Jordyn Sava

In a recent interview, Sumanta K. Pal, MD, discussing promising clinical activity observed with the combination of the TKI cabozantinib (Cabometyx) and the immunotherapy atezolizumab (Tecentriq) in patients with metastatic urothelial carcinoma (UC) in the phase 1b COSMIC-021 clinical trial.

Pal, the lead author of the study and a professor in the Department of Medical Oncology & Therapeutics Research and co-director of the Kidney Cancer Program at City of Hope Comprehensive Cancer Center, shared results from the study at the 2022 ASCO annual meeting.

 The analysis included patients with inoperable locally advanced/metastatic UC who had transitional cell histology and an ECOG performance status of 0-1.

A total of 3 patients, 1 patient in cohort 3 and 2 in cohort 4, had complete responses, while partial responses were reached by 5 patients in cohort 3, 7 in cohort 4, and 3 patients in cohort 5, respectively. Further, the objective response rates seen in the trial were 20%, 30%, and 10%, and the disease control rates were 80%, 63%, and 61%.

What were the methods and design used within the COSMIC-021 study?

 The study is designed to test the principle that targeted therapy and immunotherapy have synergy. We started with dose escalation cohorts to make sure that cabozantinib and pembrolizumab are safe and combinable. Once we reached that we expanded to multiple different disease types where we thought that the combination would have activity. We've already published our results in kidney cancer. We have data that we've presented already in prostate cancer, [and] we have some data in platinum refractory bladder cancer. This represents some of the new data that we have for previously untreated bladder cancer.

To enroll in this study, many different tumor types are included, but in the specific cohorts that we focused on at ASCO 2022, again, patients had to have cisplatin-eligible status, cisplatin-ineligible status or have received a prior immune checkpoint inhibitor. These are patients with metastatic urothelial cancer, defined by the cisplatin eligibility as defined by conventional criteria.

Can you explain the safety and efficacy results seen in the trial?

In terms of efficacy, we determined that the response rate was 30%, 20%, and 10%, across the 3 cohorts ranging from cisplatin-eligible to ineligible to immune checkpoint inhibitor pretreated. In terms of some of the other data that we presented at the meeting, we have the median duration of response that we're reporting out within this cohort, which was 7.1 months amongst those patients that were cisplatin-ineligible, and 4.1 months in those that have received prior immune checkpoint inhibitors. This is what's really compelling. The median duration of response was not reached in those both patients that were cisplatin eligible. It is going to be interesting to see how that pans out.

We saw that the vast majority of patients of a cohort had some degree of tumor shrinkage with a combination irrespective of the cohort. In terms of progression free survival [PFS], the PFS in the cisplatin eligible cohort was 7.8 months. In the cisplatin ineligible cohort, it was 5.6 months. In terms of safety and tolerability, I thought that there weren't any unusual signals that you wouldn't expect from a caveat and that based immunotherapy combination. We have seen that data and renal cell, hepatocellular, and other diseases, so nothing that really stood out in my mind.

The study showed ultimately that in patients with cisplatin-eligible disease, the response rate was 30%, patients with cisplatin-ineligible disease response rate was 20%, and in patients who receive prior checkpoint inhibitors, this is a heavily pretreated population, the response rate was around 10%.

I think what's quite impressive is that patients, particularly in the cisplatin-eligible cohort, had a fairly substantial duration of response. It is going to be interesting to see how this data translates to studies that are looking at, for instance, tablets, and then with immunotherapy in the maintenance setting.

What advancements in research do you think are soon to come in the bladder carcinoma space?

I think we are quite excited at the prospect of being able to look at a combination of cabozantinib with immunotherapy as maintenance treatment for bladder cancer. There's a study that my colleague Shilpa Gupta at the Cleveland Clinic is running, looking nivolumab, which is now approved as a maintenance strategy in bladder cancer, plus or minus cabozantinib in a very timely study. Ultimately, I think that large definitive trials like that will establish the role of cabozantinib in bladder cancer.

