Atezolizumab Plus Bevacizumab and Chemo Improves Survival in Metastatic or Recurrent Cervical Cancer

Ana Oaknin, MD, PhD

The addition of atezolizumab (Tecentriq) to bevacizumab (Avastin) and chemotherapy resulted in a significant improvement in progression-free survival (PFS) and overall survival (OS) vs standard treatment with bevacizumab and chemotherapy in patients with metastatic, persistent, or recurrent cervical cancer, meeting the co-primary end points of the phase 3 BEATcc (ENGOT-Cx10/GEICO 68-C/JGOG1084/GOG-3030) trial (NCT03556839).¹

Primary results presented during the November ESMO Virtual Plenary showed that the atezolizumab regimen (n = 206) resulted in a median PFS of 13.7 months (95% CI, 12.3-16.6) vs 10.4 months (95% CI, 9.7-11.7) with the standard approach (n = 204), translating to a 38% reduction in the risk of disease progression or death in this population (HR, 0.62; 95% CI, 0.49-0.78; P < .0001). The 24-month PFS rates in the atezolizumab and standard arms were 36% and 19%, respectively; at 36 months, these rates were 26% and 12%, respectively.

The median OS achieved with atezolizumab plus bevacizumab and chemotherapy was 32.1 months (95% CI, 25.3-36.8) vs 22.8 months (95% CI, 20.3-28.0) with bevacizumab and chemotherapy alone, translating to a 32% reduction in the risk of death (HR, 0.68; 95% CI, 0.52-0.88; P = .0046). The 24-month OS rates were 61% vs 49%, respectively, and 42% vs 26%, respectively, at 36 months.

“BEATcc confirms the clinical benefit of combining immunosuppression inhibition with angiogenesis inhibition in recurrent or metastatic cervical cancer,” Ana Oaknin, MD, PhD, who is the principal investigator of the BEATcc trial, head of the Gynecologic Cancer Program at Vall d’Hebron Institute of Oncology in Barcelona, Spain, said in a presentation of the data. “…Atezolizumab in combination with bevacizumab added to platinum-based chemotherapy should be considered a new first-line therapy option for patients with metastatic, persistent, or recurrent cervical cancer.”

Oaknin is also a faculty member of the Gynecologic Track in ESMO, chair of the Cervical Cancer Committee in Gynecologic Cancer Intergroup, Gynecologic Oncology Group, and a member of the National Cancer Institute.

The rationale to combine immune checkpoint blockade with bevacizumab chemotherapy was supported by data from the phase 3 GOG 240 (NCT00803062) and KEYNOTE-826 (NCT03635567) trials.

“Combining the anti-VEGF agent bevacizumab with platinum-based chemotherapy was established as the standard of care [SOC] following a significant improvement in OS in the phase 3 GOG 240 trial,” Oaknin noted. Bevacizumab paired with platinum-based chemotherapy (n = 115) resulted in a median OS of 17.5 months vs 14.3 months with chemotherapy alone (n = 114; HR, 0.68; 95% CI, 0.48-0.97; 1-sided P = .04).² KEYNOTE-826 then confirmed the efficacy of immunotherapy in this population, Oaknin noted. In the all-comer population, pembrolizumab (Keytruda) plus chemotherapy (n = 308) resulted in a median OS of 26.4 months vs 16.8 months with chemotherapy alone (n = 309; HR, 0.63; 95% CI, 0.52-0.77; P < .0001).³

“Clearly, both VEGF and PD-L1 are important targets in cervical cancer,” Oaknin said. “Peripheral immune tolerance and angiogenesis are closely connected and cooperate to sustain tumor growth. Therefore, inhibiting both immunosuppression and angiogenesis may result in improved and more durable clinical benefit.”

As such, for BEATcc, investigators set out to evaluate whether the addition of atezolizumab to standard bevacizumab and platinum-chemotherapy would further improve outcomes in patients with recurrent or metastatic cervical cancer. The trial enrolled those whose cancer was not amenable to curative treatment. Patients needed to have an ECOG performance status of 0 or 1 and could not have previously received systemic treatment of their disease. If they had bladder or rectal mucosa involvement, they were excluded.

A total of 410 participants were randomly assigned 1:1 to receive bevacizumab at 15 mg/kg plus paclitaxel at 175 mg/m² on day 1 with cisplatin at 50 mg/m² or carboplatin at area under the curve 5 with or without atezolizumab at 1200 mg every 3 weeks. Treatment continued until disease progression or intolerable toxicity. Patients were stratified by prior concurrent chemoradiation (yes vs no), histology (squamous cell carcinoma vs adenocarcinoma), and chemotherapy backbone (cisplatin vs carboplatin).

Notably, those who achieved a complete response (CR) after at least 6 cycles of treatment could stop chemotherapy and continue biological therapy alone, Oaknin said. Crossover from the standard arm to the atezolizumab arm was not allowed.

In addition to investigator-assessed PFS by RECIST v1.1 criteria and OS serving as the trial’s dual primary end points, secondary end points included overall response rate (ORR), duration of response (DOR), time to first subsequent treatment (TFST), time from randomization to second progression or death (PFS2), and safety.

