CME
Physicians: Maximum of 0.25 AMA PRA Category 1 Credit™
Released: April 08, 2024
Expiration: October 07, 2024
Current Standard of Care for LA/Metastatic UC
Where are we now in regard to the current standard of care for locally advanced or metastatic UC?
Initial therapy for locally advanced/metastatic UC is often chemotherapy with either gemcitabine or cisplatin, or dosedense MVAC with growth factor support, followed by checkpoint inhibitor avelumab maintenance.5
Recently, 2 large randomized, phase III clinical trials demonstrated favorable efficacy with the use of gemcitabine and cisplatin plus nivolumab followed by nivolumab maintenance13; and another with enfortumab vedotin, an ADC targeting nectin‑4 with a payload of monomethyl auristatin E (MMAE), plus pembrolizumab (EVP) as first-line therapy for advanced UC.14
Secondline options generally include the first-line options that were not previously received.5 For example, this could be chemotherapy for patients who had previous EVP, or it could be EVP for patients who had prior nivolumab plus gemcitabine and cisplatin. Then, there is erdafitinib and sacituzumab govitecan, taxane-based chemotherapy, or a clinical trial.
It is not perfectly clear what the optimal second-line option should be, but for the best possible reason, which is that HCPs have excellent frontline therapies that continue to show promise.
Summary Data for Anti-HER2 Treatment in Recurrent mUC
There are currently no HER2-directed therapies approved in GU cancers, despite several trials testing agents such as lapatinib, afatinib, trastuzumab duocarmazine, and trastuzumab plus pertuzumab in patients with refractory, recurrent, and metastatic UC.1 The historical ORR in these trials has ranged from 0% to 25.0% in patients with recurrent/metastatic disease. All of these trials enrolled smaller numbers of patients, but the results are still quite clear in that we had not previously observed substantial efficacy advantage with traditional anti-HER2 therapy. However, there is much interest in exploring the newer class of anti-HER2 agents, the ADCs, in GU cancers.
Anti-HER2 ADC Therapies in Development for mUC
In 2024, there are 2 very promising ADCs in development for metastatic UC: T-DXd is an anti-HER2 ADC with a topoisomerase I inhibitor payload; and disitamab vedotin, which has an MMAE cytotoxic payload. Here, we will cover these 2 ADCs in more detail.
HER2-Targeted ADC: Trastuzumab Deruxtecan
In T-DXd, the antibody portion is an IgG1 monoclonal antibody targeting HER2 that is linked to the cytotoxic payload by an intracellular cleavable linker.15,16 This means that the linker is designed to hold on to the payload until the antibody is endocytosed into the cancer cell and then the payload is released. The payload in T-DXd is highly potent and membrane-permeable. The cytotoxic DXd has a short half-life, an intracellular cytotoxic effect on tumor cells, and a bystander killing effect on adjacent tumor cells.
Primary Analysis From T-DXd + Nivolumab in Patients With HER2-Expressing Urothelial Carcinoma
A multicenter, 2-part, open-label, phase Ib trial evaluated nivolumab plus T-DXd in a cohort of patients with advanced/metastatic UC who had not previously received T-DXd or immunotherapy (n = 31; NCT03523572).17
Part 1 of the study determined the most effective dose and the maximum tolerated dose of T-DXd in combination with nivolumab. Once the recommended dose for expansion was determined, patients with distinct eligibility criteria received 5.4 mg/kg of T-DXd in combination with nivolumab during part 2. The primary endpoint was ORR.
For this discussion, I will focus on cohort 3 (n = 30). These were patients with HER2 IHC of 3+ or 2+, indicating that they are high expressors after previous chemotherapy. In this cohort, the ORR was approximately 37% with complete responses observed in 13.3% of patients. It is important to note that although these results are promising, the response data are not as robust as we have come to expect with other immunotherapy combinations, such as EVP, but granted that’s in first-line advanced disease.14,18 Moreover, patients treated with nivolumab as single-agent treatment were included in this study making it close to impossible to decipher how much the ADC is contributing to the response we see vs what we would expect with single-agent nivolumab (ORR: ~30%).19
I think these results make it unlikely that HCPs would select this regimen of nivolumab plus T-DXd as their first-line immunotherapy combination, based on approved treatment options.5
Primary Analysis From T-DXd + Nivolumab in HER2+ UC: Safety Summary
The combination of T-DXd and nivolumab was found to be safe and well tolerated.17 However, these data are challenging to interpret, especially in regard to the novel ADC, because they only describe the incidence of toxicity, not duration or duration plus severity, which is what patients really care about. For example, if patients have 1 day of a severe adverse event (AE) and it then resolves, that could be acceptable, whereas years with a severe AE are not.
