Why the Rova-T delay is anything but irrelevant

The six-month delay revealed on Friday to Trinity, Rova-T’s registrational small-cell lung cancer trial, casts yet more doubt on this risky asset, which Abbvie had acquired through its $5.8bn buyout of Stemcentrx.

On the face of it the delay seems innocuous enough – the US FDA simply wants the filing to include six-month durability data, pushing readout out from late this year into the second quarter of 2018. But investors should ask themselves whether this is an admission that Trinity’s design is irrelevant, and even whether the trial might already have failed.

That latter scenario is not beyond the realms of possibility, especially considering that as Trinity is an open-label, single-arm study there is no reason why Abbvie might not be privy to the data it is generating.

Trinity’s design goes to the heart of the problem. Abbvie decided to forgo a control arm in the study, in third-line SCLC, on the grounds that patients at this late stage had no approved treatment options.

Now, this might be true in theory, but in practice doctors can and do hit the tumour with more chemotherapy. Indeed, there exist several published trials detailing the responses of third-line SCLC patients to various chemo regimens, and the remission rates these reveal range from 18% to over 30%.

What Rova-T needs to beat: remission rates for chemo in 3rd-line SCLC
Trial ref 3rd-line SCLC pts Chemo regimen ORR
LeBeau et al, 2010 35 (subset) Lomustine + etoposide + cyclophosphamide 31.4%
De Jong et al, 2006 35 Various 26.0%
Park et al, 2007 33 Paclitaxel + ifosfamide 20.0%
Saruwatari et al, 2016 202 (retrospective) Various 18.0%
Simos et al, 2014 120 Various, some rechallenged with same regimen 18.0%
Source: scientific literature; ORR=overall remission rate.

How might Trinity fare on its co-primary endpoint, overall response? Abbvie's trial recruits subjects expressing DLL3, the ligand that Rova-T targets, whose presence correlates with poor prognosis. A previous study, reported at last year’s Asco, showed overall remission of 31% in patients with DLL3 expression of 50% or more.

Such a response rate lies within the efficacy shown by some chemotherapies, suggesting that Rova-T might not in fact confer a benefit over chemo. Moreover, Trinity comprises a broader patient group – those with DLL3 >1%, and if Rova-T’s mechanism holds up it is likely that the remission rates Trinity is generating are below 31%.

Yet on its third-quarter call on Friday Abbvie claimed that retrospective analyses suggested an 18% response rate in chemo-sensitive third-line SCLC patients, adding that “most experts” believed that real-world third-line objective response rates were 5% or below.

Such a claim might wash with the sellside, but perhaps not with the FDA – however lenient that regulator has shown itself to be of late. The demand for six-month durability is a roundabout way of saying that the FDA wants to see some indication of survival; true, Trinity includes overall survival as a co-primary measure, but this will not mature for some years.

It is perhaps ironic that, had Abbvie designed the study with a proper control arm, it would have avoided such polemics. Then again, that scenario might have given it even less scope to play down an ambiguous outcome.

Immuno-oncology threatens

A separate factor is the advent of immuno-oncology, in particular of Bristol-Myers Squibb’s Opdivo plus Yervoy, which last week revealed a 21% remission rate in the SCLC segment of the Checkmate-032 trial – a result that rose to 46% if only patients with high tumour mutation burden were considered.

Abbvie is unfazed, at least publicly. Its chief scientific officer, Michael Severino, on Friday denied that novel treatments had substantially raised the bar in SCLC.

Actions, however, speak louder than words: on the same call the company played up Rova-T combinations with immunotherapy, and highlighted other assets that Stemcentrx had given it, including seven currently in human trials. Three novel Stemcentrx projects are to enter the clinic each year, it said.

Since the group needs to show that its $5.8bn was money well spent this might be fair enough. For Trinity, however, the writing is on the wall.

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

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