ESMO is unstoppable in the field to hit the ADC, and a new generation is imminent

The 2022 European Society for Internal Oncology (ESMO) Annual Meeting was held
in Paris from September 9 to 13 local time.

Antibody drug conjugates (ADCs) are a hot spot in global oncology drug development in recent years, and the development of ADC drugs has enriched clinical treatment options, and a new generation of ADC drugs is also rising
.

ZW49

Zanidatamab Zovodotin (ZW49) is a novel bispecific antibody-drug conjugate (ADC) composed of the addition of the toxin MMAE to Zanidatamab, which uses the former's enhanced antibody internalization to deliver toxins to tumor cells and induce tumor cell death
.

DE cohort: in the 3+3 design, patients with HER2-positive cancer received ZW49 IV QW (3 weeks of continuous treatment, 1 week of rest; 1-1.

DX cohort: Patients with center-confirmed HER2-positive cancers and the presence of measurable lesions are treated
with ZW49 at the recommended dose (RD[s]) identified in DE.

As of 9 June 2022, there were 76 cases (DE[52] and DX[25]; Women: 58%; Median age: 59 years [range, 24-83]) receiving
ZW49.

Grade 2 [Gr] dose-limiting toxicity was observed in one patient, keratitis > for 14 days and remission to grade 1 (2.
5 mg/kg Q3W DX cohort).

70 (91%) patients experienced treatment-related adverse events (TRAEs); Most are level
1 or 2.
The most common TRAEs (20% of patients) include keratitis (43%), hair loss (25%), and diarrhea (25%)
.
9 (13%) patients developed ≥grade 3 TRAEs, including 2 grade 4 events (infusion-related reactions and decreased neutrophil counts
).
No interstitial lung disease and tumor-related deaths
have been reported.

Of the 29 patients who received ZW49 2.
5 mg/kg Q3W with a measurable efficacy, the ORR for multiple cancer types was 31% and the disease control rate (DCR) was 72%.

The study showed that ZW49 has a manageable safety profile with encouraging antitumor activity
in HER2-positive cancer patients receiving multi-line therapy.
ZW49 1.
75 mg/kg QW dose levels are continuing to be recruited in the DE cohort and 1.
5 mg/kg QW doses in the DX cohort are
being recruited.

DS-7300

B7-H3 overexpression is associated
with poor prognosis in a variety of cancers.
DS-7300 is a B7-H3-targeted ADC
with a topoisomerase I inhibitor payload (DXd).
Dose-exploratory studies of DS-7300 (NCT04145622) have shown that DS-7300 is well tolerated as well as antitumor activity
.
Investigators conducted extended cohort studies
in specific tumor types.

This Phase 1/2 first human study of DS-7300 recruited patients with tumors who did not select B7-H3 expression; The dose of 12.
0 mg/kg is used for ongoing extended cohorts
.
Efficacy/safety analysis included patients in the 4.
8-16.
0 mg/kg cohort; Efficacy
is evaluated after 2 baseline scans or in patients who discontinue the drug for any reason.

As of 30 June 2022, there were 147 patients (median age 66 years; 125 males) received treatment with DS-7300 (81 dose-increasing cohorts; Dose extension cohort 66 cases
).
The previous median number of treatment lines was 5 (range 1-14).

Remission was observed in 36/100 patients (36%) (11/19 patients with small cell lung cancer [SCLC]; 2/5 patients with squamous non-small cell lung cancer [sqNSCLC]; 18/54 patients with metastatic castration-resistant prostate cancer [mCRPC]; 5/22 patients with esophageal squamous cell carcinoma [ESCC]).

The overall safety profile is consistent with previous reports, with adverse events during treatment (TEAE) occurring in 98% of patients; The most common (>30%) were nausea (61%), infusion-related reactions (35%), and vomiting (31%)
.
The incidence of severe and grade 3 TEAE was higher in the 16.
0 mg/kg cohort compared with the 8.
0 and 12.
0 mg/kg cohorts
.

The study showed that DS-7300 has long-lasting antitumor activity in patients with SCLC, sqNSCLC, ESCC, and mCRPC who receive multiline therapy and is well
tolerated.
These data support further clinical studies of DS-7300, including Phase 2 dose optimization studies in SCLC (NCT05280470) with starting dose levels of 8 mg/kg and 12.
0 mg/kg
.

References:

1.
K.
Jhaveri,et al.
Preliminary results from a phase I study using the bispecific,human epidermal growth factor 2 (HER2)-targeting antibody-drug conjugate (ADC) zanidatamab zovodotin (ZW49) in solid cancers.
2022 ESMO.
Abstract 460MO.

2.
T.
Doi,et al.
DS-7300 (B7-H3 DXd antibody-drug conjugate [ADC]) shows durable antitumor activity in advanced solid tumors:Extended follow-up of a phase I/II study.
2022 ESMO.
Abstract 453O.