Overall, there was only 1 drug-related death. Among the 20% of patients who discontinued T-DXd, 17.6% did so because of a treatment-related AE. Dose reductions were limited, but dose interruptions were common, with 35% related to T-DXd and 20.6% related to nivolumab.
Efficacy and Safety of T-DXd in HER2-Expressing Tumors (DESTINY-PanTumor02): Study Design
Another study of T-DXd in HER2-expressing solid tumors was DESTINY-PanTumor02 (NCT04482309). In this study, investigators examined single-agent T-DXd in several advanced solid tumors not eligible for curative therapy; patients had received at least 2 previous therapies and had HER2 expression (IHC 3+ or 2+) performed locally. Previous HER2-targeted therapy was allowed. The primary endpoint was confirmed ORR by the investigator per RECIST v1.1.20
I am going to focus my discussion on the bladder cancer cohort. Patients enrolled in the bladder cohort had advanced UC with at least 2 previous therapies. Study participants were required to have IHC 3+ or 2+, indicating that they were biomarker selected to be of high likelihood to respond. The bladder cohort enrolled 41 patients who received T-DXd 5.4 mg/kg every 3 weeks.
DESTINY-PanTumor02: T-DXd Efficacy Summary
As shown in the slide on the right, the ORR was 39% among all patients with bladder cancer. Of note, ORR was highest in patients with IHC 3+ (56%) and appeared lower in patients with IHC 2+ (35%). I would say that bladder cancer is confirmed as a tumor type where T-DXd is relevant as a treatment in this population. The median DoR, PFS, and OS were 8.7 months (range: 4.3-11.8 months), 6.9 months, and 13.4 months, respectively. These data are very encouraging, although I would have liked to see a longer median DoR.
Overall, this was a relatively heterogeneous group in terms of how patients were qualified to be in the study. With the caveat about cross trial comparisons, I do not think that these data are applicable to what is currently available in this field. For instance, a limitation of this study is that patients in the bladder cancer cohort may have received chemotherapy or immunotherapy as part of their previous treatment but not previous EVP—which is the current standard of care.
DESTINY-PanTumor02: Safety Summary
Regarding safety, investigators in DESTINY-PanTumor02 examined all 267 patients enrolled for specific AEs of interest with T-DXd. One of these AEs was ejection fraction decrease, which occurred in 2.6% of patients, with only 1 patient (0.4%) experiencing a severe or grade ≥3 event. One patient (0.4%), probably the same one, experienced cardiac failure.
Another common AE of interest with T-DXd is interstitial lung disease (ILD)/pneumonitis. In all 267 patients, the rate of ILD/pneumonitis was 7.5% with only 1 instance of grade 3 or higher. I think dose modifications in these protocols are highly important as part of the AE prevention, mitigation, and management strategies.
Next-Generation ADC Disitamab Vedotin
The ADC disitamab vedotin also has a HER2-antibody moiety that is linked to the cytotoxic payload MMAE by an intracellular cleavable linker.21 It has intracellular cancer cell killing capacity as well as bystander killing effect on adjacent cells.
Efficacy/Safety of Disitamab Vedotin in HER2+ LA or Metastatic UC: A Combined Analysis of 2 Phase II Trials
A combined analysis of 2 open-label, multicenter, single-arm phase II clinical trials evaluating the efficacy and safety of disitamab vedotin in patients with HER2-positive (IHC 3+ or 2+) locally advanced or metastatic UC was published recently in the Journal of Clinical Oncology.22 In that study, patients with bladder cancer had progression after at least 1 previous line of systemic chemotherapy. Patients received disitamab vedotin 2 mg/kg intravenously every 2 weeks. The primary endpoint was ORR assessed by blinded independent review committee. Although these were 2 separate trials, they were designed relatively similarly and were pooled for analysis.
The median age of patients in the pooled analysis was 63 years, which is a bit younger than the greater bladder cancer population (average age at diagnosis is 73 years). Approximately 35% of patients had 1 previous line of therapy, suggesting that in those patients disitamab vedotin would have been introduced after either firstline checkpoint inhibitor therapy or firstline chemotherapy, as enfortumab vedotin plus pembrolizumab was not widely available at the time of this study. By contrast, approximately 65% percent of patients had 2 or more prior lines of therapy.
