Esmo weekend roundup – Opdivo’s big stumble is Keytruda’s big triumph, plus Yervoy and IDO

The European oncology congress Esmo has turned out to be the medical meeting of 2016 so far as Merck’s Keytruda stole the thunder from Bristol-Myers Squibb’s Opdivo in lung cancer. But, away from these high-profile readouts, Incyte scored impressive early results as a possible Yervoy replacement in melanoma, while Boehringer Ingelheim tried to solidify the evidence supporting its armoury of kinase inhibitors.

The presentation of full data from the Checkmate 026 trial were even more disappointing than the previous topline data release, if Bristol shares’ 9% tumble today is any indication. Not only did the first-line trial miss its primary endpoint of progression-free survival over chemotherapy in patients with PD-L1 expression of 5% or greater, it could not even show a benefit in patients with expression of 50% or greater.

In that high-expressers group, Keytruda showed a 50% reduction in the risk of progression or death and a 40% reduction in the risk of death, solidifying Merck’s hold on the first-line population (Esmo – Merck carries off first-line NSCLC prize, October 10, 2016).

What next for Yervoy

Bristol-Myers, meanwhile, tried to show that Yervoy still had a place in melanoma. Overall survival data for Yervoy in an adjuvant melanoma setting were described by the more enthusiastic at Esmo as practice changing. The findings were certainly impressive with the five year follow up data showing that the CTLA-4 drug significantly improved survival, reducing the risk of death by 28%.

However, the advancement came with a heavy price. During the course of the study five people died and 40% of patients developed grade 3/4 serious adverse events, some of which required patients to permanently use hormonal replacement therapies.

Yervoy is already approved in the adjuvant setting following its performance in improving recurrence-free survival at 2.3 years, but because of its famed toxicity investigators at Esmo warned that the 10mg/kg regimen used should only be reserved for experienced centres – a stricture that could potentially reduce the number of available patients.

Doctors might also take the decision to use the treatment only in the most serious of cases, despite the drug showing an 11 percentage point increase in overall survival after five years over placebo.

The success of Yervoy in adjuvant setting could, however, be its undoing. If checkpoint inhibitors work here, then theoretically other products like the PD-1/PD-L1s, which have much lower toxicity could also work, eventually edging Yervoy out of this new niche.

Indeed, Merck & Co has already started a trial, EORTC 1325, in this setting using Keytruda, with results due towards the end of 2017.

But for now Bristol-Myers is the only one with long-term data, a fact that should help Yervoy achieve the $2.15bn of sales it is forecast to achieve by 2022.

Epacadostat a safer Yervoy?

Incyte’s epacadostat set down another marker as the leading IDO inhibitor in the pipeline, reporting phase I data in advanced melanoma in combination with Opdivo that appear to match Opdivo plus Yervoy but with fewer side effects.

Data from the dose escalation trial showed an objective response rate of 53% in 19 melanoma patients who had never been treated with a PD-1 inhibitor, compared with 58% for the Opdivo and Yervoy combination.

Median progression-free survival had not been reached, although Incyte reported PFS of 74% at six months and 57% at 12 months, which gives it a chance of matching the Opdivo/Yervoy 11.5-month figure. Importantly, 11% in the Opdivo/epacadostat combination reported grade 3 adverse events, compared with 55% for Opdivo/Yervoy.

The IDO battle so far is in its early stages, with just epacadostat, NewLink Genetics’ indoximod, and Roche’s RG6078 having any consensus forecasts – epacadostat stands at $317m in 2022, according to EvaluatePharma. But as more data in this class come out this is sure to change rapidly.

Boehringer kinase inhibitors miss

Boehringer Ingelheim came into Esmo with a flood of data on the approved kinase inhibitors Gilotrif and Vargatef, but key studies showed no benefit on overall survival. Gilotrif registered a miss head to head against AstraZeneca’s Iressa in first-line EGFR-mutant non-small cell lung cancer.

The Lux-Lung 7 trial had already reported positive PFS and time to treatment failure data, but on overall survival Gilotrif recorded 27.9 months, which failed to show statistical significance over Iressa’s 24.5 months.

On the positive side the updated data supported the early finding of PFS benefit, and the private German group also reported that more patients taking Gilotrif were alive at 18 and 24 months (27% and 18%) than those taking Iressa (15% and 8%). On patient-reported outcomes, the two drugs registered similar results, with no significant difference in health-related quality of life, and similar treatment-related discontinuation rates (6%).

Meanwhile, Vargatef with best supportive care could not show that it extends the lives of patients with metastatic colorectal cancer better than best supportive care alone. The Lume-Colon 1 trial showed Vargatef reduced the risk of disease progression by 42%, however.

The agent achieved EU approval in non-small lung cancer in combination with docetaxel on the strength of the Lume-Lung 1 study, which beat docetaxel alone on PFS and overall survival. Boehringer did not indicate whether it would seek to expand the EU label to include colorectal cancer based on the disease progression benefit.

Product Study Trial ID
Opdivo Checkmate 026 NCT02041533
Keytruda Keynote-024 NCT02142738
Yervoy EORTC 18071  NCT00636168
Epacadostat Echo-204 NCT02327078
Gilotrif Lux-Lung 7 NCT01466660
Vargatef Lume-Colon 1 NCT02149108

To contact the writers of this story email Lisa Urquhart or Jonathan Gardner in London at or follow @LisaEPVantage or @ByJonGardner on Twitter

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