SABCS 2019 – Tecentriq stumbles in triple negative disease

Roche's Tecentriq is the only anti-PD(L)1 antibody to have won approval in triple negative breast cancer, but the extent to which these checkpoint inhibitors will play a role in this disease remains unclear. Disappointing data from a small neoadjuvant trial underline this fact: Tecentriq failed to improve response rates over chemotherapy, it was announced today, a finding that stands in contrast to Keytruda’s success in a similar trial.

Cross-trial comparisons always come with caveats: chemotherapy regimens differed in this case, for example. But investigators presenting the results at the San Antonio Breast Cancer Symposium were unsure why patients responded differently to the two therapies. 

The Tecentriq data come from the first look at the NeoTRIPaPDL1 trial. Adding Tecentriq to neoadjuvant chemotherapy for approximately six months resulted in a slightly higher rate of pathologic complete response versus neoadjuvant chemo alone, but the difference was not statistically significant. 

The academic study enrolled 280 patients with early high-risk and locally advanced or inflammatory triple-negative breast cancer. The chemo regimen in the trial was carboplatin and Abraxane; Tecentriq is already approved for use with Abraxane in some patients with locally advanced or metastatic triple-negative breast cancer.

In the very similar Keynote-522, a phase III study of neoadjuvant Keytruda plus chemo followed by adjuvant Keytruda in early triple-negative disease, Merck’s checkpoint inhibitor did yield a significant improvement in responses over chemo alone. Intriguingly in Keynote-522 the chemo arm also responded at a higher rate than NeoTRIPaPDL1’s control arm.

Presenting the NeoTRIPaPDL1 data at SABCS, Luca Gianni of the Fondazione Michelangelo in Milan, seemed to suggest that this could be down to the drugs being different. He pointed out that Keytruda is directed against PD-1 while Tecentriq binds this receptor’s ligand.

“At the end of the day they both interfere with the access between PD-1 and PD-L1, and it is largely assumed that mechanistically they will have the same effect, although there are subtle differences that may be not so subtle at the end of the day,” Dr Gianni said in a press conference.

It is also worth noting that the chemo regimens were different between the two trials, with Keynote-522 including another round of chemotherapy, post carboplatin and Abraxane. This presumably contributed to the higher response rate in Keynote-522’s control group, and could well have boosted the responses in the active arm.

Pathologic complete response is not the primary endpoint of either trial – it is merely considered a surrogate for long-term outcomes. Instead both are using event-free survival as the main outcome, measured at five years for NeoTRIPaPDL1, with full data due in 2022; Keynote-522’s event-free survival is measured at “up to approximately eight years”, its clinicaltrials.gov record says, with full data in 2025.

Coming up

Complicating the picture still further, a subgroup analysis of Keynote-522 also read out positively for Merck’s blockbuster at SABCS today. Among triple-negative breast cancer patients whose cancers had spread to the lymph nodes, 64.8% responded when Keytruda was added to chemo, compared with 44.1% given chemo alone. 

The sellside sees breast cancer as a much bigger opportunity for Keytruda than Tecentriq; 2024 forecasts sales in the indication are $3bn for the former versus just  $247m for Tecentriq. However, neoadjuvant use in triple-negative disease will only make up a fraction of these forecasts. 

Perhaps more important is the forthcoming readout of the Keynote-355 in the first-line setting. Tecentriq’s first-line breast cancer study, Impassion-130, showed strong results in PD-L1-positive patients and was duly approved here, but a wider label has eluded the Roche product (Esmo 2018 – Roche misses the bullseye in triple-negative breast cancer, October 20, 2018). It is expected that Keytruda will best Tecentriq here too. 

Lastly there is Impassion-031, Roche’s effort at proving Tecentriq’s worth in the neoadjuvant setting. The trial design is different, with Impassion-031 focusing on pathologic complete response in all-comers and PD-L1-high patients, without Keynote-522’s focus on event-free survival. The trials’ chemo arms are also subtly different, which will make it hard to be certain of the two checkpoint inhibitors’ relative merits.