Investigating nivolumab with carboplatin-paclitaxel for treatment-naïve patients.

A new phase 3 clinical trial for patients with metastatic anal cancer will determine if immunotherapy in combination with standard chemotherapy prolongs progression-free survival.

“This is the first ever randomized phase 3 trial to be conducted in treatment-naïve patients with advanced anal cancer,” said Cathy Eng, M.D., a principal investigator for the study and the David H. Johnson Chair in Surgical and Medical Oncology at Vanderbilt-Ingram Cancer Center.

Metastatic Anal Cancer

Anal cancer, while a rare disease, has been increasing in incidence in the U.S. by about 3 percent per year. Most cases of anal carcinoma are caused by infection with human papillomavirus (HPV).

Eng notes the majority of patients that present with early-stage anal cancer can be treated successfully with chemo-radiation therapy. However, for patients with advanced disease, treatment strategies are limited.

“Between 15 to 20 percent of patients with anal cancer present upfront with metastatic disease, and an additional 10 to 15 percent that originally presented with localized disease develop metastatic disease,” Eng said. “There was no established standard of care for this patient population.”

“There was no established standard of care for this patient population.”

Setting a Foundation

Eng has contributed to several clinical trials to address this treatment gap, including the recently completed InterAAct trial that identified carboplatin-paclitaxel as the optimal first-line chemotherapy regimen for inoperable anal cancer. The InterAAct trial was the first randomized phase 2 study for treatment-naïve, metastatic anal carcinoma patients.

“InterAAct was an international trial comparing carboplatin-paclitaxel and cisplatin plus 5-flourouracil,” Eng said. “Carboplatin-paclitaxel was associated with less toxicity and a trend towards improved survival, which suggests that it should become the standard of care for these patients and the backbone for future phase 3 trials.”

Eng and colleagues have also investigated the impact of immunotherapy for treatment of metastatic anal cancer, showing in a phase 2 trial that nivolumab is an effective treatment option for refractory patients.

“In short, both the InterAAct trial and the role of immunotherapy – those changed the existing treatment guidelines for the metastatic patient population and created a treatment platform upon which we can build,” Eng said.

Testing the Addition of Nivolumab

The new multicenter trial (study EA2176) is a 2:1 randomization of carboplatin-paclitaxel plus or minus nivolumab for a maximum of six months, followed by maintenance nivolumab. The study aims to enroll 205 patients, and the primary endpoint is progression-free survival. “We hope to improve the PFS from eight months, which was established in the InterAAct trial, to 12.8 months,” Eng said.

“We hope to improve the PFS from eight months, which was established in the InterAAct trial, to 12.8 months.”

Just like the groundbreaking InterAAct trial, HIV-positive patients are eligible to enroll. “This is unique,” Eng explained. “The majority of previous trials have excluded HIV-positive patients, which was an issue because these are the patients that are more prone to HPV and developing this type of cancer.”

Extending the Research Focus

Eng and colleagues will also collect biological samples as part of the study to assess the levels of circulating tumor HPV DNA. “There’s interesting data in head and neck cancer, as well as early-stage anal carcinoma, that show if circulating tumor HPV DNA goes down, it means that you are responding to therapy and will get better outcomes,” Eng said. The substudy could help connect tumor HPV DNA levels to any treatment responses observed.

Eng says that the next area that needs to be explored is immuno-oncology (I-O) failures. “There are definitely some patients that are not responding long term to immunotherapy,” Eng said. “That’s the big question for almost every single malignancy – what to do with I-O failures.”


Cathy Eng, M.D.

Cathy Eng, M.D., is David H. Johnson Chair in Surgical and Medical Oncology, director of the Vanderbilt-Ingram Cancer Center Young Adult Cancers Program, and a professor of medicine at Vanderbilt University Medical Center. Her primary clinical research interests include clinical trials involving innovative drugs for the treatment of colorectal, anal and appendiceal cancers.