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Immunotherapy and Antibody Drug Conjugates: Updates in Bladder Cancer

Presentation by Benjamin Garmezy, MD, Sarah Cannon Research Institute at Tennessee Oncology

The treatment of bladder cancer now incorporates advanced therapies, such as immuno-oncology (IO) agents, which stimulate the body’s immune system to attack the tumor, and antibody-drug conjugates, or ADCs, which deliver chemotherapy drugs to the tumor site in a very targeted and specific manner. At the 2022 OneOncology Conference in held in Nashville, Tennessee, Dr. Benjamin Garmezy from Sarah Cannon Research Institute at Tennessee Oncology discussed several updates in the treatment of bladder cancer using immunotherapies and ADCs.

Adjuvant Immunotherapy

Checkmate 274 was a trial that examined the use of an IO agent, nivolumab, in the adjuvant setting, for patients who had undergone surgery for muscle-invasive urothelial carcinoma (UC). This trial enrolled patients with or without expression of the nivolumab target, PD-L1, and the results showed better disease-free survival (DFS) for patients treated with nivolumab, as compared to those who received placebo in the overall population, and the benefit was slightly better in patients positive for PD-L1 expression on their tumors. Despite the overall positive results of the trial, however, Dr. Garmezy emphasized the need to carefully select patients in whom adjuvant IO therapy (generally consisting of 1 year of treatment after surgery) is used, as some patients can develop significant, and perhaps irreversible toxicities from IO therapy. He noted, for example, a lack of benefit observed in certain subgroups of patients within the Checkmate 274 trial, including those with “upper tract” UC (e.g., those with cancer of the ureter or renal/pelvis).

Beyond the location of the cancer (i.e., upper tract versus not), another more experimental aspect in patient selection for IO therapy involves the use of circulating tumor DNA, or ctDNA, as a means to detect so-called ‘minimal residual disease’, or MRD. Dr. Garmezy noted the results from a trial with another IO agent, atezolizumab, which showed that patients who were ctDNA negative (meaning no detectable ctDNA in their blood after surgery) did better than those who were ctDNA positive, regardless of whether they received adjuvant atezolizumab or not. By comparison, those who were ctDNA positive did benefit, significantly, from adjuvant atezolizumab use, both in terms of DFS, as well as overall survival (OS). As such, the results suggest that patients who are ctDNA negative have essentially been cured, and may not require further therapy, whereas those who are ctDNA positive after surgery would benefit. Despite the results, however, Dr. Garmezy noted that, while encouraging, further study is needed before ctDNA can be routinely used to make adjuvant and other treatment decisions in bladder cancer.

Antibody-Drug Conjugates in Metastatic Disease

For patients with metastatic UC (mUC), Dr. Garmezy outlined the overall treatment strategy, indicating that a first consideration is whether or not the patient is eligible for chemotherapy. In this regard, he noted that cisplatin chemotherapy is preferred over carboplatin, but not all patients may be eligible for cisplatin, depending on their renal function and other clinical factors. Second line therapy in mUC generally consists of immunotherapy, either in the maintenance or in the refractory setting. Thereafter, patients should be evaluated for biomarkers, such as an FGFR gene mutation, which would be an indication for the targeted agent, erdafitinib. If no such biomarker is present, he indicated that the ADCs enfortumab vedotin (EV) or sacituzumab govitecan (SG) would be a consideration for further treatment.

Dr. Garmezy noted results from JAVELIN Bladder 100, a trial evaluating maintenance IO treatment with avelumab (a PD-L1 inhibitor molecule) versus best supportive care (BSC) in patients with locally advanced or metastatic UC who did not have progression after first line chemotherapy. The results showed a significant benefit of avelumab maintenance therapy, in both the overall population, as well as in the subgroup of patients whose tumors were positive for PD-L1. He emphasized that while the benefit of this IO was again greater in PD-L1 positive patients, there was also a benefit in the “all comers” population, and as such this has become a new standard of care for patients with metastatic disease.

Dr. Garmezy also noted results for enfortumab vedotin (EV), an ADC which targets a molecule called Nectin-4, expressed in UC. He noted updated results from the EV-301 trial, which showed a significant benefit of EV over chemotherapy in median OS (12.9 vs. 8.9 months; hazard ratio [HR] = 0.70; P=0.00142) and a median progression-free survival (PFS) benefit of 5.6 vs. 3.7 months (HR=0.63). He also noted results of the phase II trial with EV (EV-201) which showed shrinkage of tumors in most (84%) of patients, and an overall response rate (ORR) of 55% in this very refractory patient population. With regard to adverse events, Dr. Garmezy noted potentially severe skin reactions such as Stevens-Johnson Syndrome, and other events such as peripheral neuropathy which necessitate careful monitoring of the patient while on therapy. Dr. Garmezy also noted the efficacy of EV in combination with the IO agent pembrolizumab (EV-103; Cohort A). In this study of 45 patients who were ineligible for cisplatin in the first-line setting, 93% of assessable patients had a reduction in their tumor volume; the ORR was 73.3% and 17.8% of patients had a complete response (CR). The median duration of response (mDoR) was 25.6 months, median PFS was 12.3 months, and median OS was 26.1 months. He noted that the efficacy of EV with pembrolizumab combination therapy (relative to chemotherapy alone) is currently being studied in another study, EV-302.

Dr. Garmezy also noted results with sacituzumab govitecan (SG), an ADC targeted against the cell surface protein Trop-2. In the TROPHY U-01 study (N=113 patients with prior chemotherapy and immunotherapy), SG resulted in an ORR of 27.4%, and a mDoR of 7.2 months, with GI and hematologic events and fatigue as the main toxicities. In more recent results, Dr. Garmezy highlighted the combination of SG with pembrolizumab in patients with mUC, which reported an ORR of 34% and a clinical benefit rate of 61%.

With regard to ADC target expression, Dr. Garmezy highlighted a small trial comparing the degree of expression of Nectin-4, TROP-2, and human epidermal growth factor-2 (HER2) in bladder cancer, noting a very high expression of Nectin-4 (~80-100%) and TROP-2 (~80%) in conventional urothelial carcinoma, squamous carcinoma, as well as the nested and micropapillary variants, with lower expression in tumors with small cell histology. He also noted that, although currently there are no ADCs targeting HER2 approved for use in bladder cancer, the study showed expression of HER2 in ~20-30% across many of the histologic variants. In this regard, he cited results for a new HER2-targeting ADC, disitamab vedotin (RC-48) in patients with UC; in this small study of 43 patients, 51% of patients had a partial response and 40% had stable disease, with a median PFS of 6.9 months, a median OS of 13.9 months, and a DoR of 6.9 months. Although further study is needed, he suggested that responses with this newer HER2-targeting agent have been much more encouraging as compared with historical results with agents targeting HER2 in bladder cancer. He also suggested that, although results cannot be compared across different clinical trials, there may be evidence for better responses with one type of payload, or chemotherapy used in the ADC backbone, versus another when combined with IO, with the MMAE payload resulting in ORRs of about 70%, while ORRs with the SN-38 payload were lower (about 30%). Forthcoming results from ongoing clinical trials should help to answer this question more definitively.

See more from the 2022 OneOncology Conference here.

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