Most of the attention on the use of immune checkpoint blockers in breast cancer has fallen on Roche’s Tecentriq. But investors should soon find out whether Merck & Co’s Keytruda could seize a significant chunk of this market, thanks to the readout of Keynote-522, a trial that has largely flown under the radar.
Roche has a long-standing presence in breast cancer, and it recently positioned Tecentriq as a new first-line treatment for the highly aggressive triple-negative form of the disease. However, its Impassion-130 study, in the metastatic setting, fell short of expectations, with a progression-free survival benefit that was strongly driven by PD-L1-positive patients.
Keynote-522, however, targets a different setting, namely neoadjuvant use. Of course Roche is active here too, as well as in the related adjuvant setting, but the Merck trial will be the first to read out, with data expected some time this month; its co-primary endpoints are pathological complete response (pCR) and event-free survival.
Important and underappreciated
The importance of Keynote-522 has been highlighted by Evercore ISI’s Umer Raffat, who reckons that it could open up a near $2bn opportunity for Keytruda. Despite this it remains underappreciated by the sellside, with EvaluatePharma’s consensus sales estimates by indication suggesting that breast cancer will account for just $397m of Keytruda’s $14.4bn 2024 revenues.
There is a nuance, however, relating to the precise setting of Keynote-522. The trial’s clinicaltrials.gov entry suggests that Keytruda is being tested as adjuvant treatment – a much bigger market – as well neoadjuvant, but in fact this does not appear to be the case.
Keynote-522’s design has the drug given along with chemotherapy for eight cycles before surgery, and this is the neoadjuvant setting. After surgery patients get nine more cycles of therapy, which strictly speaking is classified as adjuvant use.
However, Mr Raffat stresses that no patients will have received nothing followed by surgery and then Keytruda, versus placebo, which is what would have been needed to demonstrate a benefit in the adjuvant setting. Thus, assuming a positive result, Keynote-522 is unlikely to open up the adjuvant market for Keytruda.
This is potentially significant. Evercore reckons that the global adjuvant market is nearly three times as big as that for neoadjuvant use. Still, 65% penetration of the latter, and no use in the former, still translates into Keytruda sales of $1.2bn, they estimate, with any adjuvant sales being the icing on the cake.
How likely is Keynote-522 to succeed? A key guide is the charity-sponsored I-Spy-2 trial, which tested various agents in neoadjuvant breast cancer. Keytruda monotherapy yielded a pCR rate of 60% versus 20% for control.
Some caution needs to be employed as those were values predicted by Bayesian analysis, though it should also be stressed that an effect for Keytruda plus chemo, as being tested in Keynote-522, could be greater. The one caveat is that Keynote-522 was recently upsized by 35%, hinting at concerns that it might have been insufficiently powered to yield a statistically significant result.
|(Neo)adjuvant studies of anti-PD-(L)1 MAbs in triple-negative breast cancer|
|Study||Treatment||Sponsor||Setting||Trial ID||Primary completion|
|Geparnuevo||Imfinzi + chemo||German Breast Group||Neoadjuvant||NCT02685059||Reported (ph II trial)|
|Keynote-522||Keytruda + chemo||Merck & Co||Neoadjuvant||NCT03036488||Nov 2018|
|Impassion-031||Tecentriq + chemo||Roche||Neoadjuvant||NCT03197935||Mar 2019|
|A-Brave||Bavencio||Istituto Oncologico Veneto IRCCS||Adjuvant||NCT02926196||Jun 2021|
|Impassion-030||Tecentriq + chemo||Roche||Adjuvant||NCT03498716||Jan 2022|
|NeoTRIPaPDL1||Tecentriq + Abraxane||Fondazione Michelangelo||Neoadjuvant||NCT02620280||May 2022|
|MO39875||Tecentriq + chemo||Roche||Neoadjuvant||NCT03281954||Dec 2023|
It is clear that, should Keynote-522 succeed, Merck would not have the market to itself for long. Next year, for instance, should see readout of Roche’s Impassion-031 trial of neoadjuvant Tecentriq, and given the Swiss firm’s existing presence in breast cancer Tecentriq should pose formidable competition.
However, it cannot be denied that Tecentriq has disappointed in front-line treatment of metastatic triple-negative disease, likely explaining Roche’s caution in estimating that this setting would yield sales of CHF500m-1bn ($500m-1bn), which underwhelmed analysts (Esmo 2018 – Roche misses the bullseye in triple-negative breast cancer, October 20, 2018).
It will be up to Merck to make the most of any first-mover advantage.