Nivolumab Nears EU Approval for Second-Line Esophageal Squamous Cell Carcinoma

The European Medicines Agency’s (EMA) Committee for Medicinal Products for Human Use (CHMP) has adopted a positive opinion for nivolumab (Opdivo) in the treatment of adult patients with unresectable advanced, recurrent, or metastatic esophageal squamous cell carcinoma (ESCC) following previous fluoropyrimidine- and platinum-based chemotherapy.¹

The CHMP recommendation is based on data from the phase 3 ATTRACTION-3 trial (NCT02569242), which showed that the PD-1 inhibitor significantly extended overall survival (OS) in patients with previously treated advanced ESCC compared with chemotherapy.²

“The positive CHMP opinion underscores the potential of [nivolumab] in the EU treatment landscape for ESCC, with the ATTRACTION-3 trial showing clinically meaningful survival coupled with a favorable safety profile,” said Ian M. Waxman, MD, development lead of gastrointestinal (GI) cancers at Bristol Myers Squibb.¹ “We look forward to the European Commission’s final decision, which could mark the first time an immunotherapy is approved for any upper GI cancer in the EU. We remain committed to continuing to explore the potential benefits of [nivolumab] in earlier settings of esophageal cancer.”

A total of 419 patients with unresectable advanced or recurrent ESCC refractory to or intolerant of 1 prior fluoropyrimidine-/platinum-based chemotherapy were enrolled to the phase 3 trial. Results showed that at a minimum follow-up of 17.6 months, the median OS was 10.9 months with nivolumab versus 8.4 months with chemotherapy; this translated to a 23% reduction in the risk of death (HR, 0.77; 95% CI, 0.62-0.96; P = .019). Notably, the benefit was observed, irrespective of PD-L1 expression.²

Of the patients enrolled, 31% in the investigational arm were alive (95% CI, 24-37) at 18 months versus 21% in the control arm (95% CI, 15-27). At 12 months, 47% of patients who received nivolumab were alive (95% CI, 24-37) compared with 34% of those who were given chemotherapy in the form of either docetaxel or paclitaxel (95% CI, 28-41).

The improvement in median OS was reported despite a nearly identical objective response rate (ORR) noted between the arms and a median progression-free survival that favored the control arm. Specifically, the ORR was 33% in the investigational arm versus 34% in the control arm. Moreover, the median PFS was 1.7 months with nivolumab versus 3.4 months with chemotherapy (HR, 1.08; 95% CI, 0.87-1.34).

For the trial, participants were randomized in a 1:1 fashion to receive an intravenous (IV) 240-mg dose of nivolumab every 2 weeks or investigator’s choice of taxane chemotherapy comprised of either IV docetaxel at 75 mg/m2 every 3 weeks or IV paclitaxel at 100 mg/m2 every week for 6 weeks, then 1 week off.

The primary end point of the trial was OS, and the data cutoff for the analysis was November 2018. A total of 417 patients received at least 1 dose of their treatment. The overwhelming majority of participants were male (~90%) and 96% were Asian. Half of the participants had an ECOG performance status of 0, while the other half had a status of 1. Approximately 50% had undergone previous surgery and about 70% had previously received radiotherapy. About half of the participants had PD-L1 expression of 1% or greater, and around 85% of patients were either current or former smokers.

The median duration of treatment was 2.6 months in either treatment arm. In the nivolumab arm, the median relative dose intensity was 100% versus 81% in the chemotherapy arm. Over 90% of patients in either arm discontinued therapy; 64% of patients in the nivolumab arm discontinued due to progressive disease, along with 66% of those in the chemotherapy arm.

With regard to response to treatment, the disease control rate in the nivolumab arm was 37% versus 63% in the chemotherapy arm. The median time to response was a bit longer in the nivolumab arm, at 2.6 months, versus 1.5 months in the chemotherapy arm.

However, those who received the PD-1 therapy experienced more durable responses than those who responded to the chemotherapy. The median duration of response with nivolumab versus chemotherapy was 6.9 months versus 3.9 months, respectively. Moreover, approximately 21% of those in the investigational arm still had ongoing responses at the time of data presentation versus 6% of those in the control arm.

Notably, nivolumab was found to significantly improve health-related quality of life compared with chemotherapy when using the EQ-5D-3L Visual Analog Scale, according to results from exploratory analyses performed.

With regard to safety, those in the nivolumab arm experienced less treatment-related adverse effects (TRAEs) compared with those in the chemotherapy arm, at 18% versus 63%, respectively. TRAEs that were grade 3 or 4 in severity were reported at a rate that was over 3 times lower with the PD-1 inhibitor.

The most frequently reported treatment-related toxicities in the nivolumab arm included rash (n = 11), diarrhea (n = 11), and fatigue (n = 7). In the chemotherapy arm, the most common TRAEs were alopecia (n = 47), a decline in neutrophil count (n = 37), a decline in white blood cell count (n = 35), decreased appetite (n = 27), anemia (n = 24), peripheral sensory neuropathy (n = 23), malaise (n = 22), fatigue (n = 21), and neutropenia (n = 19).

Nivolumab has been approved in 5 countries, including the United States and Japan, for use as second-line treatment in patients with unresectable advanced, recurrent, or metastatic ESCC.

References

1. Bristol Myers Squibb receives positive CHMP opinion recommending Opdivo (nivolumab) as second-line treatment for unresectable advanced, recurrent or metastatic esophageal squamous cell carcinoma. New release. Bristol Myers Squibb. October 16, 2020. Accessed October 16, 2020. https://bit.ly/2HbmU6Y.
2. Cho BC, Kato K, Takahashi M, et al. Nivolumab versus chemotherapy in advanced esophageal squamous cell carcinoma (ESCC): the phase III ATTRACTION-3 study. Ann Oncol. 2019;30(suppl 5):V873-V874. doi:10.1093/annonc/mdz394.028