Approximately 25% of participants had previously received checkpoint inhibitor therapy. This is somewhat unusual in this setting because a patient who did not have a checkpoint inhibitor after being treated with chemotherapy would not yet go on to receive this targeted therapy—they would have received immunotherapy.5
Regarding the primary endpoint of ORR (n = 107), it was approximately 50%. In total, 32% of patients achieved stable disease as their best response, and approximately 18% experienced disease progression.
Phase II Study of Disitamab Vedotin: Responses
The figures on the right depict the data for depth of response and DoR. The image on the left shows the percent change from baseline in target lesion diameter with a remarkable depth of response.22
The image on the right shows the DoR achieved by most patients, with a median DoR of 7.3 months. We can see that for some of the patients the DoR was quite short, which I found surprising. Some patients did experience a longer DoR, but by 6 to 9 months most had lost their response.
Taken together, these results are interesting albeit in a population that is less heavily treated than would normally be enrolled in a similar trial conducted in the United States.
Other Disitamab Vedotin Trials in Pretreated LA or Metastatic Urothelial Cancer
Disitamab vedotin has also been examined in other phase II trials with smaller cohorts of patients (14-19) who had previously treated, locally advanced or metastatic UC. In patients with HER2‑negative disease (n = 19), however, the ORR was 26%. This is a somewhat counterintuitive result—but certainly very provocative—and more research is needed to better understand how HER2-negative tumors can respond to disitamab vedotin. Another phase II trial is exploring the combination of disitamab vedotin plus toripalimab, a PD-L1 inhibitor, in refractory metastatic UC, and there we see an ORR of approximately 80% in 8 of 10 evaluable patients, which could also reflect the small sample size of that study (n = 14).23
Disitamab Vedotin ± Pembrolizumab in HER2-Expressing Urothelial Cancer
There is an ongoing open-label, multicenter, multicohort phase II trial exploring disitamab vedotin with or without pembrolizumab in patients with HER2expressing locally advanced/metastatic UC (N = 332; NCT04879329). Patients in cohort A and B are allowed to have received previous platinum-containing chemotherapy, but those in cohort C are not. In cohorts A (HER2-positive; n = 75) and B (HER2-low; n = 75), patients receive disitamab vedotin monotherapy intravenously every 2 weeks. In cohort C (HER2-positive/HER2-low; n = 120), a nonrandomized subset of 20 patients received therapy with disitamab vedotin plus pembrolizumab to confirm safety; the remaining patients were thereafter randomized to either single-agent disitamab vedotin or disitamab vedotin plus pembrolizumab.24
Although the comparison of disitamab vedotin monotherapy vs disitamab vedotin plus pembrolizumab is relevant, this study is limited by small sample sizes. The cohort allocation or randomization is not powered to show statistically significant differences between the 2 treatment arms. However, I think the results of this study will provide clues as to how these agents work in this setting. Another criticism I have of this study design is that this setting may be obsolete by the time investigators report the results. I say this because first-line therapy already encompasses enfortumab vedotin with immunotherapy or chemotherapy, followed by immunotherapy, and patients would likely have had both of those treatments before getting to this point in their treatment algorithm.
When Should You Incorporate HER2 Testing in mUC?
Overall, there is much more to learn about these novel agents and how they work in our patients with advanced bladder cancer. The available clinical data for ADCs in bladder cancer specifically are limited by relatively small cohorts of patients, so it is difficult to draw meaningful conclusions. Future trials will need to enroll larger populations of patients in order to ascertain both the efficacy and AE profiles that are observed with these agents in patients with bladder cancer.
My present advice is to use HER2 testing to determine if a patient should consider a clinical trial. Most of the trials that I discussed selected patients with HER2 IHC positivity 2+ or 3+. Some studies allowed for FISH as a reflex test for IHC 2+ to drive eligibility, and only 1 enrolled patients who were HER2 negative. That was certainly an interesting trial with intriguing results, but I think most patients will require some level of HER2 expression to be considered for a trial. In all, if the patient is HER2-positive, I would consider a clinical trial of an anti-HER2 ADC. More clinical trials will be available for patients with metastatic UC, and there may be others that will open to patients with renal cell carcinoma or penile cancer as well.
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