In Regard to ramu, filing looks unlikely until Rainbow’s end

Ramucirumab, Lilly’s unexpected best supporting actor of 2012, looks unlikely to be filed on data from the Regard gastric cancer monotherapy study alone after it was revealed yesterday that the survival benefit it gave was at best marginal.

Although the median overall survival benefit versus placebo was broadly in line with expectations, what disappointed was that the result met statistical significance by only a whisker. Lilly’s shares were off 2% in early trade today. While a US filing on Regard alone is possible, the company will more likely have to wait for results from the Rainbow study of ramucirumab on top of chemotherapy before determining how to proceed in this cancer type.

According to clinicaltrials.gov Rainbow is due to be completed this October, implying data release at some point between then and October 2014.

Causing a stir

Ramucirumab (IMC-1121B) had caused a stir last October when topline data from the Regard trial, in 355 second-line gastric cancer patients, showed it to have hit its primary endpoint of a significant increase in median OS, as well as prolonging progression-free survival, a key secondary (Lilly’s ramucirumab comes off the bench with a clutch single, October 16, 2012).

Until then ramucirumab, a former ImClone Systems antibody that had been fast-tracked from phase I straight into phase III, had flown under most investors’ radars. Lilly subsequently said results from Regard were strong enough to discuss with regulators the possibility of making a standalone submission, even though nothing had yet been revealed about the magnitude of the benefits seen.

The latest data, revealed in an abstract due to be presented at this week’s ASCO-GI conference, detailing the magnitude – and significance – of the earlier result, have made it clear that such discussions are unlikely to provide much joy.

Median OS for patients on ramucirumab and best supportive care was 5.2 months versus 3.8 months for best supportive care alone. This 1.4-month benefit was – at a stretch – broadly within expectations, the only other monoclonal to have hit an OS endpoint in gastric cancer being Roche’s Herceptin, approved on an improvement of under two months.

But what left analysts underwhelmed was that the endpoint only just met statistical significance, with a p value of 0.0473. Consistent with other anti-VEGF therapies, median PFS improved with a highly statistically significant 0.8 months (p<0.0001).

UBS analysts said the OS benefit was of relatively small magnitude, while Leerink Swann said it was less compelling than hoped for, differing little from single-agent chemotherapy in second-line gastric cancer.

Thus it is now important for ramucirumab to demonstrate a survival effect when added on top of paclitaxel  in the larger, 665-patient, Rainbow study; given the borderline Regard result, the FDA will likely want to see the results of Rainbow before approving ramucirumab for gastric cancer.

Cold comfort

It will be cold comfort that ramucirumab is ahead of Novartis’s Afinitor, which showed a non-significant 1.05-month median OS increase in a second-line monotherapy trial and was discontinued for gastric cancer. Avastin, meanwhile, is used in combination with chemotherapy despite showing a numerical two-month increase in median OS that also failed to hit statistical significance.

Leerink analysts see ramucirumab generating global sales in gastric cancer of $600m by 2020, of which monotherapy use will account for $400m. EvaluatePharma data for all indications combined show consensus sales of $711m by 2018, translating into a 75% risk-adjusted NPV of just under $3bn in all indications.

This alone illustrates how analysts’ expectations have surged since last October, when ramu’s consensus-based NPV stood at $1.3bn, and no doubt expectations will now be reined in – at least until the Rainbow study reads out. But that might not happen for another year or so.

Phase III trials of ramucirumab
Study Detail Primary completion Trial ID
Regard 355 gastric cancer patients, second line, single agent  Completed NCT00917384
 –  1,144 breast cancer patients, first line, addition to docetaxel  Feb 2013 NCT00703326
Rainbow 665 gastric cancer patients, second line, addition to paclitaxel  Oct 2013 NCT01170663
 – 1,242 NSCLC patients, second line, addition to docetaxel  Jan 2014 NCT01168973
Reach 544 hepatocellular carcinoma patients, second line, single agent  Mar 2014 NCT01140347
 – 1,050 colorectal cancer patients, second line, addition to FOLFIRI Sep 2014 NCT01183780

To contact the writer of this story email Jacob Plieth in London at jacobp@epvantage.com or follow @JacobEPVantage on Twitter

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