Immunotherapy

The international multicenter BEATcc trial (NCT03556839) included 410 women with stage IVB, persistent, or recurrent squamous cell or adenocarcinoma of the cervix not amenable to curative surgery or radiation therapy. Patients had not received previous systemic therapy. Patients were randomly assigned to receive either bevacizumab plus chemotherapy (carboplatin or cisplatin with paclitaxel) (the control arm) or the experimental arm, which added atezolizumab to the control regimen. The dual primary end points were progression-free survival (PFS) and overall survival (OS), and the trial was biomarker unselective for PD-L1 expression.[1]

The international multicenter BEATcc trial (NCT03556839) included 410 women with stage IVB, persistent, or recurrent squamous cell or adenocarcinoma of the cervix not amenable to curative surgery or radiation therapy. Patients had not received previous systemic therapy. Patients were randomly assigned to receive either bevacizumab plus chemotherapy (carboplatin or cisplatin with paclitaxel) (the control arm) or the experimental arm, which added atezolizumab to the control regimen. The dual primary end points were progression-free survival (PFS) and overall survival (OS), and the trial was biomarker unselective for PD-L1 expression.[1]

After a median follow-up of 32.9 months, the median PFS was 10.4 months for patients in the control arm and 13.7 months for patients in the experimental arm (hazard ratio [HR], 0.62; 95% confidence interval [CI], 0.48–0.78; P < .0001). The median OS was 22.8 months for patients in the control arm and 32.1 months for patients in the experimental arm (HR, 0.68; 95% CI, 0.52–0.88; P = .0046).[1][Level of evidence A1]

KEYNOTE-826 (NCT03635567) was a multicenter, phase III, randomized trial that included 617 women with persistent, recurrent, or metastatic adenosquamous or squamous cell carcinoma of the cervix not amenable to curative treatment. Patients had measurable disease. All patients were treated with cisplatin or carboplatin combined with paclitaxel, with the option to add bevacizumab at the treating physician’s discretion. Patients received six cycles and were randomly assigned 1:1 to receive pembrolizumab or placebo every 3 weeks for up to 35 cycles. The median follow-up was 39.1 months, with dual primary end points of PFS and OS. Approximately 89% of women had a PD-L1 CPS score of 1 or higher.[2]

KEYNOTE-826 (NCT03635567) was a multicenter, phase III, randomized trial that included 617 women with persistent, recurrent, or metastatic adenosquamous or squamous cell carcinoma of the cervix not amenable to curative treatment. Patients had measurable disease. All patients were treated with cisplatin or carboplatin combined with paclitaxel, with the option to add bevacizumab at the treating physician’s discretion. Patients received six cycles and were randomly assigned 1:1 to receive pembrolizumab or placebo every 3 weeks for up to 35 cycles. The median follow-up was 39.1 months, with dual primary end points of PFS and OS. Approximately 89% of women had a PD-L1 CPS score of 1 or higher.[2]

The median OS was 26.4 months for patients who received pembrolizumab and 16.8 months for patients who received placebo (HR, 0.63; 95% CI, 0.52–0.77). This benefit was not maintained in women with a CPS score less than 1. The benefit was maintained in the group of women who did not receive bevacizumab.[2][Level of evidence A1]

KEYNOTE-826 (NCT03635567) was a multicenter, phase III, randomized trial that included 617 women with persistent, recurrent, or metastatic adenosquamous or squamous cell carcinoma of the cervix not amenable to curative treatment. Patients had measurable disease. All patients were treated with cisplatin or carboplatin combined with paclitaxel, with the option to add bevacizumab at the treating physician’s discretion. Patients received six cycles and were randomly assigned 1:1 to receive pembrolizumab or placebo every 3 weeks for up to 35 cycles. The median follow-up was 39.1 months, with dual primary end points of PFS and OS. Approximately 89% of women had a PD-L1 CPS score of 1 or higher.[2]

The median PFS was 10.4 months for patients who received pembrolizumab and 8.2 months for patients who received placebo (HR, 0.61; 95% CI, 0.50–0.74).

