Turning Point on the straight track, but to where?

Repotrectinib looks promising, but for a real shot at the market the data cannot deteriorate, and a partner needs to be found.

Turning Point cheerleaders will have been happy with yesterday’s update on repotrectinib, the company’s Ros1/NTRK targeted project that sits in the hugely attractive targeted oncology space. Response rates continue to look competitive versus Roche and Pfizer assets, and recent talks with US regulators have laid out a clear path to filing.

But two crucial components are still missing from this story: evidence that repotrectinib has greater durability than the aforementioned rivals, and a partner with deep pockets. Generating the former is likely to lead to the latter, of course, but the likelihood of this chain of events unfolding remains very hard to call.

The company’s $2.8bn valuation suggests that investors see a bright future. Shares in the company have more than tripled since they floated in April 2019. Given the huge sums have that been paid for targeted oncology assets perhaps such enthusiasm is reasonable – think of the $8bn that Lilly paid for Loxo and the $11bn Pfizer paid for Ariad.

But the fact remains that repotrectinib will face entrenched competition in the niche it is ultimately gunning for. The kinase inhibitor hits Ros1 and NTRK, though the former is of greater interest. This mutation drives around 2% of non-small cell lung cancers, with NTRK accounting for a further 1%.

Both Pfizer’s Xalkori and Roche’s Rozlytrek are approved for Ros1-positive patients, although nothing is available for the big proportion of patients that develop resistance mutations to these. Repotrectinib has been specifically designed to overcome these tumour evasion tactics and offer an option to patients who fail Xalkori and Rozlytrek, but Turning Point wants a shot at the first-line market as well.

Cross-trial comparison in treatment-naive Ros1 +ve NSCLC 
  Repotrectinib (n=14)  Rozlytrek (n=161) Xalkori  (n=50)
ORR 86% 67% 66%
DoR (months; median or range) 0.9-17.6  16.5 18.3
Source: Turning Point presentation of Trident-1 data, EMC website for Rozlytrek, & US drug label for Xalkori.

This is why it is so important for repotrectinib to emerge as more durable, and on this measure it is too soon to make a call. The range of durations presented yesterday in front-line patients, from the ongoing Trident-1 study, is certainly encouraging. The phase I portion of the trial generated a response that lasted 23 months, albeit at a different dose than is being carried forward. This all needs confirming in a larger group, however.

On response rates repotrectinib also looks good, but again these results were generated in only 14 patients. Leerink analysts point out that in a more recent cut of the Rozlytrek data, revealed in a European medicines registry, this drug’s ORR had slipped to 67%, from the 78% on its US label. It is seems highly likely that the repotrectinib data will also trend downwards.

Safety is also something to watch, with high rates of dizziness being the most worrying issue. Again, more data are needed, but any differentiation here could prove crucial, not only for approval but for finding a partner, which is surely essential with two big pharma players already on the market. 

Assuming that response rates in patients who have relapsed after Xalkori and/or Rozlytrek hold up, repotrectinib looks like emerging as an important new option. But it is clear that the company’s ambitions – along with investor expectations – stretch beyond this opportunity.

On a call yesterday executives said more information on recruitment and filing timelines would be given early next year – the pandemic makes trial recruitment difficult – adding that the FDA requires 12 months' follow-up before it can file in treatment-naive patients, and six months in pretreated cohorts.

They also acknowledged that for any hope of accelerated approval, based on an interim look at the data, Rozlytrek has to be beaten. This also surely applies to repotrectinib’s wider commercial potential, where on-par efficacy will simply not cut it.

The stats so far on repotrectinib in later lines:  Trident-1 interim data
  Ros1+, TKI + chemo pretreated (n=12) Ros1+, TKI pretreated, no chemo (n=9) Ros1+, 2 prior TKIs, no chemo (n=6) NTRK+, TKI pretreated (n=7)
ORR 50% 67% 33% 45%
DoR range in mth 2.7-11.1 (n=6) 0.8-5.7 (n=6) 1.9-1.9  (n=2) 1.7-3.6 (n=3)
Source: Turning Point presentation      

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