1. Pal SK, Agarwal N, Singh P, et al. Cabozantinib (C) in combination with atezolizumab (A) in urothelial carcinoma (UC): Results from Cohorts 3, 4, 5 of the COSMIC-021 study. 

 40, 2022 (suppl 16; abstr 4504). doi: 10.1200/JCO.2022.40.16_suppl.4504

Articles

In the phase 1b COSMIC-021 trial, the combination of cabozantinib and atezolizumab showed clinical activity with manageable toxicity across several setting in urothelial carcinoma.

Dr. Sumanta K. Pal discusses promising immunotherapy/TKI combo in bladder cancer

A new database analysis presented at the 2022 AUA Annual Meeting showed that complementary approaches to quantifying overdiagnosis generated a more beneficial harm-benefit tradeoff of PSA screening compared with previous estimates that used shorter follow-up from the introduction of screening in Black patients with prostate cancer.

These data strongly support prostate-specific antigen (PSA) screening, particularly in Black men, for whom there is a paucity of clinical trial evidence, according to Spyridon Basourakos, MD, urology resident at New York Presbyterian Weill Cornell Medical Center, who presented the data.

The epidemiology of prostate cancer within the United States has been impacted by prostate-specific antigen screening. Because of persistent racial disparities in outcomes for Black men, re-examination within this patient population is needed to provide understanding of the harms and benefits of screening relative to cancer-specific mortality.

During the study, experts estimated both overdiagnosis and overtreatment for all races, including Black men ranging between 50-84 years of age until 2016, which was the most recent year with treatment data available. Investigators looked at the potential harms and benefits of this population based on screening for prostate cancer in the United States based on the Surveillance, Epidemiology, and End Results (SEER) registry and United States census data between 1986-2016. Further, an established microsimulation model of prostate cancer natural history was used.

By combining estimates with plausible mortality benefits, the numbers needed to diagnose (NND) and numbers needed to treat (NNT) were calculated in order to prevent prostate cancer deaths. Researchers looked at the ways in which all races, and specifically Black men, differ with prostate-specific mortality.

Patients of all races were evaluated, and findings estimated there to be 1.5-1.9 million (range between estimation approaches) overdiagnosed and 0.9-1.5 million overtreated prostate cancers in the United States by 2016. Over the period of 1986-2016, researchers looked at where PSA screening started, and the 2 estimation approaches produced similar age-standardized burdens of overdiagnosis.

Prostate cancer mortality showed an initial rise in and then declined relative to 1986, with 270,000 fewer deaths among men of all races and 55,000 fewer deaths among Black men. By assuming that half of the 270,000 total prostate cancer deaths that were avoided until 2016 were due to screening, the NND and NNT would be 11-14 and 7-11 for all races and 8-12 and 5-9 for Black men.

Further, the estimated NND and NNT for Black men reaches well into the low single digits when researchers account for the lag between incidence and mortality.

Overall, there was a greater benefit in NND and NNT was shown within Black men compared to all races. While a dramatic improvement was seen in prostate cancer mortality in Black men, comparing this rate of death to individuals of all races showed that there was a still higher than double mortality rate seen in Black men with prostate cancer.

Still, the need to quantify overdiagnosis, overtreatment, and the harm-benefit trade off in PSA treatment in Black men exists. More work is needed to be done to understand why Black men are having a significantly higher and dramatic mortality rate, according to Basourakos et al.

1. S Basourakos, R Gulati, R Vince, et al. Harm-to-Benefit of Three Decades of Prostate Cancer Screening in Black Men. Presented at: 2022 American Urology Association Annual Meeting; May 13-16, 2022; New Orleans, LA. Abstract LBA01-01.

The study data strongly support PSA screening, particularly in Black men, for whom there is a paucity of clinical trial evidence, according to lead author Spyridon Basourakos, MD. 

New analysis supports PSA screening for Black men

Treatment of advanced urothelial carcinoma (UC) with maintence avelumab (Bavencio) plus best supportive care (BSC) vs BSC alone was associated with prolonged overall survival, according to a recent study.

