Enhertu with Opdivo exhibited clinical efficacy with an ORR of 36.7% in HER2+ urothelial cancer in Phase Ib study

On the second day of ASCO-GU 2022, the rapid abstract session highlighted the results from the DS8201-A-U105 trial (NCT03523572; Active, not recruiting) of Enhertu (trastuzumab deruxtecan) with Opdivo (nivolumab) in patients with HER2 expressing urothelial carcinoma. The results which were presented at the ASCO-GU symposium were from cohort 3 of the U105 Phase Ib trial, and the objective response rate by independent central review (ICR) was 36.7%, with 13.3% patients experiencing complete response (CR) and 23.3% patients experiencing the partial response. The median duration of response (DoR) was 13.1 months, and the progression-free survival (PFS) was 1.9 months.

“The combination of T-DXd with nivolumab showed antitumor activity in patients with high-expressing HER2 Urothelial carcinoma. Ongoing clinical trials are further exploring the role of T-DXd in this population.” – Expert Opinion

Analyst Opinion: There has been a lot of discussions and progress in the field of HER2 breast cancer. HER2 overexpression has also been observed in a significant proportion of individuals with urothelial cancer. According to studies published, HER2 molecular alterations occur in up to 20–30% of bladder cancers, and urothelial carcinoma accounts for about 90% of bladder cancers. Despite such a significant contribution to the overall case burden, there appear to be no significant breakthroughs in this area. Sadly, there are no approved treatments that target this population. Many attempts have been undertaken, but the early generation HER2 ADC’s have failed to show meaningful efficacy. The majority of patients in this trial had at least some antitumor activity. Despite the study’s small sample size, there appears to be a link between the degree of response and the level of HER2 protein expression.

To conclude, these findings are vital because there is no alternative in the untapped market, establishing HER2 as an essential target in urothelial cancer. Moreover, the early promising signals also indicate that HER2 is a viable target for urothelial carcinoma.

Trodelvy builds up promise in second-line metastatic urothelial carcinoma in combination with Keytruda: TROPHY-U-01 study

Both of these combination products are already approved for UC treatment, and the company is trying to improve the efficacy of the combination products. Merck and Gilead have come forward to establish the efficacy of Trodelvy (sacituzumab govitecan) and Keytruda (pembrolizumab) in metastatic Urothelial cancer and have published the results from their cohort 3 results from the Phase II TROPHY-U-01 trial (NCT03547973), which has shown a 34% objective response rate (ORR) at a median follow-up of 5.8 months and an ORR of 38% among the evaluable patients. One patient experienced the complete response (CR), and 13 had experienced a partial response (PR), and 11 achieved the stable disease. The median PFS was 5.5 months. The 6-month PFS rate was 47%, and the median time to respond was 2.0 months (95% CI 1.3–2.8). The median duration of response and median overall survival in this trial have not yet been determined; however, two patients have had responses that have lasted more than a year.

“Sacituzumab govitecan in combination with pembrolizumab demonstrated encouraging ORR and CBR, with an overall manageable safety profile with no new safety signal in [checkpoint inhibitor]-naive [patients] who progressed after prior [platinum]-based chemotherapy.” – Expert Opinion

Analysts Opinion: Trop-2 overexpression is emerging as a promising biomarker in tumors since it is found in normal human tissues and is upregulated in malignancies like breast cancer, lung cancer, urothelial cancer, gastric cancer, colorectal cancer, pancreatic cancer, prostate cancer, cervical cancer, head and neck cancer, and ovarian cancer. Data suggests that Trop-2 overexpression has also been linked to poor outcomes among the abovementioned cancer patients. The promise of ADCs as a therapeutic strategy is tremendous, and it extends beyond the domain of oncology. Non-oncological illnesses (autoimmune and cardiovascular disorders, diabetes, and antimicrobial infections) are already being studied with ADCs. TROP2 ADC category, on the other hand, is underrepresented. Apart from Daiichi Sankyo/AstraZeneca [DS-1062 (Datopotamab deruxtecan): for NSCLC], hardly many companies are looking at the TROP2 ADC option. Since Trodelvy is only approved for Trop-2 in Urothelial Cancer patients who have previously received platinum-containing chemotherapy and either a PD-1 or a PD-L1 inhibitor, we believe this combination should be studied further.

Drug NameDeveloperTargetFirst FDA Approval YearApproved Indication Based on FDA label
AdcetrisTakeda/Seattle GeneticsCD30[A1] August 2011Hodgkin lymphoma, systemic anaplastic large cell lymphoma
KadcylaRoche/GenentechHER2February 2013HER2-positive breast cancer
BesponsaPfizerCD22August 2017Acute lymphoblastic leukemia
MylotargPfizerCD33Approved 2000, Withdrawn 2010; Reapproved September 2017Acute myeloid leukemia
LumoxitiAstraZenecaCD22September 2018Relapsed hairy cell leukemia
PadcevAgensys/AstellasNectin-4December 2019Solid and urothelial tumors
PolivyRoche/GenentechCD79June 2019Relapsed or refractory diffuse large B-cell lymphoma
TrodelvyImmunomedicsTROP-2April 2020Triple-negative breast cancer, urothelial and other cancers
BlenrepGlaxoSmithKlineBCMAAugust 2020Multiple myeloma
EnhertuAstraZeneca/ Daiichi SankyoHER2January 2021HER2-positive breast cancer
ZynlontaADC TherapeuticsCD19April 2021Large B-cell lymphoma
TivdakSeagenTissue factorSeptember 2021Metastatic cervical cancer