In the Journals

Bevacizumab extends survival in advanced cervical cancer

Krishnansu S. Tewari

The addition of bevacizumab to chemotherapy continued to show significant survival benefits in women with advanced cervical cancer, according to final analysis of a randomized, open-label, phase 3 trial published in The Lancet.

Patients who received the combination therapy lived 3.5 months longer than those assigned chemotherapy alone, according to study results.

“Women with metastatic and/or nonoperable recurrent cervical cancer have not had very good options,” Krishnansu S. Tewari, MD, professor of gynecologic oncology at University of California Irvine Medical Center, told HemOnc Today. “Chemotherapy in these settings is barely even palliative, with short-lived responses, rapid deterioration in quality of life, and median survival in the real world ranging from 7 to 12 months. These are relatively young women in the midst of their careers with small children at home. This study was done to identify a therapeutic option that was tolerable and would lead to improved survival and, in some cases, cures.”

Despite being preventable with HPV vaccination, cervical cancer is the fourth most common cancer affecting women, with more than 500,000 new cases and more than 260,000 deaths worldwide in 2012.

Bevacizumab (Avastin, Genentech) is an antiangiogenesis drug that received FDA approval for advanced cervical cancer in 2014, following a second interim analysis of 271 deaths in the Gynecologic Oncology Group (GOG) 240 trial. Tewari and colleagues reported the prespecified final analysis of the primary objectives, OS and adverse events.

Between 2009 and 2012, researchers assigned 452 women with metastatic, persistent or recurrent cervical cancer from 81 centers in the United States, Canada and Spain, to chemotherapy alone (n = 225) or with bevacizumab (n = 227).

All patients received treatment in 21-day cycles until disease progression, unacceptable toxic effects, voluntary patient withdrawal or complete response. Chemotherapy consisted of either cisplatin (50 mg/m2 on day 1 or 2) plus paclitaxel (135 mg/m2 or 175 mg/m2 on day 1) or topotecan (0.75 mg/m2 on days 1-3) plus paclitaxel (175 mg/m2 on day 1). Those assigned bevacizumab received 15 mg/kg on day 1.

Inclusion criteria included a GOG performance status of 0 or 1; adequate renal, hepatic and bone marrow function; adequately anticoagulated thromboembolism; a urine protein to creatinine ratio of less than 1; and measurable disease.

OS in the intention-to-treat population and adverse events served as primary endpoints.

The final analysis occurred after 348 deaths.

The chemotherapy plus bevacizumab group showed significant improvement in OS in the intention-to-treat population (16.8 months vs. 13.3 months; HR = 0.77; 95% CI, 0.62-0.95) and among women who did not receive previous pelvic radiotherapy (24.5 months vs. 16.8 months; HR = 0.64; 95% CI, 0.37-1.1).

Postprogression OS did not appear to be significantly different between the two arms (8.4 months vs. 7.1 months; HR = 0.83; 95% CI, 0.66-1.05).

More patients assigned the combination experienced fistula — an abnormal opening in the vagina wall — of any grade (15% vs. 1%) and grade 3 fistula (6% vs. < 1%). No fistulas resulted in surgical emergencies, sepsis or death.

“At the protocol-specified final analysis, we demonstrated that the earlier, activity of bevacizumab and its impact on survival was sustained, that there was no negative rebound effect (shorter survival) after following discontinuation of bevacizumab and, finally, that median survivals in excess of 20 months can be achieved in women who had never received prior irradiation,” Tewari said. “We also identified a new toxicity of bevacizumab, which is the development of vaginal fistula.”

With nine phase 3 randomized trials completed over the past 3 decades, the new challenge is to identify tolerable treatments that can further extend survival in this patient population, the researchers wrote. Upcoming trials likely will assess different classes of antiangiogenesis agents, immune modulators and checkpoint inhibitors, chemotherapy-free combinations, and translational science.