The findings were observed in patients with UC that has not progressed with first-line platinum-containing chemotherapy. The study, derived from long-term follow-up data from the phase 3 JAVELIN Bladder 100 trial (NCT02603432), was presented at the 2022 American Urological Association Annual Meeting in New Orleans, Louisiana.

These results further support the standard-of-care role of avelumab as frontline maintenance in this patient population, according to the authors, led by Petros Grivas, MD, PhD, global co-principal investigator on the JAVELIN Bladder 100 trial and associate professor and clinical director of the Genitourinary Cancers Program at Seattle Cancer Care Alliance, and associate professor, Division of Medical Oncology, University of Washington School of Medicine.

The multicenter, multinational, randomized, open-label, parallel-arm JAVELIN Bladder 100 trial examined avelumab plus the BSC vs BSC alone in patients with advanced UC that had not progressed with first-line platinum-containing chemotherapy.

A total of 700 patients with unresectable locally advanced or metastatic UC without disease progression with 4-6 cycles of first-line gemcitabine plus cisplatin or carboplatin were randomized in a 1:1 ratio to receive avelumab in addition to BSC or BSC alone. There were 350 participants per arm, 358 of which had PD-L1-positive tumors (51.1%).

In the experimental arm, arm A, patients were administered a 1-hour intravenous (IV) infusion of avelumab every 2 weeks in 4-week cycles along with the BSC which was administered as deemed appropriate by the treating physician, while arm B administered patients the BSC alone.

The primary end point of the study was OS as assessed from randomization to discontinuation from the study, death, or date of censoring, whichever occurred first, in all patients. Secondary end points included progression-free survival (PFS), safety, objective response, time to tumor response, duration of response, percentage of participants with disease control, and more.

With extended follow-up of a median 38 months in both arms for all patients and at a data cutoff of June 4, 2021, the OS was significantly longer in the avelumab plus BSC vs BSC alone arm in all randomized patients, as well as in patients with PD-L1-positive tumors. These findings remained consistent with previous conclusions, and an OS benefit was observed across prespecified subgroups.

PFS assessed by investigators was longer in patients administered avelumab plus BSC compared to those given BSC alone in all randomized patients and in patients with PD-L1-positive tumors. A total of 185 patients (52.9%) within the avelumab plus BSC arm and 185 patients (52.9%) in the BSC alone arm received a subsequent anticancer drug therapy, including a PD-L1 inhibitor in 40 (11.4%) vs 186 (53.1%) patients.

In regard to safety, long-term data was consistent with previous avelumab monotherapy studies, with no new safety signals.

Grivas P, Bellmunt J, Park SH et al. Avelumab first-line maintenance for advanced urothelial carcinoma: Long-term follow-up results from the JAVELIN bladder 100 trial. Presented at: 2022 AUA Annual Meeting; New Orleans, LA; May 13-16, 2022. Abstract PD10-02

A study of avelumab in patients with locally advanced or metastatic urothelial cancer (JAVELIN Bladder 100). ClinicalTrials.gov. Accessed May 12, 2022. https://clinicaltrials.gov/ct2/show/NCT02603432

The OS was significantly longer in the avelumab plus BSC vs BSC alone arm in all randomized patients, as well as in patients with PD-L1-positive tumors.

Prolonged overall survival is observed with maintenance avelumab in advanced urothelial carcinoma

In a recent interview, Matthew Galsky, MD, discussed the phase 1b DS8201-A-U105 trial, in which the combination of the antibody-drug conjugate trastuzumab deruxtecan (T-DXd; Enhertu) and the immunotherapy nivolumab (Opdivo) demonstrated antitumor activity in patients with HER2-expressing urothelial carcinoma (UC).

Galsky is a professor of medicine and director of genitourinary medical oncology at the Icahn School of Medicine, Mount Sinai, and the co-director of the Center of Excellence for Bladder Cancer and associate director for translational research at the Tisch Cancer Institute in New York City, New York.

Can you explain HER2 overexpression and its impact on patient prognosis?