KEYNOTE-A18 (NCT04221945) was a multicenter, phase III, randomized trial that included 1,060 women with newly diagnosed squamous cell carcinoma, adenocarcinoma, or adenosquamous carcinoma of the cervix. Patients had stage IB2 or IIB node-positive disease or stage III to IVA disease and had received no prior treatment. Patients were randomly assigned to receive either chemoradiation therapy (with cisplatin) plus pembrolizumab (every 3 weeks for five cycles) or chemoradiation therapy plus placebo. All patients received maintenance therapy with pembrolizumab or placebo every 6 weeks for 15 cycles. All patients received brachytherapy, and 94% of patients had PD-L1–positive disease. The dual primary end points were PFS and OS. The median follow-up time was 17.9 months.[3]

KEYNOTE-A18 (NCT04221945) was a multicenter, phase III, randomized trial that included 1,060 women with newly diagnosed squamous cell carcinoma, adenocarcinoma, or adenosquamous carcinoma of the cervix. Patients had stage IB2 or IIB node-positive disease or stage III to IVA disease and had received no prior treatment. Patients were randomly assigned to receive either chemoradiation therapy (with cisplatin) plus pembrolizumab (every 3 weeks for five cycles) or chemoradiation therapy plus placebo. All patients received maintenance therapy with pembrolizumab or placebo every 6 weeks for 15 cycles. All patients received brachytherapy, and 94% of patients had PD-L1–positive disease. The dual primary end points were PFS and OS. The median follow-up time was 17.9 months.[3]

The 24-month OS rate was 87% in the pembrolizumab group and 81% in the placebo group (HR, 0.73; 95% CI, 0.49–1.07).[3][Level of evidence B1]

KEYNOTE-A18 (NCT04221945) was a multicenter, phase III, randomized trial that included 1,060 women with newly diagnosed squamous cell carcinoma, adenocarcinoma, or adenosquamous carcinoma of the cervix. Patients had stage IB2 or IIB node-positive disease or stage III to IVA disease and had received no prior treatment. Patients were randomly assigned to receive either chemoradiation therapy (with cisplatin) plus pembrolizumab (every 3 weeks for five cycles) or chemoradiation therapy plus placebo. All patients received maintenance therapy with pembrolizumab or placebo every 6 weeks for 15 cycles. All patients received brachytherapy, and 94% of patients had PD-L1–positive disease. The dual primary end points were PFS and OS. The median follow-up time was 17.9 months.[3]

There was a statistically significant improvement in PFS (HR, 0.70; 95% CI, 0.55–0.89). The 24-month PFS rate was 68% in the pembrolizumab group and 57% in the placebo group.

KEYNOTE-A18 (NCT04221945) was a multicenter, phase III, randomized trial that included 1,060 women with newly diagnosed squamous cell carcinoma, adenocarcinoma, or adenosquamous carcinoma of the cervix. Patients had stage IB2 or IIB node-positive disease or stage III to IVA disease and had received no prior treatment. Patients were randomly assigned to receive either chemoradiation therapy (with cisplatin) plus pembrolizumab (every 3 weeks for five cycles) or chemoradiation therapy plus placebo. All patients received maintenance therapy with pembrolizumab or placebo every 6 weeks for 15 cycles. All patients received brachytherapy, and 94% of patients had PD-L1–positive disease. The dual primary end points were PFS and OS. The median follow-up time was 17.9 months.[3]

Patients with stage III or IV disease had a greater improvement in PFS (HR, 0.58; 95% CI, 0.42–0.80).

KEYNOTE-158 (NCT02628067) was a multicenter nonrandomized trial that included 98 patients with recurrent or metastatic cervical cancer. Patients received 200 mg of pembrolizumab every 3 weeks intravenously until unacceptable toxicity or disease progression.[4] A separate analysis was performed in 77 patients whose tumors expressed PD-L1 (CPS ≥1); 92% had squamous histology.

KEYNOTE-158 (NCT02628067) was a multicenter nonrandomized trial that included 98 patients with recurrent or metastatic cervical cancer. Patients received 200 mg of pembrolizumab every 3 weeks intravenously until unacceptable toxicity or disease progression.[4] A separate analysis was performed in 77 patients whose tumors expressed PD-L1 (CPS ≥1); 92% had squamous histology.

