In the investigator-initiated phase III BEATcc study, the investigators for the first time evaluated the addition of a PD-L1 inhibitor, atezolizumab, to the standard of care bevacizumab plus chemotherapy regimen established previously in the GOG240 study for metastatic, persistent, or recurrent cervical cancer. The BEATcc study met both of its dual primary endpoints, showing significant and clinically meaningful improvements in both progression-free survival (PFS) and overall survival (OS) in the group with atezolizumab added to first-line standard regimen.
The threshold for significance was met at the interim OS analysis, with an increase in median OS of almost 10 months. Median OS exceeding 2.5 years, with 61% of patients alive at 2 years, represents the current benchmark for first-line treatment of advanced cervical cancer according to Prof. Ana Oaknin of the Medical Oncology Service, Vall d’Hebron Institute of Oncology, Vall d’Hebron Barcelona Hospital Campus in Barcelona, Spain, and colleagues, who published the findings on 1 December 2023 in The Lancet.
Patients diagnosed with metastatic, recurrent, or persistent cervical cancer not amenable to local control require systemic treatment and have a poor prognosis. Median OS in GOG240 study was less than 17 months, although this phase III study combining bevacizumab with standard chemotherapy was the first one since studies of platinum agents to show significantly improved OS in this setting. In the subsequent phase III KEYNOTE-826 study, addition of pembrolizumab to first-line chemotherapy with or without bevacizumab significantly improved OS with a median of 26 months.
The authors explained that both VEGF and PD-L1 play a role in cervical cancer pathogenesis. Angiogenesis and immune suppression are two facets of a linked biological programme; given the intimate relationship between angiogenesis and immunosuppression, inhibiting both pathways might potentially result in an improved and more durable clinical benefit. The BEATcc study was designed to establish whether combining atezolizumab with bevacizumab plus chemotherapy improves efficacy in the setting of metastatic, persistent, or recurrent cervical cancer.
In this investigator-initiated, randomised, open-label, phase III study, patients from 92 sites in Europe, Japan, and the USA with metastatic (stage IVB), persistent, or recurrent cervical cancer that was measurable, previously untreated, and not amenable to curative surgery or radiation were randomly assigned 1:1 to receive standard treatment of cisplatin 50 mg/m2 or carboplatin area under the curve of 5, paclitaxel 175 mg/m2, and bevacizumab 15 mg/kg, all on day 1 of every 3-week cycle with or without atezolizumab 1200 mg. Treatment was continued until disease progression, unacceptable toxicity, patient withdrawal, or death.
Stratification factors were previous concomitant chemoradiation (yes versus no), histology (squamous cell carcinoma versus adenocarcinoma including adenosquamous carcinoma), and platinum backbone (cisplatin versus carboplatin). Dual primary endpoints were investigator-assessed PFS according to RECIST v1.1 and OS analysed in the intention-to-treat population.
Between 8 October 2018 and 20 August 2021, 410 of 519 patients assessed for eligibility were enrolled. Median PFS was 13.7 months (95% confidence interval [CI] 12.3–16.6) with atezolizumab and 10.4 months (95% CI 9.7–11.7) with standard treatment (hazard ratio [HR] 0.62, 95% CI 0.49–0.78; p < 0.0001). At the interim OS analysis, median OS was 32.1 months (95% CI 25.3–36.8) versus 22.8 months (95% CI 20.3–28.0) with HR of 0.68 (95% CI 0.52–0.88; p = 0.0046). OS follow-up continues with final results expected in 2024.
Secondary efficacy endpoints also showed consistently more favourable outcomes in the group with added atezolizumab; 84% of patients responded to atezolizumab-containing treatment, 32% with a complete response, representing clinically meaningful tumour shrinkage in this typically symptomatic disease.
Grade 3 or worse adverse events occurred in 79% of patients in the group with added atezolizumab and in 75% of patients in the standard treatment group. Grade 1–2 diarrhoea, arthralgia, pyrexia, and rash were increased with atezolizumab. Consistent with previous phase III studies of atezolizumab in gynaecological cancers, hypothyroidism, and rash, both predominantly grade 1–2, were more common in the group with atezolizumab.