 HER2 overexpression in urothelial cancer has been noted for quite a long time. HER2 is overexpressed in a subset of urothelial cancers at the protein level, and we know that it links to HER2 gene amplification in a subset of patients. HER2 mutations are also found in your local cancer. There are a range of HER2 alterations in urothelial cancer that have been attempted to be targeted with therapeutics over the years. Unfortunately, to date, there haven't been successes in translating HER2 overexpression, HER2 gene amplifications, HER2 genomic alterations at the level of the tumor with treatments, and that's changing recently.

What prior safety and efficacy results have been observed with nivolumab alone in this patient population?

Nivolumab is approved by the FDA for the treatment of metastatic urothelial cancers in patients who have progressed, despite prior platinum-based chemotherapy, and it is now approved in the adjuvant setting as well after surgery, cystectomy, or nephroureterectomy for patients at high risk for recurrence. In patients with metastatic urothelial cancer who have progressed despite prior platinum-based chemotherapy, nivolumab and other PD-1 and PD-L1 inhibitors in that space have been associated with objective response rates between about the 15-30% range depending on the study.

What's been observed in preclinical studies examining trastuzumab deruxtecan plus nivolumab for these patients?

We know that antibody-drug conjugates in model systems of cancer, and this includes several different antibody-drug conjugates in different model systems of cancer, we know that those seem to have some pro immunogenic effects that has potentially caused what's been referred to as immunogenic cell death. This is a specific form of cell death that leads to the release of dangerous signals that might result in activation of innate immune response and subsequently potentiate an adaptive immune response. There seems to be some evidence that that occurs in model systems with antibody-drug conjugates.

Of course, it occurs with a range of treatments and a range of chemotherapies, but there seems maybe to be something specific about antibody-drug conjugates that potentiates this effect. In combination with immune checkpoint blockade in model systems, there seems to be potentially at least additive effects and potentially synergistic effects combining that class of therapies with immune checkpoint inhibitors.

Can you discuss the design of the DS8201-A-U105 trial?

This was a phase 1B study and explored the combination of trastuzumab deruxtecan plus nivolumab in patients with metastatic breast cancer and in patients with metastatic urothelial cancer. Those were the 2 expansion cohorts in this study. The rationale for pursuing this in breast cancer is that anti HER2 therapies have a long track record of activity and breast cancer are standard treatments. This antibody-drug conjugate is explored extensively in breast cancer and has been approved in breast cancer so there was a rationale combining that class of drugs with immune checkpoint blockade in urothelial cancer is sort of the flip side.

We know that immune checkpoint blockade has activity in this patient population, and we know that HER2 is overexpressed, but there really haven't been anti-HER2 strategies that have shown activity in the clinic. Those were the 2 tumor types that were included in this phase 1B study for those reasons.

There was a small dose escalation in part 1 of this study, and then part 2 of this study explored the combination at the recommended phase 2 dose in those 2 different patient populations, but in four cohorts. Two of the cohorts enrolled patients with metastatic urothelial cancer, both of those cohorts enrolled patients who had progressed despite prior platinum based chemotherapy with metastatic urothelial cancer. But the difference between the 2 cohorts was that cohort 3 enrolled patients who had HER2 overexpression by immunohistochemistry at the 2+ or 3+ level, and the cohort for enrolled patients with HER2 overexpression at the 1+ level by immunohistochemistry.

What were the overall findings of the study?

The cohort of patients who had tumors with HER2 overexpression at the 2+ or 3+ level and enrolled 30 patients, cohort 3, interestingly showed that the cohort that enrolled patients with lower to expression that is 1+ overexpression enrolled only 4 patients, so that cohort was closed due to poor accrual. I say interestingly, because we think the HER2 1+ expression may be even more common than 2+/3+. Potentially, that reflected enthusiasm is on the part of investigators or your patients in terms of enrolling patients with lower levels of HER2 expression.