“Regarding the statistical analysis plan, in order to control the overall type 1 error at 0.05, we split the alpha between the dual primary end points: PFS and OS.” Oaknin explained. “Alpha was recycled if either PFS or OS was positive. I must stress that the statistical testing was not hierarchical. We preplanned an interim OS analysis at the same time as the PFS analysis.”

Of the 410 patients who underwent randomization, 47 on the atezolizumab arm were still receiving treatment vs 14 on the standard arm. The most common reason for treatment discontinuation on the atezolizumab arm was disease progression (n = 110), followed by adverse effects (AEs; n = 20), withdrawn consent (n = 12), physician decision (n = 9), death (n = 6), and other (n = 2).

The median age of patients in the atezolizumab arm was 51.0 years (range, 24-90) vs 52.5 years (range, 21-79) in the standard arm, with 82.5% of patients under 65 years. Most patients were White (54% vs 55%), had an ECOG performance status of 0 (67% vs 63%), had squamous cell carcinoma (80% vs 77%), recurrent disease status (73% vs 74%), and pelvic or distant disease (50% vs 44%) at the time of screening.

In the atezolizumab arm, 34% of patients had received concurrent chemotherapy as primary therapy, 31% received surgery followed by chemoradiation, 8% had surgery and/or radiotherapy, and 27% had none; in the standard arm, these rates were 42%, 22%, 14%, and 23%, respectively.

PFS and OS improvements achieved with the atezolizumab regimen vs the standard approach were consistent across protocol-specified subgroups. “The similarity between the left and right sides of the slide illustrated the remarkable consistency in treatment effect between the two primary end points,” Oaknin noted.

Atezolizumab plus bevacizumab and chemotherapy induced a higher ORR than that achieved with bevacizumab and chemotherapy alone, at 84% (95% CI, 79%-89%) and 72% (95% CI, 66%-78%), respectively. The CR rate was also higher in the atezolizumab arm vs the standard arm, at 32% vs 20%, respectively.

Responses also proved to be longer in the atezolizumab arm vs the standard arm, with a median DOR of 13.6 months (95% CI, 10.6-21.3) vs 8.6 months (95% CI, 8.0-10.6), respectively (HR, 0.60; 95% CI, 0.46-0.78). “The numbers above the Kaplan-Meier curves show that the proportion of patients still in response at 2 and 3 years is approximately double with the addition of atezolizumab to standard therapy,” Oaknin said.

The hazard ratios for TFST and PFS2 were 0.60 (95% CI, 0.47-0.76) and 0.61 (95% CI, 0.48-0.79), respectively.

Any-grade AEs were experienced by 99% of those who received atezolizumab vs 99% of those who did not; grade 3 or higher AEs occurred in 79% and 75% of patients, respectively, and grade 5 AEs occurred in 3% of patients in both arms. AEs of special interest for atezolizumab were reported in 21% of patients, and 5% of these effects were grade 3 or higher. Fifteen percent of those in the atezolizumab arm experienced AEs that resulted in discontinuation of any treatment.

All-cause AEs experienced by 20% or more of patients in the atezolizumab or placebo arms included peripheral or sensory neuropathy (54% vs 51%), asthenia (52% vs 52%), nausea (49% vs 48%), alopecia (43% vs 39%), anemia (42% vs 37%), constipation (42% vs 34%), diarrhea (40% vs 26%), neutropenia (40% vs 41%), hypertension (36% vs 39%), arthralgia (33% vs 20%), proteinuria (29% vs 26%), pyrexia (24% vs 11%), urinary tract infection (23% vs 21%), myalgia (23% vs 16%), thrombocytopenia (21% vs 16%), rash (21% vs 9%), and abdominal pain (19% vs 23%).

“There was slightly more grade 1 and 2 diarrhea, arthralgia, pyrexia, and rash with atezolizumab, as suspected,” Oaknin concluded. “But no major increase in a specific grade 3 or greater AE with atezolizumab-containing therapy.”

References

1. Oaknin A, Gladieff L, Martinez-Garcia J, et al. Primary results from BEATcc (ENGOT-CX10/GEICO 68-C/JGOG1084/GOG-3030), a randomised phase III trial of first-line atezolizumab (atezo) combined with a platinum doublet and bevacizumab (bev) for metastatic (stage IVB), persistent or recurrent cervical cancer (R/M CC). Presented at: 2023 November ESMO Plenary; November 3, 2023. Accessed November 3, 2023. https://cattendee.abstractsonline.com/meeting/10421/Session/53
2. Tewari KS, Sill MW, Long HJ, et al. Improved survival with bevacizumab in advanced cervical cancer. N Engl J Med. 2014;370(8):734-742. doi:10.1056/NEJMoa1309748
3. Monk BJ, Colombo N, Tewari KS, et al. KEYNOTE-826: final overall survival results from a randomized, double-blind, phase 3 study of pembrolizumab + chemotherapy vs placebo + chemotherapy for first-line treatment of persistent, recurrent, or metastatic cervical cancer. J Clin Oncol. 2023;41(suppl 16):5500. doi:10.1200/JCO.2023.41.16_suppl.5500