merck, Eisai, Novocure, Kora Healthcare, Corcept Therapeutics, ImmunoGen, and Canaribio Inc. AGR reports speaker honoraria from Roche, Pfizer, and Janssen; support for attending meetings/travel from Novartis, Roche, and Pfizer; and participation in data safety monitoring or advisory boards for Roche and Novartis. RSab reports consulting/advisory roles for Eisai, and GSK; speaker honoraria from Clovis, GSK, MSD, Seagen, Eisai, and Novartis; research funding to institution from AstraZeneca; and travel/accommodation support from MSD, GSK, and Novartis. NC reports honoraria from AstraZeneca, Novartis, Clovis Ocology, GSK, MSD/Merck, and Eisai; consulting/advisory roles for AstraZeneca, Clovis Oncology, Eisai, GSK, ImmunoGen, Mersana, MSD/Merck, Nuvation Bio, Onxerna, Pfizer, Pieris, Roche, Novocure, and Eisai; research funding (to institution) from GSK, Roche, and AstraZeneca; leadership for ACTO onlus - Chair, Scientific Committee, and travel/accommodation/expenses from AstraZeneca. YH, VK, LM, YF, NK, MC, and YGL are employees of Roche/Genentech and hold shares in Roche. BJM reports consulting fees from Acrivon, Adaptimmune, Agenus, Akeso Bio, Amgen, Aravive, AstraZeneca, Bayer, Clovis, Eisai, Elevar, EMD Merck, Genmab/Seagen, GOG Foundation, Gradalis, Heng Rui, ImmunoGen, Karyopharm, Iovance, Laekna, Macrogenics, Merck, Mersana, Myriad, Novartis, Novocure, OncoC4, Panavance, Pieris, Pfizer, Puma, Regeneron, Roche/Genentech, Sorrento, Tesaro/GSK, US Oncology Research, VBL, Verastem, and Zentalis; and speaker honoraria from AstraZeneca, Eisai, Myriad, Roche/Genentech, and Tesaro/GSK. All remaining authors report no conflict of interest.

      • Provenance and peer review Not commissioned; externally peer reviewed.

      • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.