ASCO Preview: Major Solid Tumor Readouts Include AstraZeneca/Daiichi, Gilead ADCs

Therapies ranging from small molecules to immuno-oncology drugs will make appearances at the 2025 American Society of Clinical Oncology meeting. These include drugs that are seen as having the potential to cause shifts in clinical practice, to help their sponsors become bigger players in the oncology space or to find success in an immunotherapy class that has been marked by multiple failures.

AstraZeneca/Daiichi Sankyo Enhertu May Be Practice-Changing

One of the potentially practice-changing datasets slated for presentation at the ASCO meeting is from the Phase III DESTINY-Breast09 trial of AstraZeneca and Daiichi Sankyo’s antibody-drug conjugate (ADC) Enhertu (trastuzumab deruxtecan) combined with Roche’s HER2-targeting drug Perjeta (pertuzumab), in first-line treatment of HER2-positive breast cancer. When AstraZeneca and Daiichi Sankyo announced the interim analysis of the trial on 21 April, it marked the first time in more than a decade that a study showed superior efficacy to the standard of care in that population.

Enhertu already has US Food and Drug Administration approval for previously treated HER2-positive and HER2-low breast cancer, non-small cell lung cancer (NSCLC) and gastric or gastroesophageal junction cancer that expresses HER2, and other HER2-positive solid tumors. But an approval in first-line HER2-positive breast cancer is expected to serve as a major growth-driver for the product.

Daiichi Sankyo CEO Ken Keller said in an interview at the J.P. Morgan Healthcare Conference in January that approvals in first-line disease, along with adjuvant and neoadjuvant treatment, would more than double the ADC’s addressable patient population. The Phase III DESTINY-Breast11 trial is the companies’ study in the adjuvant setting and they announced positive results from that trial on 7 May, results that an analyst said could add about $2bn to its annual revenue.

In addition, AstraZeneca and Daiichi Sankyo plan to present data from the primary analysis of the Phase III DESTINY-Gastric04 study, which compares Enhertu against Eli Lilly’s Cyramza (ramucirumab) combined with paclitaxel in second-line HER2-positive unresectable or metastatic gastric and gastroesophageal junction cancer. The companies originally gained approval for Enhertu in gastric cancer based on the Phase II DESTINY-Gastric01 trial in January 2021.

Gilead Makes ASCENT In Triple-Negative Breast Cancer

Gilead Sciences plans to present primary results in a late-breaking abstract on 31 May from the ASCENT-04 study, also known as KEYNOTE-D19, comparing its ADC Trodelvy (sacituzumab govitecan) with Merck & Co.’s PD-1 inhibitor Keytruda (pembrolizumab) against Keytruda plus chemotherapy in patients with PD-L1-positive advanced or metastatic triple-negative breast cancer (TNBC).

The drug maker announced positive topline results from ASCENT-04 on 21 April, with superior progression-free survival (PFS) for Trodelvy/Keytruda compared with the Keytruda/chemotherapy arm, among patients whose tumors were PD-L1-positive, defined as a combined positive score of 10 or greater. The results also showed a favorable trend for overall survival (OS), but those data were not yet mature.

An analyst said at the time that the results boded well for ASCENT-03, a trial testing Trodelvy among metastatic TNBC patients who are not candidates for PD-1/PD-L1 inhibitor therapy due to being PD-L1-negative or ineligible to receive immunotherapy. And on 23 May, that prediction came true as Gilead said ASCENT-03 met its PFS primary endpoint.

Trodelvy’s main competition comes from AstraZeneca and Daiichi Sankyo’s TROP2-targeting ADC Datroway (datopotamab deruxtecan-dlnk), which the FDA approved on 17 January for previously treated HR-positive/HER2-negative breast cancer patients and is also in Phase III development for metastatic TNBC patients who are not candidates for immunotherapy.

