AstraZeneca, Daiichi Sankyo show off ADC portfolio with safety top of mind

A tiny slice of early-stage data for AstraZeneca’s Daiichi Sankyo-partnered antibody drug conjugate showed a high objective response and disease control rate when combined with immune checkpoint inhibitor Imfinzi in patients with non-small cell lung cancer. (NSCLC).

The news comes two months after a phase 3 readout for the therapy, nicknamed Dato-DXd, spooked investors with data showing progression-free survival in lung cancer patients but also an undetermined number of fatal adverse events.

AstraZeneca and Daiichi Sankyo showcased their ADC work at the International Association for the Study of Lung Cancer 2023 World Conference over the weekend, including data for Dato-DXd, and Daiichi's patritumab deruxtecan and ifinatamab deruxtecan.

Starting with the former, initial results from just over two dozen patients in the phase 1b TROPION-Lung04 study found that Dato-DXd combined with Imfinzi with or without chemotherapy led to objective response rates of 77% and 50% and disease control rates of 92% and 93%, respectively. AstraZeneca said the results were encouraging and there were no new safety signals in the patients, who had previously untreated advanced or metastatic NSCLC without actionable genomic alterations.

Fourteen patients received the study drug plus Imfinzi, resulting in zero complete responses but seven partial responses.

AstraZeneca noted a higher response rate in the triplet arm, which saw 10 partial responses but still no complete responses in the 13 patients evaluated. The data is in its early stages, with just a few dozen patients from the two cohorts having reported so far. The partners ultimately plan to enroll 232 patients.

The results contrast with data released at the same conference last year combining Dato-DXd with Merck & Co.’s blockbuster Keytruda, with and without chemotherapy. The doublet showed an overall response rate of 37% while the triplet posted 41%. Both combinations had a disease control rate of 84% in the overall population for first-and second-line treatment.

The big question for Dato-DXd, a potential follow-up to breast cancer blockbuster Enhertu, is safety. In July, the partners reported that Dato-DXd significantly improved progression-free survival compared to the standard chemotherapy docetaxel in the phase 3 TROPION-Lung01 study. There was also “an early trend” towards overall survival. But investors were scared off by the safety data, with “some” of the phase 3 patients experiencing fatal adverse events. The adverse event of concern is interstitial lung disease, or ILD, which causes scarring and stiffness in the lungs.

AstraZeneca and Daiichi Sankyo have not released full safety data from the TROPION-Lung04 cohorts but said there were no new safety signals and no grade 5 ILD events—meaning no deaths from this known adverse event. There were four cases of ILD across the two cohorts that an independent committee determined were drug-related, including one grade 4 event, two grade 2s and one grade 1.

The companies have three phase 3 programs underway testing Dato-DXd as a first-line treatment for advanced or metastatic NSCLC without actionable genomic alterations. Evaluate recently projected worldwide product revenues of $2.6 billion by 2028 for the therapy if approved.

Elsewhere at the conference, Daiichi Sankyo showcased patritumab deruxtecan, or HER3-DXd, which demonstrated durable responses in patients with EGFR-mutated locally advanced or metastatic NSCLC after disease progression with other therapies in a phase 2 study called HERTHENA-Lung01.

The HER3-directed ADC had a confirmed objective response rate of 29.8% in a group of 225 patients, including one complete response, 66 partial responses and 99 cases of stable disease. The Japanese pharma also reported a median duration of response of 6.4 months and a disease control rate of 73.8%. The data, which cut off as of May 18, also showed median progression-free survival of 5.5 months and median overall survival of 11.9 months.

There was a low rate of patient discontinuations due to treatment-emergent adverse events and the safety profile was consistent with previous findings, Daiichi Sankyo said. But 64.9% of patients experienced treatment-emergent adverse events that were grade 3 or higher, including one death from ILD. There were 12 cases of ILD overall, the majority of which were grade 2 events. The most common events reported were low platelet counts, low white blood cell counts and anemia, among others.

Finally, ifinatamab deruxtecan, or I-DXd, had a confirmed objective response rate of 52.4% in 21 patients with heavily pretreated advanced small cell lung cancer during the dose escalation portion of a phase 1/2 trial. There was one complete response and 10 partial responses, with a median duration of response of 5.9 months. Median overall survival was 12.2 months as of Jan. 31.

While the ADC is aimed towards the B7-H3 protein and tumor reductions were seen across the trial, “no apparent trend of correlation between clinical efficacy parameters and B7-H3 protein expression was observed.”

Daiichi Sankyo is currently conducting a phase 2 study of I-DXd called IDeate-01.

Editor's Note: This story was updated at 3:48 p.m. ET on Sept. 11, 2023, to clarify that patritumab deruxtecan and ifinatamab deruxtecan are owned by Daiichi Sankyo.