“Although HPV vaccines can prevent cervical cancer and Pap smears and high-risk HPV DNA testing can detect cervical neoplasia before it becomes invasive, women who are neither vaccinated [nor] screened are at risk for invasive cervical cancer, particularly those whose immune systems do not clear HPV infection acquired through sexual activity,” Tewari said. “Early-stage cervix cancers can be cured through surgery, and many locally advanced cervix cancers that are too large to operate on may still be eradicated with chemoradiation.”

The earlier analysis of this study already changed clinical practice for advanced cervical cancer, Tewari added.

“We now have a foot in the door, but we need to do so much more,” he said. “We now need to find out if we can salvage patients who progress on bevacizumab with anti-PD-1 immunotherapy.”

Susana Banerjee

Although impressive, the results of the GOG 240 trial are not likely to change the outcomes for most women with cervical cancer, especially in low-income countries where 85% of all cervical cancer diagnoses and 87% of all cervical cancer deaths occur, Susana Banerjee, MA, MBBS, MRCP, PhD, wrote in an accompanying editorial.

“The addition of bevacizumab costs more than 13 times ... chemotherapy alone, adding $73,791 per 3.5 months of life gained,” Banerjee wrote. “Measures such as introduction of biosimilars, generic drugs and reduced bevacizumab dose have the potential to reduce cost and hopefully have a positive effect on accessibility to antiangiogenic therapy.

“In parallel with the quest for improved therapies, the focus needs to be on investment in and education about screening and HPV vaccination programs worldwide so that palliative treatment of metastatic or recurrent cervical cancer becomes a situation of the past,” Banerjee added. – by Chuck Gormley

For more information:

Krishnansu S. Tewari, MD , can be reached at Division of Gynecologic Oncology, University of California, Irvine Medical Center, Orange, CA 92868; email: ktewari@uci.edu.

Disclosures: Genentech funded this study. Tewari reports an advisory role with Genentech. Banerjee reports honoraria from Roche. Please see the full study for a list of all other authors’ relevant financial disclosures.

Krishnansu S. Tewari

The addition of bevacizumab to chemotherapy continued to show significant survival benefits in women with advanced cervical cancer, according to final analysis of a randomized, open-label, phase 3 trial published in The Lancet.

Patients who received the combination therapy lived 3.5 months longer than those assigned chemotherapy alone, according to study results.

“Women with metastatic and/or nonoperable recurrent cervical cancer have not had very good options,” Krishnansu S. Tewari, MD, professor of gynecologic oncology at University of California Irvine Medical Center, told HemOnc Today. “Chemotherapy in these settings is barely even palliative, with short-lived responses, rapid deterioration in quality of life, and median survival in the real world ranging from 7 to 12 months. These are relatively young women in the midst of their careers with small children at home. This study was done to identify a therapeutic option that was tolerable and would lead to improved survival and, in some cases, cures.”

Despite being preventable with HPV vaccination, cervical cancer is the fourth most common cancer affecting women, with more than 500,000 new cases and more than 260,000 deaths worldwide in 2012.

Bevacizumab (Avastin, Genentech) is an antiangiogenesis drug that received FDA approval for advanced cervical cancer in 2014, following a second interim analysis of 271 deaths in the Gynecologic Oncology Group (GOG) 240 trial. Tewari and colleagues reported the prespecified final analysis of the primary objectives, OS and adverse events.

Between 2009 and 2012, researchers assigned 452 women with metastatic, persistent or recurrent cervical cancer from 81 centers in the United States, Canada and Spain, to chemotherapy alone (n = 225) or with bevacizumab (n = 227).

All patients received treatment in 21-day cycles until disease progression, unacceptable toxic effects, voluntary patient withdrawal or complete response. Chemotherapy consisted of either cisplatin (50 mg/m2 on day 1 or 2) plus paclitaxel (135 mg/m2 or 175 mg/m2 on day 1) or topotecan (0.75 mg/m2 on days 1-3) plus paclitaxel (175 mg/m2 on day 1). Those assigned bevacizumab received 15 mg/kg on day 1.