PARP Inhibitor Plays Into GSK’s Oncology Comeback

Johnson & Johnson’s Akeega (niraparib) will feature in the Phase III AMPLITUDE study testing it in combination with abiraterone acetate (J&J’s Zytiga and generics) plus prednisone in patients with metastatic castration-sensitive prostate cancer (mCSPC) with alterations in homologous recombination repair genes. Metastatic CSPC accounts for about 15% of new prostate cancer cases in the US.

But niraparib, a PARP inhibitor, has played an even more important role for GSK, which markets the drug under the brand name Zejula for ovarian cancer and is in the process of staging a renaissance in oncology. GSK acquired niraparib’s original developer, Tesaro, in 2018, when it had an existing collaboration with J&J for the drug for prostate cancer.

Overall, GSK has been looking to make a comeback in the field, and the company’s global head of oncology, Hesham Abdullah, said as much in an interview when the company announced positive data from the Phase III DREAMM-7 and DREAMM-8 trials of the BCMA-targeted ADC Blenrep (belantamab mafodotin), a drug that the company had pulled from the US and other markets after it failed to meet its progression-free survival endpoint in third-line disease. But this time around, Blenrep outperformed well-established therapies like Johnson & Johnson’s CD38-targeting Darzalex (daratumumab) and Bristol Myers Squibb’s Pomalyst (pomalidomide).

On top of Zejula, Blenrep and the PD-1 inhibitor Jemperli (dostarlimab), GSK has also built out its oncology pipeline by in-licensing ADCs from Duality Biologics and Hansoh, as well as developing ADCs and T-cell engagers in-house.

Can AstraZeneca Break The TIGIT Curse?

When it comes to next-generation immune checkpoint inhibitors, the anti-TIGIT class has not had very much success. The most recent flop was belrestotug, which iTeos Therapeutics had been developing under partnership with GSK, a pact that the two discontinued after a Phase II non-small cell lung cancer study failed to meet efficacy expectations. However, a Phase III candidate from AstraZeneca and Compugen, the PD-1/TIGIT-directed bispecific antibody rilvegostomig, may offer some hope.

AstraZeneca plans to present data in posters from substudy 2, cohort A of the Phase II GEMINI-Hepatobiliary trial and from cohort 5 of the Phase III TROPION-Lung04 study of rilvegostomig and Datroway in advanced and metastatic NSCLC.

In TROPION-Lung04, in which 40 patients received the combination, confirmed overall response rate (ORR) for all patients was 57.5% and disease control rate was 95%, with responses seen in both squamous and non-squamous histologies. Among 30 patients with biliary tract cancers in GEMINI-Hepatobiliary, median PFS was 8.3 months, rate of PFS at six months was 73%, and ORR was 31%.

In a 23 May note, Leerink Partners analyst Daina Graybosch said the outcomes “suggest modest additive benefit from TIGIT when compared indirectly to anti-PD(L)1 benchmarks, though we continue to believe that the asset is set up for clinical success, and thus a royalty stream to Compugen.”

Arcus Looks To Stand Out In HIF-2α Space

Merck has managed to carve out a lucrative niche for itself with Welireg (belzutifan), its HIF-2α inhibitor for von Hippel-Lindau disease patients who require therapy for associated renal cell carcinoma (RCC), central nervous system hemangioblastomas or pancreatic neuroendocrine tumors, RCC and – most recently – pheochromocytoma and paragangioma (PPGL). But it may soon face potential competition in the form of Arcus Biosciences’ HIF-2α inhibitor, casdatifan.

Arcus plans to present data in an oral presentation from its Phase I/Ib study of casdatifan combined with Exelixis’s Cabometyx (cabozantinib) in clear cell RCC (ccRCC). According to the abstract, the ORR was 41% among 22 patients, including one complete response and eight partial responses.

Arcus has sought to differentiate casdatifan from Welireg amid Gilead’s decision not to opt in to develop the drug in February. Leerink’s Graybosch said the results “suggest positive differentiation,” boding well for the pivotal Phase III PEAK-1 trial.

[Editor’s note: This article has been updated to clarify the sponsor of the AMPLITUDE trial and the phase of DESTINY-Gastric01.]