When used as neoadjuvant therapy, the combination of Opdivo (nivolumab) and Yervoy (ipilimumab) was effective, but also showed high levels of adverse events (AEs) in a cohort of patients with melanoma. Further research into dosing schemes is needed, said Christian U. Blank, who presented the findings from the OpACIN trial at the 2016 Society for Melanoma Research Annual Meeting.
"Ipilimumab plus nivolumab in the neoadjuvant setting is feasible, and all patients underwent a lymph node dissection on time," said lead investigator Blank, M.D., a medical oncologist at The Netherlands Cancer Institute, Amsterdam, Netherlands. "However, we saw a high percentage of grade 3/4 toxicities, resulting in only two of the 18 patients receiving the full courses of ipilimumab plus nivolumab."
In the phase 1b study, 20 patients were treated with Opdivo plus Yervoy before or after surgery for stage 3 palpable melanoma with no in-transit metastases in the last six months. Across both arms, Yervoy was administered at 3 mg/kg and Opdivo was given at 1 mg/kg every three weeks. In the neoadjuvant arm, patients received two cycles of therapy prior to surgery followed by two cycles of the combination after resection. In the adjuvant arm, four cycles of Opdvio and Yervoy were administered following resection.
At the time of the September 2016 data cutoff, eight patients in the adjuvant arm and 10 in the neoadjuvant arm were assessable. The mean age of patients in the adjuvant group was 53 ± seven years. In the neoadjuvant group, the mean age was 55 ±12 years. Seven patients in each arm had stage 3b disease and the remainder had stage 3c melanoma. All patients had normal LDH and ALC levels and all patients had a WHO performance status of 0.
The overall response rate in the neoadjuvant setting was 80 percent, which included 3 patients (30 percent) who experienced a pathologic complete response (pCR). Six patients (60 percent) had detectable micrometastatic disease following resection, of which four were labeled as near pCRs, said Blank. Two patients (20 percent) had disease detected in the lymph nodes.
"So far we have only the CR rates, so we still have to wait to see whether these patients with CRs and near CRs will relapse, " said Blank. "If this holds true, from what we know about immunotherapy, this could become a really interesting treatment options."
Overall, two patients had relapsed, one had received only two courses of treatment due to grade 3 colitis and the other had only received one course as a result of grade 3 dermatitis.
In the adjuvant arm, three patients had relapsed at the time of the analysis. One of these patients had received three courses of treatment and stopped due to colitis. The remaining two patients had received just two courses of therapy following the development of hypophysitis and colitis, respectively.
A difference in surgery-related AEs was not observed between the two arms, suggesting that neoadjuvant Yervoy plus Opdivo did not complicate resection. Overall, however, only two of the 18 evaluable patients completed four courses of therapy, with the majority stopping as a result of grade 3/4 AEs.
Across the full study, the most common all-grade AEs were elevated ALT (15 patients), diarrhea (11 patients), elevated lipase (10 patients), rash (nine patients), fatigue (nine patients), nausea (nine patients), colitis (seven patients), hypothyroidism (seven patients), hyperthyroidism (six patients), vomiting (six patients) and headache (six patients). The most common grade 3/4 AEs were elevated lipase (seven patients), colitis (six patients), diarrhea (six patients) and elevated ALT (four patients).
The rate of AEs seen in the study was above expectations, based on data from trials conducted in the metastatic setting. This could be related to systemic immune suppression in later stage melanoma. In the phase 3 EORTC 18071 trial, which explored adjuvant Yervoy at 10 mg/kg for patients with advanced melanoma, the rate of grade 3/4 AEs was higher in those with stage 3 disease (45.4 percent) versus those with stage 4 melanoma (34 percent).
"With the higher stages, the possibility to restimulate the T cells drops dramatically," said Blank. "There have been hints from different trials that the higher the stage gets the more systemic immune suppression there is."
Ongoing studies are exploring whether this toxicity can be ameliorated while preserving efficacy through various dosing strategies. To this end, the phase 2 OpACIN-Neo trial will assess three treatment schedules prior to surgery. This study is expected to open in the next two weeks, according to Blank.
In the first arm of the study, which will enroll patients with stage 3 measurable melanoma, patients will receive two three-week cycles of Yervoy at 3 mg/kg with Opdivo at 1 mg/kg. In the second group, two three-week cycles of Yervoy will be given at 1 mg/kg with Opdivo at 3 mg/kg. A sequential approach will be examined in the 3 arm, with Yervoy at 3 mg/kg given for two cycles followed by two cycles of Opdivo at 3 mg/kg.