Asco Preview – a Second Wind for Antibody-Drug Conjugates

May 22, 2018 Asco preview – A second wind for antibody-drug conjugates

Jacob Plieth

Antibody-drug conjugates are enjoying something of a resurgence, notwithstanding the fact that Seattle Genetics’ Adcetris and Roche’s Kadcyla are still this technology’s only notable successes.

Several presentations at next month’s Asco conference could show how much further this approach could go. Already one company, Immunomedics, has enjoyed an Asco-assisted share price run-up, after shaking Seattle off as a suitor a year ago, while several others including Takeda and Daiichi Sankyo are attempting to ride on Kadcyla’s coattails (see table below).

However, developing an efficacious antibody-drug conjugate (ADC) is not easy, and the technology relies on several elements coming together: an appropriate linker must release a payload after targeting a relevant protein. Just last month ADC Therapeutics ditched ADCT-502, an asset that like Kadcyla targeted Her2.

No doubt Takeda and Daiichi are paying attention. Asco updates are expected from clinical trials of their respective anti-Her2 assets trastuzumab deruxtecan and XMT-1522, licensed from Mersana Therapeutics, while Remegen, a virtually unknown Chinese group, will present several posters on another Her2-targeting ADC, RC48-ADC.

Immunomedics shines

The biggest spotlight might fall on Immunomedics’ sacituzumab govitecan, due to feature in the Asco presentation of data from HR-positive/Her2-negative breast cancer patients in a phase I/II basket study.

This company is notorious for having fended off the advances of Seattle Genetics almost exactly a year ago. The senior party had signed a deal over sacituzumab worth $250m up front, but this was scrapped with the help of a group of activist investors (Venbio completes its Immunomedics rout, May 5, 2017).

The deal’s termination lumbered Immunomedics with the cost of developing sacituzumab, and the project’s timeline has slipped – filing had been pushed back from late 2017 to early 2018, and was only submitted yesterday. Nevertheless, the market has reacted well, with Immunomedics stock almost tripling since May 2017; the shares rose 8% on the Asco abstract release last week.

Seattle had intended the Immunomedics deal to serve as part of a plan to diversify beyond Adcetris. That plan suffered another blow last year when the anti-CD33 ADC vadastuximab talirine was discontinued, and now rests on assets like enfortumab vedotin, which will feature at Asco in the setting of a urothelial cancer trial.

A January data cut 122 of 155 heavily pretreated subjects received the recommended phase II dose, yielding a 33% confirmed remission rate.

Don’t mention Rova-T

Attention will also fall on results of a study in several cancers of Pfizer/Abbvie’s cofetuzumab pelidotin, especially as this asset was originated by Stemcentrx, a group bought by Abbvie for $5.8bn.

Abbvie’s business development team was left with egg on its face when Stemcentrx’s lead ADC asset, Rova-T, crashed and burned in a small cell lung cancer trial in March. Cofetuzumab represents one chance for Abbvie to show that it had not thrown $5.8bn down the toilet, and Asco promises an update on remissions and survival beyond the October 2017 data cut cited in the abstract.

Also of interest will be the next big regulatory test of the ADC approach – Astrazeneca’s moxetumomab pasudotox, which has been filed for hairy cell leukaemia. Moxetumomab has a likely PDUFA date of October 3, and the Asco data will include an analysis of its pivotal ’1053 trial.

The recent ADC field might have more failures than successes to its name, but companies and investors have not given up yet. Selected Asco 2018 presentations on antibody-drug conjugates

Asco Project Company Target Payload Detail Trial ID abstract

Pivotal Moxetumomab hairly cell Astrazeneca CD22 PE38 NCT01829711 7060 pasudotox leukaemia trial

Basket trial, data Sacituzumab from Immunomedics Trop-2 SN-38 NCT01631552 1004 govitecan HR+/Her2- ve breast cancer

Forward II Avastin combo Mirvetuximab Folate Immunogen DM4 trial in Pt- NCT02606305 5549 soravtansine receptor α resistant ovarian cancer

Enfortumab Urothelial Seattle Genetics Nectin-3 MMAE NCT02091999 4504 vedotin cancer

Various Her2- Trastuzumab Topoisomerase expressing Daiichi Sankyo Her2 NCT02564900 2501 deruxtecan I inhibitor cancers (to be updated)

Her3- Topoisomerase expressing U3-1402 Daiichi Sankyo Her3 NCT02980341 2512 I inhibitor breast cancer

ORR & PFS, Cofetuzumab various Pfizer/Abbvie PTK7 Auristatin NCT02222922 5565 pelidotin cancers (Oct 2017 cut)

Various Mersana Her2- XMT-1522 Her2 AF-HPA NCT02952729 2546 Therapeutics/Takeda expressing cancers

Her2+ve RC48-ADC Remegen Her2 MMAE breast NCT02881138 1030 cancer

2nd-line Tisotumab Tissue Seattle Genetics MMAE cervical NCT02001623 TPS5601 vedotin factor cancer

Dose escalation Menarini/Oxford MEN1309/OBT076 CD205/Ly75 DM4 in NCT03403725 TPS2606 Biotherapeutics CD205+ve patients

This story was corrected to reflect the filing of sacituzumab govitecan. EP Vantage will be reporting from Asco, which begins in Chicago on June 1. For live tweets follow @ByAmyBrown and @ByJonGardner on Twitter.