Clinical trialPhase 3Cervical cancer

Bevacizumab for advanced cervical cancer: final overall survival and adverse event analysis of a randomised, controlled, open-label, phase 3 trial (Gynecologic Oncology Group 240)

Lancet · 2017452 patients

Tewari KS, Sill MW, Penson RT, Huang H, Ramondetta LM, Landrum LM, et al. Lancet. 2017. 390:1654-1663

Study type: Clinical trial
Study name: GOG 240
Phase: Phase 3
Design: Randomised, controlled, open-label, factorial trial (1:1:1:1) at 81 centres in the USA, Canada and Spain
Sample size: 452 patients
Source: Lancet · 2017
Trial registration: NCT00803062

In plain words

In the final analysis of this trial, adding bevacizumab to chemotherapy in advanced or recurrent cervical cancer increased the median length of life from 13.3 to 16.8 months. Fistula (an abnormal connection between organs) was an important side effect that was seen only in patients who had had radiotherapy to the pelvis before.

Key results

16.8 vs 13.3 months

Median overall survival

HR 0.77 (0.62–0.95); p=0.007

24.5 vs 16.8 months

Overall survival in patients without prior pelvic radiotherapy

HR 0.64 (0.37–1.10); p=0.11

15% vs 1%

Fistula (any grade)

All in patients with prior radiotherapy; grade 3 fistula: 6% vs less than 1%

Drugs in this study:Bevacizumab (Avastin)Cisplatin (Platinol)Paclitaxel (Taxol)

Dose and schedule cards

Paclitaxel + cisplatin + bevacizumab (GOG 240)

First-line metastatic, persistent or recurrent disease; GOG performance status 0–1; no nonhealing wound or active bleeding; urine protein-to-creatinine ratio less than 1Cycle length: Every 21 daysOn the page “Cervical cancer” · Metastatic, persistent or recurrent disease: first line

First-line metastatic, persistent or recurrent disease; GOG performance status 0–1; no nonhealing wound or active bleeding; urine protein-to-creatinine ratio less than 1

Drug	Dose	Route	Schedule
Paclitaxel	175 mg/m² (3-hour infusion); or 135 mg/m² (24-hour infusion)	IV	Day 1
Cisplatin	50 mg/m²	IV	Day 1 or 2
Bevacizumab	15 mg/kg (30- to 90-minute infusion)	IV	Day 1

Cycle length: Every 21 days
Duration: Until disease progression, unacceptable toxicity or complete response

Platinum-free alternative: topotecan 0.75 mg/m² on days 1–3 + paclitaxel 175 mg/m² on day 1 (with or without bevacizumab), which was not superior to cisplatin–paclitaxel (HR for death 1.20). In KEYNOTE-826 and BEATcc, carboplatin AUC 5 on day 1 was also permitted instead of cisplatin. Source for doses and infusion durations:.

On the page “Cervical cancer” · Metastatic, persistent or recurrent disease: first line

GOG 240 (cervix)

Metastatic, persistent or recurrent cervical cancerCycle length: Every 21 daysOn the page “Paclitaxel (Taxol)” · Other regimens: key trials and nab-paclitaxel

Metastatic, persistent or recurrent cervical cancer

Drug	Dose	Route	Schedule
Paclitaxel	135 or 175 mg/m²	IV	Day 1
Cisplatin	50 mg/m²	IV	Day 1
Bevacizumab	15 mg/kg	IV	Day 1

Cycle length: Every 21 days
Duration: Until progression, unacceptable toxicity or complete response

The GOG 240 trial regimen.

On the page “Paclitaxel (Taxol)” · Other regimens: key trials and nab-paclitaxel

Doses follow the trial protocol, guideline or official drug label (source given in the notes of each regimen). Before prescribing, check blood counts, renal and hepatic function, drug interactions and the patient’s condition, and adjust the dose according to the drug label.

Treatment arms and regimens

1Chemotherapy + bevacizumab

One of two IV chemotherapy backbones every 21 days: (1) cisplatin 50 mg/m² (day 1 or 2) + paclitaxel 135 mg/m² (24-hour infusion) or 175 mg/m² (3-hour infusion) on day 1; or (2) topotecan 0.75 mg/m² (30-minute infusion, days 1 to 3) + paclitaxel 175 mg/m² (over 3 hours, day 1); with bevacizumab 15 mg/kg IV (over 30 to 90 minutes) on day 1.

Continued until disease progression, unacceptable toxicity, voluntary withdrawal or complete response.

The bevacizumab dose was adjusted only for a weight change of more than 10%; if chemotherapy was delayed because of low neutrophil or platelet counts, bevacizumab was also held; bevacizumab was delayed or discontinued for uncontrolled hypertension (systolic above 150 or diastolic above 100 mmHg), proteinuria (urine protein-to-creatinine ratio 3.5 or higher), arterial or venous thrombosis, coagulopathy and bowel obstruction or perforation.

2Chemotherapy alone

The same two chemotherapy backbones (cisplatin–paclitaxel or topotecan–paclitaxel at the same doses, every 21 days) without bevacizumab, until progression, unacceptable toxicity, withdrawal or complete response.

Source of the regimen details: Abstract and full text of the paper (Lancet 2017, PMC5714293; bevacizumab doses and modification rules) and ClinicalTrials.gov NCT00803062 (infusion duration and day of administration)

Doses are given for the information of specialists, as in this study’s protocol, and are not a prescription. Every drug must be prescribed by the treating physician for the individual patient.

Study population

Patients with metastatic, persistent or recurrent cervical carcinoma with a GOG performance status of 0 or 1 and measurable disease, who had not received chemotherapy for recurrence.

Endpoints

Primary endpoints: overall survival (intention to treat) and adverse events.

Safety and side effects

Fistula (any grade) in 32 of 220 (15%) in the bevacizumab groups and 3 of 220 (1%) in the chemotherapy-alone groups, all in patients with prior radiotherapy; grade 3 fistula in 6% versus less than 1%. No fistula led to surgical emergency, sepsis or death.

Clinical significance and place in guidelines

The final analysis confirmed the durable benefit of bevacizumab and made platinum-based chemotherapy with paclitaxel and bevacizumab the backbone of first-line treatment of advanced disease, which became the basis for the later immunotherapy trials (KEYNOTE-826 and BEATcc).

Limitations

Open-label design; risk of fistula in patients with prior pelvic radiotherapy.

Original article (DOI)PubMed ClinicalTrials.gov

This summary was prepared by the editorial team from the published paper; the original paper is the final reference. Read the original abstract on PubMed.