The overall response rate among PD-L1–positive patients was 16% (95% CI, 8.8%–25.9%) with 3 complete responses and 10 partial responses; 17 patients were stable.

KEYNOTE-158 (NCT02628067) was a multicenter nonrandomized trial that included 98 patients with recurrent or metastatic cervical cancer. Patients received 200 mg of pembrolizumab every 3 weeks intravenously until unacceptable toxicity or disease progression.[4] A separate analysis was performed in 77 patients whose tumors expressed PD-L1 (CPS ≥1); 92% had squamous histology.

The median PFS was 2.1 months, and OS was 9.4 months in these marker-positive patients.

KEYNOTE-158 (NCT02628067) was a multicenter nonrandomized trial that included 98 patients with recurrent or metastatic cervical cancer. Patients received 200 mg of pembrolizumab every 3 weeks intravenously until unacceptable toxicity or disease progression.[4] A separate analysis was performed in 77 patients whose tumors expressed PD-L1 (CPS ≥1); 92% had squamous histology.

Treatment-related adverse events were noted in 65% of patients. The most common were hypothyroidism (10.2%), decreased appetite (9.2%), fatigue (9.2%), and diarrhea (8.2%).[4][Level of evidence B4]

GOG-0240 (NCT00803062), which enrolled patients with metastatic, persistent, or recurrent cervical carcinoma, was designed to answer the following two questions:[5]Patients were randomly assigned to one of the following four treatment arms:Additional study methods and results included the following:

GOG-0240 (NCT00803062), which enrolled patients with metastatic, persistent, or recurrent cervical carcinoma, was designed to answer the following two questions:[5]Patients were randomly assigned to one of the following four treatment arms:Additional study methods and results included the following:

Can a nonplatinum combination show improvement over the standard of cisplatin-paclitaxel in this population, which was previously treated with cisplatin during radiation therapy?

GOG-0240 (NCT00803062), which enrolled patients with metastatic, persistent, or recurrent cervical carcinoma, was designed to answer the following two questions:[5]Patients were randomly assigned to one of the following four treatment arms:Additional study methods and results included the following:

Can the addition of bevacizumab improve combination chemotherapy in patients with stage IVB, persistent, or recurrent cervical cancer?

GOG-0240 (NCT00803062), which enrolled patients with metastatic, persistent, or recurrent cervical carcinoma, was designed to answer the following two questions:[5]Patients were randomly assigned to one of the following four treatment arms:Additional study methods and results included the following:

Cisplatin (50 mg/m2) + paclitaxel (135 mg/m2 or 175 mg/m2) on day 1 (PC).

GOG-0240 (NCT00803062), which enrolled patients with metastatic, persistent, or recurrent cervical carcinoma, was designed to answer the following two questions:[5]Patients were randomly assigned to one of the following four treatment arms:Additional study methods and results included the following:

PC + bevacizumab (15mg/kg) on day 1.

GOG-0240 (NCT00803062), which enrolled patients with metastatic, persistent, or recurrent cervical carcinoma, was designed to answer the following two questions:[5]Patients were randomly assigned to one of the following four treatment arms:Additional study methods and results included the following:

Topotecan (0.75 mg/m2) on days 1–3 + paclitaxel (175 mg/m2) on day 1 (PT).

GOG-0240 (NCT00803062), which enrolled patients with metastatic, persistent, or recurrent cervical carcinoma, was designed to answer the following two questions:[5]Patients were randomly assigned to one of the following four treatment arms:Additional study methods and results included the following:

PT + bevacizumab (15 mg/kg) on day 1.

GOG-0240 (NCT00803062), which enrolled patients with metastatic, persistent, or recurrent cervical carcinoma, was designed to answer the following two questions:[5]Patients were randomly assigned to one of the following four treatment arms:Additional study methods and results included the following:

The primary end point was OS, and 452 patients were evaluable.

GOG-0240 (NCT00803062), which enrolled patients with metastatic, persistent, or recurrent cervical carcinoma, was designed to answer the following two questions:[5]Patients were randomly assigned to one of the following four treatment arms:Additional study methods and results included the following:

The combination PT was not superior to PC and had a HRdeath of 1.2 (99% CI, 0.82–1.76). Previous exposure to platinum did not affect this result.

