The heat is on Gilead as Tropics readout nears

Trodelvy has a chance to score in a study designed to expand its use, but given Gilead’s R&D track record nothing is certain.

Company events

Gilead’s $21bn acquisition of Immunomedics was squarely focused on the Trop-2 directed antibody-drug conjugate Trodelvy, which is about to face a key label-expansion catalyst: progression-free survival data from the Tropics-02 study are due by the end of this year.

The drug is already approved in third-line or later triple-negative breast cancer, as well as in post-chemo/PD-(L)1 urothelial bladder cancer. Tropics-02 tests it against chemo in third-line Her2-negative breast cancer patients who are still ER-positive, and the readout is especially important given Gilead’s recent R&D setbacks.

Those setbacks centre on the disastrous Galapagos tie-up, which saw Gilead shell out $5bn, while a paucity of meaningful data mean that the jury is probably still out on a separate deal with Arcus. Immunomedics forms a key part of Gilead’s post-hep C strategy, and the group confirmed on its second-quarter call that the event-driven Tropics-02 trial was on track for year-end readout.

Pretty confident

Two other points of note emerged from that call. Firstly, Gilead said it had not done a futility analysis on Tropics-02, and secondly that it was “pretty confident” about the study’s powering, especially since the trial was expanded “to make sure that we are able to hit the progression-free survival endpoint”.

Tropics-02 was enlarged from 400 to 543 patients, and had its primary measures amended from PFS and objective response rate to a sole PFS primary endpoint. It seems, therefore, that Gilead is trying to maximise its chances of success and focusing statistical powering squarely on PFS.

One reason for this, and for investor caution, is that Tropics-02 might struggle to show the statistical significance of a relatively small improvement in mPFS versus chemo. This is a result of the study’s design, which is driven by the changing nature of available treatments for ER-positive Her2-negative breast cancer.

Specifically, Tropics-02 enrolled only those patients who had failed at least one CDK4/6 inhibitor, meaning Pfizer’s Ibrance, Novartis’s Kisqali or Lilly’s Verzenio. After failing on these relatively new standards of care patients have a much reduced prognosis.

For instance, an earlier uncontrolled basket study run by Immunomedics in late-line ER-positive Her2-negative disease suggested 6.8 months of mPFS for Trodelvy, which compared favourably against the three months or so that chemo would be expected to achieve.

However, mPFS in those naive to CDK4/6 inhibition was 7.6 months, while on those who had progressed on CDK4/6 the number was just 3.8 months. And ORR and overall survival showed a similar divergence according to CDK4/6 treatment status.

Selected Trodelvy studies
      Result
Study Design Key endpoints CDK4/6 naive Post CDK4/6
Basket trial Uncontrolled, 515 pts in various solid tumours Safety & ORR (primary), OS & PFS (secondary) ORR 41%, mOS 21.7mth, mPFS 7.6mth* ORR 25%, mOS 11.0mth, mPFS 3.8mth*
Tropics-02 543 pts with ≥3L ER+/Her2- breast cancer, vs chemo PFS (primary), ORR & OS (secondary) NA Due Q4 2021
Note: *ER+/Her2- breast cancer cohort. Source: Annals of Oncology & clinicaltrials.gov.

Little wonder that Tropics-02 was upsized: though chemo alone would also be expected to work less well in CDK4/6-exposed subjects, Gilead might ultimately be trying to demonstrate the significance of an mPFS increase of just a month or two.

Trodelvy appears to be one of just four clinical-stage Trop2-targeting industry assets in clinical trials, the others being Astra/Daiichi’s datopotamab deruxtecan, Kelun’s ADC SKB264 and Shanghai Junshi’s naked antibody JS108. None of the others is being studied specifically in ER-positive Her2-negative breast cancer.

Though a detailed split of consensus forecasts is not available, the sellside expects Trodelvy’s revenues to climb from $388m this year to $2.7bn in 2026, according to Evaluate Pharma. Much of this will be down to the new breast cancer indication, showing why Tropics-02 is so crucial for Gilead.

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