Bristol-Myers Squibb’s Phase III first-line head and neck squamous cell carcinoma (HNSCC) trial of Opdivo (nivolumab) and Yervoy (ipilimumab) has several experts pessimistic on trial success while others said a prior failed trial makes conclusions tough.

With another combination trial of the two agents versus Opdivo monotherapy (NCT02823574) failing, several had dampened expectations for the ongoing Phase III CheckMate 651 (NCT02741570), and noted low response numbers are likely. The combination should beat Merck’s Keytruda (pembrolizumab) to impress, they said. However, others said results cannot be predicted, with one of the experts noting more time is needed to predict a response. CheckMate 651 tests Opdivo and Yervoy versus Eli Lilly’s Erbitux (cetuximab) plus chemotherapy (cisplatin/carboplatin + fluorouracil).

If the drug does have positive results and is approved, it could face market challenges due to its potentially subpar efficacy and safety profile, experts said, with expected high toxicity levels. This is especially true when it is hard to identify the population that will respond to it, and even that is expected to be small, they said.

The 947-patient, randomised, open-label CheckMate 651 is expected to have results in 1H20, according to analysts. BMS did not return requests for comment.

Opdivo’s peak sales are estimated at $12bn and Yervoy’s at $2bn globally, according to one analyst report. Bristol-Myers Squibb’s market cap is $93.93bn.

Mostly pessimistic views toward trial results

There is little hope the combination will prove effective considering a similar combination, in the form of Opdivo and Yervoy against single-agent Opdivo, failing in the randomized Phase II CheckMate 714 trial, said Dr Hisham Mehanna, professor of Head and Neck Surgery, University of Birmingham, Birmingham, UK, and Dr Aarti Bhatia, assistant professor of Medicine (Medical Oncology), Yale Cancer Center, New Haven. A 25 April BMS press release reported that the study did not meet its primary endpoint of overall response and duration of response, with no further details.

In CheckMate 651, a low response rate benchmark of 20–25% is expected, as well as overall survival (OS) of 12 months and progression-free survival (PFS) of four months, as most immunotherapy trials have shown similar results, said Bhatia. OS is the primary study endpoint whilst PFS is a secondary endpoint.

In order for this combination to succeed in clinical practice, BMS must demonstrate a 95% overall response rate and 80% survival rate, added Dr Marshall Posner, director, Head and Neck Medical Oncology, Icahn School of Medicine, Mount Sinai, New York. That would demonstrate this combination is better than Keytruda (pembrolizumab), he said, which is approved as first line for recurrent/metastatic HNSCC in combination with platinum and fluorouracil (5-FU).That said, he said he had low hopes these numbers would be shown, considering the CheckMate 714 results.

However, the CheckMate 714 trial does not give indication of a failure for the CheckMate 651 trial, as it is hard to predict whether results will correspond, said Dr Steven Wang, chair, Department of Otolaryngology, University of Arizona College of Medicine, Arizona, and Dr Antoine Eskander, assistant professor, University of Toronto, Canada. Head and neck cancer treatment options have been relatively scant, and therefore it is better to offer patients a combination of treatment options when single agents fail, Wang said. This combination needs more time to predict the responsive patient population, Wang added. The study monitors OS for 51 months.

Experts maintained these low expectations despite the results of the 506-patient CheckMate 141 trial (NCT02105636). The trial showed significantly longer OS, PFS, and a higher response rate with Opdivo monotherapy in comparison with standard, single-agent systemic therapy (methotrexate, docetaxel or cetuximab). They agreed that the results between the studies will unlikely be significantly important, with Eskander noting the CheckMate 141 results are not extremely impressive but rather what is usually seen in these types of immunotherapy in HNSCC patients.

Toxic expectations on efficacy and safety

In theory the dual engagement of both drugs should lead to a stronger response and increase survival, but this is unlikely to be the case as there is a toxicity profile which will impact the latter, said Dr Eyal Talor, chief scientific officer, CEL-SCI, Vienna, Virginia. Due to the toxicity profile of the PD-L1 being higher than the PD-1 inhibitor on its own, there will be stronger side effects, however this can be justified if efficacy is proven, added Bhatia.

This toxic combination will lead to 80% of patients having side effects and 20% having severe side effects, from which 30% will experience diarrhoea, said Dr Doru Paul, physician, Monter Cancer Center, New York. Severe side effects may be present in 60–70% of the population in the CheckMate 651 trial, added Mehanna. Data from CheckMate 141 showed 15–24% of the patients experienced diarrhoea, fatigue, nausea, anaemia and asthenia. Posner said he expects 6–10% of patients to have toxicity levels of Grade 3 and 4, which will lead to hospitalisation, basing these numbers on his experience with head and neck cancer patients.

Hormonal changes, bronchitis, skin rashes, nonhealing fiscal tracts in the presence of a tumour, hypothyroidism and odd immune toxins are common expected adverse effects, said Marshall.

Dampened market expectations

The market uptake will be difficult, as it will be hard to predict whether the Opdivo and Yervoy combination in comparison to chemotherapy is more efficacious, as it has been shown it is not superior to Opdivo alone, said Bhatia.

The population in the trial should be parsed out further in order to detect the groups that will respond to this drug, however it is expected that only a small portion of patients will be responsive, added Eskander. This is because the inclusion criteria require patients with metastatic or recurrent squamous cell carcinoma of the head and neck that is not amenable to curative therapy, no previous systemic cancer treatment for recurrent or metastatic disease and a presence of tumour tissue for PD-L1 expression testing, which restricts the targeted population, added Posner.

Due to a small proportion of patients expected to respond, identifying this population will be troubling, with expectations of it being administered to only 15–20% of responsive patients, said Mehanna. Even in the CheckMate 141 study, in terms of response, the rate of PFS at six months after platinum-based chemotherapy for patients receiving Opdivo or standard, single-agent systemic therapy (methotrexate, docetaxel or cetuximab) was only 19.7% in patients, added Mehanna. In terms of competitors, Merck’s Keytruda will still be its biggest barrier, Posner and Bhatia said.

by Bernarda Tundzhay in London

Bernarda Tundzhay is a Reporter for Clinical Trials Arena parent company GlobalData’s investigative journalism team. A version of this article originally appeared on the Insights module of GlobalData’s Pharmaceutical Intelligence Center. To access more articles like this, visit GlobalData.