The authors commented that little is known about the efficacy of PD-L1 inhibition after previous treatment with PD1 inhibitor, which might become more relevant if the ENGOT-cx11–GOG-3047–KEYNOTE-A18 study evaluating pembrolizumab with chemoradiation for newly diagnosed high-risk locally advanced cervical cancer shows OS benefit in the future. Targeting PD-L1 rather than PD1 might be of interest rather than re-exposure to PD1 in patients progressing after initial anti-PD1 treatment, thus these first data on the use of PD-L1 inhibitor are an important addition to immune checkpoint strategies.
Although crossover to atezolizumab was not permitted in BEATcc, 33% of patients whose disease progressed on standard treatment subsequently received immune checkpoint inhibitor (ICI), which could confound survival given the efficacy of ICIs after platinum-based treatment. However, the observed improvement in median OS was almost 10 months with atezolizumab and this benefit was shown in a patient population that was unselected for PD-L1 status.
In an invited comment, Drs. Linda R Mileshkin and Sathya Manoharan of the Department of Medical Oncology, Peter MacCallum Cancer Centre, and University of Melbourne, both in Melbourne, Australia wrote that unlike KEYNOTE-826, PD-L1 status was not used to stratify patients in BEATcc, which makes sense given that most patients have PD-L1 positive disease, as PD-L1 is upregulated in response to human papillomavirus infection. After many decades of little improvement in treatment options for advanced cervical cancer, it is exciting to see these new developments translating into improved outcomes for patients.
However, several questions remain, including the exact contribution of bevacizumab to the combination with immunotherapy. Cancer-related angiogenesis driven by VEGF in cervical cancer prevents immune cells from infiltrating tumours efficiently, favouring ICI resistance. Adding bevacizumab might reprogramme the tumour microenvironment, increasing the effectiveness of immunotherapy. Although both BEATcc and KEYNOTE-826 suggest added benefit from bevacizumab, there is a lack of randomised data investigating this, as neither study had a bevacizumab-free group.
Another interesting finding in BEATcc was the similar improvement in survival seen with either cisplatin or carboplatin as the chemotherapy backbone, which is good for patients given the lower toxicity profile of carboplatin. The results of translational studies and cost-effectiveness data are awaiting with interest.
Although crossover was not permitted in BEATcc, it is interesting to see an OS benefit despite 33% of patients in the control group subsequently receiving ICI. This suggests that ICIs should be used early where possible according to the commentators. It is unclear whether the choice of ICIs matters when treating advanced cervical cancer. Benefit to date has mostly been seen with PD1 inhibitors such as pembrolizumab. Although the CALLA study did not find a similar benefit with the use of the PD-L1 inhibitor durvalumab in this setting, the BEATcc results suggest this was not because of differential efficacy of PD1 versus PD-L1 inhibitors.
The commentators wrote that we would need a different approach for treating patients who relapse after receiving ICI for treating locally advanced cervical cancer, possibly including novel immunotherapy options, such as bispecific antibodies targeting PD1 plus CTLA-4 or newer antibody–drug conjugates showing activity in cervical cancer.
The BEATcc study was funded by F Hoffmann-La Roche.
References
- Oaknin A, Gladieff L, Martínez-García J, et al. for the ENGOT-Cx10–GEICO 68-C–JGOG1084–GOG-3030 Investigators. Atezolizumab plus bevacizumab and chemotherapy for metastatic, persistent, or recurrent cervical cancer (BEATcc): a randomised, open-label, phase 3 trial. The Lancet; Published online 1 December 2023. DOI: https://doi.org/10.1016/S0140-6736(23)02405-4
- Mileshkin LR, Manoharan S. Improving survival from metastatic, recurrent, or persistent cervical cancer. The Lancet; Published online 1 December 2023. DOI: https://doi.org/10.1016/S0140-6736(23)02690-9