Another checkpoint combo blow-up fuels Darzalex doubts

Genmab had hoped to add billions to sales of its multiple myeloma blockbuster, Darzalex, by pushing into solid tumours. Instead, the discontinuation of a study testing the drug alongside Roche’s Tecentriq in non-small cell lung cancer wiped $2.4bn off the Danish company’s market cap yesterday.

It was probably not the setback per se that caused the mass exodus – the trial in question was in second-line disease, an increasingly irrelevant setting – but rather the fact that the pairing of Darzalex and PD-(L)1s looks dead in the water. This does not bode well for other Darzalex combination trials, including several with Bristol-Myers Squibb’s Opdivo (see table below).

Worse Luc

The phase I/II Callisto trial, aka Luc2001, of Darzalex plus Tecentriq had been due to read out in the second half of 2018, giving an early indication of whether the combo might have utility in solid tumours.

But the study was discontinued over the weekend because of a lack of effect and, more worryingly, an increase in deaths in the combination arm. Berenberg analysts said it was still unclear whether the deaths with Darzalex plus Tecentriq had been caused by adverse events or progressive disease, but the future of this combination looks bleak.  

A second combination trial, MMY2036, testing Darzalex plus Johnson & Johnson’s anti-PD-1 antibody JNJ-63723283 in multiple myeloma, has also been halted.

As for whether any more Darzalex-PD-(L)1 combo trials might meet a similar fate, Genmab would only say that it had contacted its partners “to discuss ceasing enrolment and dosing of the combination while the data is being further investigated”.

A spokesperson for Genmab told EP Vantage that the company would not give more details as it could not speak for Johnson & Johnson, its partner on Darzalex. J&J is developing and commercialising the drug under an exclusive licensing deal signed in 2012 – the company had not responded to a request for more information on the remaining combo trials at the time of publication.

Darzalex/PD-(L)1 combo trials
Trial Setting  Combination ID Status
LUC2001/Callisto 2L NSCLC  + Tecentriq NCT03023423 Discontinued
MMY2036 Relapsed/refractory MM + JNJ-63723283 NCT03357952 Discontinued
Checkmate-142   Colon cancer  + Opdivo  NCT02060188 Primary completion Dec 2018
Keynote-668 Relapsed/refractory MM + Keytruda NCT03221634 Primary completion Mar 2019
Checkmate-358 Virus-associated tumours + Opdivo  NCT02488759  Primary completion May 2019
- Metastatic pancreatic, NSCLC, TNBC  + Opdivo  NCT03098550 Primary completion Jun 2019
- Relapsed/refractory MM + Opdivo  NCT01592370 Primary completion Jun 2020
- Relapsed/refractory MM + Tecentriq NCT02431208 Primary completion Sep 2020
Source: & EvaluatePharma.

Bernstein analysts do not hold out much hope for the remaining trials. They assume the worst for the Darzalex-Opdivo combo, posing the question: “Why would Opdivo be very different versus Tecentriq?”

They had given Darzalex a 50:50 chance in solid tumours, citing strong preclinical data supporting the combo approach.

Genmab’s chief executive, Jan van de Winkel, previously told EP Vantage that CD38 inhibition with Darzalex might help overcome resistance to PD-(L)1 blockade, with CD38-positive immune-suppressing cells seen in various solid cancers (Interview – Genmab aims at multiple new markets for Darzalex, February 19, 2018).

Still, the Bernstein analysts conceded that human data supporting the combination in solid tumours were lacking. And though the sellside had not factored solid tumour indications into their projections for Darzalex, confirmation that this huge opportunity will come to nothing was clearly a disappointment to some.

On the cards?

The writing was arguably on the wall for this combination strategy last year when the FDA placed on hold various combination trials of Astrazeneca’s PD-L1 inhibitor Imfinzi in blood cancers, including two studies involving Darzalex.

These trials, FusionMM-003 and FusionMM-005, were being carried out under a partnership with Celgene, and have since been discontinued. At the time of the cancellation, Celgene blamed the trial halts on deaths seen with the combination of another PD-1 inhibitor, Merck & Co’s Keytruda, with Celgene’s Revlimid and Pomalyst in multiple myeloma trials. 

Any hope that Darzalex’s different mechanism of action might have allowed it to avoid the PD-(L)1 combo safety concerns have been dashed by the latest news.

Still, even without this combination setting Darzalex is expected to be hugely successful in multiple myeloma – the indication accounts for the entire $6bn of EvaluatePharma's consensus forecast in 2024. And Genmab has more important readouts coming up, with the first-line Maia and Cassiopeia trials due to report this year.

Knock-out results will help rebuild confidence in the company, but any hint of disappointment – or any more safety worries – would be another big blow to sentiment.

To contact the writer of this story email Madeleine Armstrong in London at [email protected] or follow @ByMadeleineA on Twitter

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