Now we know as the data have evolved with this antibody-drug conjugate in with some other antibody-drug conjugates that are similarly directed against HER2, we know that even with low HER2 expression, patients can benefit from treatment. Even though we only have a small cohort in this study, the same signal is being seen. Specifically, in cohort 4, which only enrolled for patients with HER2 1+ overexpression, 2 of the 4 patients had an objective response.

In cohort 3 that enrolled 30 patients with HER2 2+ or 3+ overexpression, the objective response rate was 36%. Even though I just said patients with HER2 1+ overexpression can benefit from treatment and can respond. When you look at the expression level of HER2, there does seem to be some association between the level of expression and the activity of the therapy in that in the small cohort of patients with HER2 3+ overexpression. Of the 8 patients enrolled in cohort 3, 5 of those 8 patients had an objective response, so small numbers, but there seems to be some relationship between the level of expression and likelihood of response even though patients with lower levels of expression can respond to treatment.

What treatment emergent adverse events were seen in patients and how are they managed?

The most common adverse events were fatigue, nausea, vomiting, diarrhea, and poor appetite. Side effects that we see in a lot of studies with cytotoxic therapy and that we also see in a lot of studies in patients with metastatic cancer that are potentially unique to this combination or to the individual components of the of the combination of trastuzumab deruxtecan can has been associated with interstitial lung disease or pneumonitis. Immune checkpoint inhibitors, PD-1 inhibitors, can also cause pneumonitis. That was an adverse event that particular attention to those events were centrally adjudicated. If there was concern about 1 of those side effects, it was reviewed centrally by a team, including review of the imaging.

There was interstitial lung disease or pneumonitis seen in this study. Among the 34 patients in combined cohorts 3 and 4, it occurred in 8 patients. Six of those 8 events were grade 1 or 2 in severity. There were very conservative guidelines in terms of management of those adverse events, including stopping treatment.

The other potential adverse event of interest with anti-HER2 strategies is a decrease in the cardiac ejection fraction. That was only seen in 1 patient of the 34 patients who were enrolled in cohorts 3 and 4. That event occurred after the patient had already been off treatment with trastuzumab deruxtecan, and they were continuing nivolumab as a single agent. That event occurred later and was somewhat atypical, but only occurred in that 1 patient.

Are there any ongoing clinical trials to further explore the role of T-DXd in this population right now?

In the study, this combination was pursued based on compelling scientific rationale. Prior to there being studies of single agent trastuzumab deruxtecan in this patient population so now there's actually a large basket study with trastuzumab deruxtecan that is enrolling patients with metastatic urothelial cancer, that study will establish the single Legion activity of this therapy.

What unmet needs would you hope that research focuses on in the near future?

We are seeing a couple of strategies directed against HER2 in urothelial cancer that are showing activity in the clinic. Therapies directed against HER2 have been explored for a couple of decades now in urothelial cancer without a lot of activity and without a lot of promise. I think we are now seeing that this target is credentialed in urothelial cancer, and it is a relevant therapeutic target. I think we will start to see a biomarker defined population of patients with urothelial cancer for whom treatment is directed against HER2.

1. Galsky MD, Del Conte G, Foti S, et al. Primary analysis from DS8201-A-U105: A phase 1b, two-part, open-label study of trastuzumab deruxtecan (T-DXd) with nivolumab (nivo) in patients (pts) with HER2-expressing urothelial carcinoma (UC). 

. 2022;40(6):438-438. doi: 10.1200/JCO.2022.40.6_suppl.438

In the DS8201-A-U105 trial, the combination of the antibody-drug conjugate trastuzumab deruxtecan and the immunotherapy nivolumab demonstrated antitumor activity in patients with HER2-expressing urothelial carcinoma.

Jordyn Sava

Articles

Dr. Sumanta K. Pal discusses promising immunotherapy/TKI combo in bladder cancer

New analysis supports PSA screening for Black men

Prolonged overall survival is observed with maintenance avelumab in advanced urothelial carcinoma

Dr. Galsky discusses combo of nivolumab plus trastuzumab deruxtecan in urothelial carcinoma