GOG-0240 (NCT00803062), which enrolled patients with metastatic, persistent, or recurrent cervical carcinoma, was designed to answer the following two questions:[5]Patients were randomly assigned to one of the following four treatment arms:Additional study methods and results included the following:

The addition of bevacizumab to combination chemotherapy led to: (1) improved OS: 17 months for chemotherapy plus bevacizumab versus 13.3 months for chemotherapy alone (HR, 0.71; 98% CI, 0.54–0.95) and (2) extended PFS: 8.2 months for chemotherapy plus bevacizumab versus 5.9 months for chemotherapy alone (HR, 0.67; 95% CI, 0.54–0.82).

GOG-0240 (NCT00803062), which enrolled patients with metastatic, persistent, or recurrent cervical carcinoma, was designed to answer the following two questions:[5]Patients were randomly assigned to one of the following four treatment arms:Additional study methods and results included the following:

The addition of bevacizumab was well tolerated and showed no difference in quality of life between the two groups.

GOG-0240 (NCT00803062), which enrolled patients with metastatic, persistent, or recurrent cervical carcinoma, was designed to answer the following two questions:[5]Patients were randomly assigned to one of the following four treatment arms:Additional study methods and results included the following:

Patients who received bevacizumab were more likely to have grade 3 or higher fistulae (6% vs. 0%), and grade 3 or higher thromboembolic events (8% vs. 1%) compared with patients who received chemotherapy alone.

GOG-0240 (NCT00803062), which enrolled patients with metastatic, persistent, or recurrent cervical carcinoma, was designed to answer the following two questions:[5]Patients were randomly assigned to one of the following four treatment arms:Additional study methods and results included the following:

As a result, the addition of bevacizumab may be considered for this patient population.

In a phase III international trial (NCT04697628) 502 women were randomly assigned to receive either tisotumab vedotin (2 mg/kg every 3 weeks) or the investigator’s choice of chemotherapy. Patients had metastatic or recurrent cervical cancer (squamous cell, adenocarcinoma, or adenosquamous histology) with measurable disease after prior systemic therapy (paclitaxel plus a platinum or topotecan, with or without bevacizumab and with or without an anti–PD-1 or anti–PD-L1 agent). One or two prior systemic treatments were required (not including adjuvant, maintenance, or neoadjuvant chemotherapy or chemoradiation therapy). Imaging was done every 6 weeks for 30 weeks and then every 12 weeks thereafter. The primary end point was OS.[6]

In a phase III international trial (NCT04697628) 502 women were randomly assigned to receive either tisotumab vedotin (2 mg/kg every 3 weeks) or the investigator’s choice of chemotherapy. Patients had metastatic or recurrent cervical cancer (squamous cell, adenocarcinoma, or adenosquamous histology) with measurable disease after prior systemic therapy (paclitaxel plus a platinum or topotecan, with or without bevacizumab and with or without an anti–PD-1 or anti–PD-L1 agent). One or two prior systemic treatments were required (not including adjuvant, maintenance, or neoadjuvant chemotherapy or chemoradiation therapy). Imaging was done every 6 weeks for 30 weeks and then every 12 weeks thereafter. The primary end point was OS.[6]

After a median follow-up of 10.8 months, the median OS was 11.5 months for patients who received tisotumab vedotin and 9.5 months for patients who received chemotherapy.[6][Level of evidence A1]

In a phase III international trial (NCT04697628) 502 women were randomly assigned to receive either tisotumab vedotin (2 mg/kg every 3 weeks) or the investigator’s choice of chemotherapy. Patients had metastatic or recurrent cervical cancer (squamous cell, adenocarcinoma, or adenosquamous histology) with measurable disease after prior systemic therapy (paclitaxel plus a platinum or topotecan, with or without bevacizumab and with or without an anti–PD-1 or anti–PD-L1 agent). One or two prior systemic treatments were required (not including adjuvant, maintenance, or neoadjuvant chemotherapy or chemoradiation therapy). Imaging was done every 6 weeks for 30 weeks and then every 12 weeks thereafter. The primary end point was OS.[6]

Common adverse events in the tisotumab vedotin group included ocular events (52.8%), peripheral neuropathy (38.4%), and bleeding (42%).