Inclusion criteria included a GOG performance status of 0 or 1; adequate renal, hepatic and bone marrow function; adequately anticoagulated thromboembolism; a urine protein to creatinine ratio of less than 1; and measurable disease.

OS in the intention-to-treat population and adverse events served as primary endpoints.

The final analysis occurred after 348 deaths.

The chemotherapy plus bevacizumab group showed significant improvement in OS in the intention-to-treat population (16.8 months vs. 13.3 months; HR = 0.77; 95% CI, 0.62-0.95) and among women who did not receive previous pelvic radiotherapy (24.5 months vs. 16.8 months; HR = 0.64; 95% CI, 0.37-1.1).

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Postprogression OS did not appear to be significantly different between the two arms (8.4 months vs. 7.1 months; HR = 0.83; 95% CI, 0.66-1.05).

More patients assigned the combination experienced fistula — an abnormal opening in the vagina wall — of any grade (15% vs. 1%) and grade 3 fistula (6% vs. < 1%). No fistulas resulted in surgical emergencies, sepsis or death.

“At the protocol-specified final analysis, we demonstrated that the earlier, activity of bevacizumab and its impact on survival was sustained, that there was no negative rebound effect (shorter survival) after following discontinuation of bevacizumab and, finally, that median survivals in excess of 20 months can be achieved in women who had never received prior irradiation,” Tewari said. “We also identified a new toxicity of bevacizumab, which is the development of vaginal fistula.”

With nine phase 3 randomized trials completed over the past 3 decades, the new challenge is to identify tolerable treatments that can further extend survival in this patient population, the researchers wrote. Upcoming trials likely will assess different classes of antiangiogenesis agents, immune modulators and checkpoint inhibitors, chemotherapy-free combinations, and translational science.

“Although HPV vaccines can prevent cervical cancer and Pap smears and high-risk HPV DNA testing can detect cervical neoplasia before it becomes invasive, women who are neither vaccinated [nor] screened are at risk for invasive cervical cancer, particularly those whose immune systems do not clear HPV infection acquired through sexual activity,” Tewari said. “Early-stage cervix cancers can be cured through surgery, and many locally advanced cervix cancers that are too large to operate on may still be eradicated with chemoradiation.”

The earlier analysis of this study already changed clinical practice for advanced cervical cancer, Tewari added.

“We now have a foot in the door, but we need to do so much more,” he said. “We now need to find out if we can salvage patients who progress on bevacizumab with anti-PD-1 immunotherapy.”

Susana Banerjee

Although impressive, the results of the GOG 240 trial are not likely to change the outcomes for most women with cervical cancer, especially in low-income countries where 85% of all cervical cancer diagnoses and 87% of all cervical cancer deaths occur, Susana Banerjee, MA, MBBS, MRCP, PhD, wrote in an accompanying editorial.

“The addition of bevacizumab costs more than 13 times ... chemotherapy alone, adding $73,791 per 3.5 months of life gained,” Banerjee wrote. “Measures such as introduction of biosimilars, generic drugs and reduced bevacizumab dose have the potential to reduce cost and hopefully have a positive effect on accessibility to antiangiogenic therapy.

PAGE BREAK

“In parallel with the quest for improved therapies, the focus needs to be on investment in and education about screening and HPV vaccination programs worldwide so that palliative treatment of metastatic or recurrent cervical cancer becomes a situation of the past,” Banerjee added. – by Chuck Gormley

For more information:

Krishnansu S. Tewari, MD , can be reached at Division of Gynecologic Oncology, University of California, Irvine Medical Center, Orange, CA 92868; email: ktewari@uci.edu.

Disclosures: Genentech funded this study. Tewari reports an advisory role with Genentech. Banerjee reports honoraria from Roche. Please see the full study for a list of all other authors’ relevant financial disclosures.