Bristol-Myers Squibb‘s Opdivo (nivolumab) is superior to chemotherapy for treating patients with advanced or recurrent esophageal squamous cell carcinoma (ESCC) that cannot be removed surgically, and who are resistant or intolerant to combination therapy with fluoropyrimidine and platinum-based treatments, the ATTRACTION-3 clinical trial shows.
Opdivo demonstrated a significant improvement over chemotherapy, with a 23% reduction in risk of death and a 2.5-month improvement in the median time patients survived, compared to those on chemotherapy. Opdivo’s safety profile was consistent with that reported previously.
The data were presented Sept. 30 at the European Society for Medical Oncology (ESMO) 2019 Congress in Barcelona, Spain.
Detailed findings also were simultaneously made available in the report, “Nivolumab versus chemotherapy in patients with advanced oesophageal squamous cell carcinoma refractory or intolerant to previous chemotherapy (ATTRACTION-3): a multicentre, randomised, open-label, phase 3 trial,” published in the journal Lancet Oncology.
Opdivo is a PD-1 blocking antibody that is indicated for several advanced solid tumors and certain lymphomas, that also has shown promise in advanced ESCC. In a prior Phase 2 trial, called ATTRACTION-1, 17% of heavily pretreated patients responded to treatment and they had a median overall survival of 10.8 months.
Seeking to confirm those findings in a larger, controlled trial, researchers designed the open-label ATTRACTION-3 Phase 3 trial (NCT02569242) to compare Opdivo to standard chemotherapy in ESCC patients who were resistant or intolerant to first-line combination therapy with fluoropyrimidine and platinum-based therapies.
Patients were aged 20 years or older, and enrolled across 90 clinical sites in Denmark, Germany, Italy, Japan, South Korea, Taiwan, the U.K., and the U.S., but nearly all the patients (96%) lived in Asia.
A total of 419 participants were assigned randomly to Opdivo (240 mg for 30 minutes every two weeks) or chemotherapy with docetaxel or paclitaxel, all given by intravenous infusions until disease progression or unacceptable toxicity.
The trial was sponsored by the Japanese company Ono Pharmaceutical, a development partner of Bristol-Myers Squibb.
After a minimum follow-up time of 17.6 months, Opdivo-treated patients lived more time overall compared with the chemotherapy group — a median of 10.9 versus 8.4 months.
At 12 and 18 months of treatment, 47% and 31% of the patients given Opdivo were alive, while in those treated with chemotherapy, survival rates were 34% and 21%, respectively.
This survival benefit was observed regardless of tumor PD-L1 status (meaning if cancer cells expressed, or not, the PD-L1 protein). Usually, when cancer cells have a high amount of PD-L1, the patient may benefit from immunotherapies such as Opdivo.
An exploratory analysis of patient-reported outcomes also indicated that Opdivo significantly improved the overall quality of life, compared to chemotherapy.
“The significant survival benefit coupled with the favorable safety profile and patient-reported outcomes observed in this trial suggest Opdivo has the potential to represent an important new second-line treatment option for patients with advanced esophageal squamous cell carcinoma, offering the possibility to extend their survival and improve their quality of life during treatment,” ByoungChul Cho, MD, said in a press release. Cho is a professor at Yonsei University College of Medicine in Seoul, South Korea, and the researcher who presented the data at the ESMO conference.
The proportion of patients responding favorably to treatment was comparable in the Opdivo and chemo groups (19% versus 22%). But responses to Opdivo lasted substantially longer (6.9 months) compared to chemotherapy (3.9 months).
Regarding safety, fewer adverse side effects were reported with Opdivo. Taken together, 66% of patients taking Opdivo reported side effects, compared to 95% of the patients receiving chemotherapy.
The most common serious or life-threatening adverse side effects were anemia (2% of patients in Opdivo) and low counts of neutrophils, a type of white blood cell (28% of patients in the chemotherapy group).
Five deaths were related to treatment: two in the Opdivo group, due to interstitial lung disease and pneumonitis; and three in the chemo group, due to pneumonia, spinal cord abscess, and interstitial lung disease. The percentage of patients discontinuing treatment due to side effects was the same in both arms (9%).
“These are very promising results for patients with advanced esophageal squamous cell carcinoma for whom prognosis is typically poor and are particularly important given Opdivo improved survival regardless of PD-L1 status,” said Ian M. Waxman, MD, Bristol-Myers Squibb’a development lead for gastrointestinal cancers.
“We are encouraged to see important progress being made in this tumor type and look forward to broadening our research in gastrointestinal tumors,” he said.
“Despite accounting for more than 90% of esophageal cancers globally, esophageal squamous cell carcinoma has historically been underserved by research”, Elizabeth C. Smyth, MD and Florian Lordick, MD, wrote in a Lancet editorial.
Despite the limitations of the trial (e.g., very few non-Asian patients) these issues should not detract the many patients with ESCC “for whom the results of ATTRACTION-3 will provide renewed hope,” they wrote.