Binimetinib withdrawal reveals Array of issues

The withdrawal of Array Biopharma’s filing for binimetinib is, on the face of it, not too big a deal. The company had sought approval in Nras-mutant melanoma, a much smaller indication than the Braf-mutant melanoma population it is targeting with its binimetinib/encorafenib combination, which is expected to be filed in the mid-year.

But the development undermines investor confidence in Array before a final readout with the binimetinib/encorafenib combo, and calls into doubt its commercial strategy. There are also lingering questions about how large the market for the doublet will be, given that checkpoint inhibitors dominate the melanoma space.

Array stock fell as much as 27% in premarket trading this morning, but recovered to open down 7%.

Losing Nemo

Array had hoped for approval of binimetinib monotherapy on the back of the Nemo trial; it had a PDUFA date of June 30, and had been due for an adcom review on March 29.

But the company has now said that after “thorough discussions and communications with the FDA” the benefit shown in the Nemo trial would not be enough to support approval.

The monotherapy could still get the go-ahead in Europe, where a marketing application, submitted by its partner Pierre Fabre, is under evaluation by the CHMP.

Nras mutations are only responsible for around 20% of cases of metastatic melanoma. The bigger prize is Braf-mutant melanoma, which accounts for up to 50% of metastatic disease and could be much more lucrative for Array, according to Leerink analyst estimates.

Array’s US sales – Leerink analyst estimates
Product Indication 2022e sales ($m)
Binimetinib/encorafenib BRAF+ melanoma 235
Binimetinib NRAS+ melanoma 27*
Encorafenib Colorectal cancer 130
*Now removed from model.

But the withdrawal is still a blow to the group, which had hoped to use the approval in the smaller population to build its commercial infrastructure before the expected launch of the binimetinib/encorafenib combo next year.

And approval of the doublet is not a given, hinging on results from the second part of the Columbus trial, from which data are expected mid-year before a US filing in June or July.

The first part of Columbus found a significant benefit with binimetinib plus encorafenib versus Roche’s Braf inhibitor Zelboraf – but the doublet failed to show a statistically significant benefit over encorafenib monotherapy, a key secondary endpoint (Array plays catch-up in Braf-Mek derby, September 26, 2016). 

The second part of the study could address any questions about this finding. It compares binimetinib plus encorafenib with encorafenib alone, and is designed to help evaluate the contribution of binimetinib to the combination.

Even if approved, Array will have a job carving out a niche for the doublet in the face of established Mek and Braf inhibitor combos such as Novartis’s Mekinist/Tafinlar and Roche’s Zelboraf/Cotellic. Checkpoint inhibitors like Opdivo and Keytruda have transformed melanoma treatment, though they are not indicated for first-line treatment of Braf-mutated disease. 

However, immuno-oncology was a problem in the design of the Nemo trial. This showed a progression-free but not overall survival benefit, presumably because progressing patients were switched to checkpoint-blocking drugs, which eliminated any survival advantage.

This is not the first misfortune for the project – last April, Array discontinued a phase III trial of binimetinib monotherapy in low-grade serous ovarian cancer on futility.

The company still has another valuable indication in play in the shape of colorectal cancer, where it is testing the binimetinib/encorafenib combo alongside Lilly’s Erbitux in the Beacon CRC study. However, with data from this trial a couple of years away, Array’s near-term value depends on getting a result in melanoma.

Study Details Trial ID Primary completion
Columbus Binimetinib + encorafenib in BRAF-mutant melanoma NCT01909453 Part 1 reported;
part 2 due mid-2017
Beacon CRC Encorafenib + Erbitux +/- binimetinib in 2nd-line BRAF-mutant CRC NCT02928224 July 2019

To contact the writer of this story email Madeleine Armstrong in London at [email protected] or follow @ByMadeleineA on Twitter

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