US agency to rule on Tecentriq’s most important use

Roche will find out by September 5 whether its shot at a first-line US lung cancer label has hit the mark.

Roche made little noise about filing Tecentriq for first-line lung cancer, and in recent presentations it almost seems like the emphasis is being taken off this indication. But make no mistake: the use is still set to account for the vast majority of the drug’s forecast sales.

If the Swiss company has toned down its excitement this can only be down to the stranglehold that Merck & Co’s rival, Keytruda, has managed to establish on the first-line setting. Thus Tecentriq, like Bristol-Myers Squibb’s Opdivo, is now fighting for small subgroups, and the FDA will soon decide which of these settings are approvable.

After generating plenty of clinical data over the past year Roche remained cagey about when it would file, quietly disclosing in May that an application had been made on the back of Impower-150, Tecentriq’s Avastin/chemo combo trial. Under priority review a Pdufa date of September 5 was set.

How broad?

The specific label sought is first-line non-squamous NSCLC, and given the positive readout of Impower-150 and the FDA’s keenness to greenlight anti-PD-(L)1 agents it would be surprising for the agency not to approve. Rather, the question will probably be about the breadth of the label.

One of the most important issues will be whether approval is granted for patients with Alk or EGFR mutations, and those with liver metastases; all these were highlighted by Roche as subgroups in Impower-150, and Keytruda's first-line label excludes treating patients with Alk or EGFR mutations.

Alk and EGFR-mutated disease is normally treated with small molecules like Pfizer’s Xalkori and Astrazeneca’s Iressa respectively, and Roche’s bet, should it get this label, could be to pitch Tecentriq as an NSCLC treatment without the need to analyse patients' tumours genetically.

On the other hand, if the FDA restricts Tecentriq to wild-type disease Roche would be in a head-to-head battle against Keytruda, which is already approved in PD-L1-high patients as monotherapy, and in all-comers as part of an Alimta chemo combo, thanks to the respective Keynote-24 and 21 trials.

And should the FDA decide additionally to limit Tecentriq use to PD-L1-high patients – Impower-150 showed Tecentriq’s effect being driven by PD-L1 positivity – it would put Roche at a disadvantage much more serious than merely being second behind a strong market leader.

1st-line non-squamous metastatic NSCLC: the near-term battleground
Regimen Trial PD-L1 >50% PD-L1 1-49% PD-L1 <1%
Keytruda + chemo  Keynote-021G (NCT02039674) Approved (accelerated)
Keytruda + chemo  Keynote-189 (NCT02578680) Filed for confirmatory approval*
Keytruda monotherapy Keynote-024 (NCT02142738) Approved (accelerated) NA NA
Keytruda monotherapy Keynote-042 (NCT02220894) +ve for OS +ve for OS NA
Tecentriq + Avastin + chemo Impower-150 (NCT02366143) Filed
Opdivo + Yervoy  Checkmate-026 (NCT02041533) Failed in PD-L1 >5%
Opdivo + Yervoy  Checkmate-227 (NCT02477826) Positive in TMB-high
NA=not applicable. *PDUFA date September 23, 2018.

Already Merck has seized on its Keytruda monotherapy data to market its drug as a chemo-free regimen. Roche, on the other hand, is relying on doctors who are already familiar with Avastin simply to add Tecentriq into the mix; however, in Impower-150 it was by no means clear how much additional benefit Avastin brought.

That said, this issue could simply come down to marketing. In terms of efficacy, Tecentriq and Keytruda are broadly in line on median overall survival if data across different studies are compared (Asco 2018 – Merck's dominance leaves rivals scrabbling for subsets, June 4, 2018).

Thus Roche finds itself in a similar situation to Bristol, which as a latecomer has sought to play up a subgroup benefit – in the case of Opdivo plus Yervoy activity in PD-L1-low subjects with high tumour mutation burden. Astrazeneca’s Imfinzi, like Tecentriq an anti-PD-L1, is probably out of the race here, but does have approval in earlier, stage III NSCLC.

So far this year Tecentriq has generated sales of $324m, a modest amount, from its currently approved uses in urothelial carcinoma and second-line NSCLC. Sellside consensus, as compiled by EvaluatePharma, is for 2024 revenues of $4.8bn, with lung cancer accounting for $3bn of this amount.

Given that thanks to the dominance of front-line checkpoint blockade the second-line setting will soon be obsolete, most of that £3bn must therefore come from Tecentriq’s first-line use. Unfortunately for Roche, subgroups alone might not be enough.

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