Experts Review Important Treatment Options in Urothelial Cancer

Alan H. Bryce, MD

During a Targeted Oncology Case-Based Peer Perspectives Roundtable, two Mayo Clinic experts, Alan H. Bryce, MD, medical director, Genomic Oncology Clinic chair, Division Hematology/Oncology, Department of Internal Medicine, and Roxana S. Dronca, MD, chair, Division Hematology/Oncology, Department of Internal Medicine, discuss treatment options for a 66-year-old woman with urothelial carcinoma.

Targeted Oncology^TM: How do factors such as age, performance status, renal function, smoking history, and comorbidities affect your treatment?

BRYCE: When we’re considering treatment in urothelial cancer, renal function is often impaired or borderline because of the smoking history and the age of these patients. The primary consideration for the eligibility for treating with platinum is managing toxicity and risk.

What is the current standard for chemotherapy for patients with urothelial cancer?

BRYCE: Before the era of checkpoint inhibitors, it was all a conversation [focused on] chemotherapy, and it was the preferred regimen. The question was whether [to use] cisplatin versus carboplatin. Generally, cisplatin is always more effective than carboplatin, but it’s [also] more toxic. Dose-dense MVAC [methotrexate, vinblastine sulfate, doxorubicin hydrochloride cisplatin], gemcitabine/cisplatin, and gemcitabine/carboplatin [are some options].

What are your takeaways from this poll? Would you use avelumab (Bavencio) maintenance in this setting?

BRYCE: This is really the primary point of the data we want to look at—we are now in the phase of maintenance immunotherapy, which is based upon phase 3 clinical trial data that we will review.

Most people [chose] avelumab maintenance. [This patient has received] prior chemotherapy, and there are only 2 variances of treatment in the frontline setting, maybe 3, and it’s all platinum based. Ultimately, that doesn’t necessarily change whether we would consider avelumab maintenance or not, but…the point I’d make here is that the clinical trial data looked at using avelumab in patients who had at least stable disease or response.

But if the patient didn’t respond, then we’re not [considering] maintenance therapy anymore. Now you have progression and now you’re talking about second-line therapy. So, that is a different situation for which there are different data, but again, immunotherapy is certainly an [approved] option.

Roxana S. Dronca, MD

How does the patient’s response to previous treatment affect your decisions going forward? What data are there for maintenance with avelumab?

DRONCA: I think the most important thing that you would look at is [the type of] response that has been achieved with chemotherapy, [to see if they] at least [achieved] stable disease or an objective response. I also look at the comorbidities to identify if the patient is a candidate for immunotherapy.

The [JAVELIN Bladder 100] study [NCT02603432; of avelumab maintenance] looked at patients who received treatment in the metastatic setting, and I think a lot of [individuals] now extrapolate a lot of the data.1 If you start in first line with anon–platinum-based regimen…the main question here relates to patients who either received cisplatin- or carboplatinbased treatment.

The JAVELIN bladder clinical trial established the usefulness and the efficacy of maintenance avelumab in patients with advanced urothelial cell cancer.

What are the results from the JAVELIN Bladder 100 trial?

BRYCE: What this was [looking at] was taking avelumab and moving it up to be started immediately after induction chemotherapy as opposed to waiting for progression before starting immunotherapy in the second line.1 This is chemotherapy leading into avelumab. To prove that it should be moved up earlier, this randomized clinical trial looked at avelumab versus best supported care after 4 cycles of first-line chemotherapy. In this case, they allowed both carboplatin- and cisplatinbased chemotherapy.

The primary end point [was overall survival (OS)] in the PD-L1–positive population versus all randomized patients. Secondary end points looked at progression-free survival [PFS], safety, patient-reported outcomes, etc. Now, because this was with avelumab, the PD-L1 status was defined as PD-L1 expression on greater than or equal to 25% of tumor cells.

There was a clear advantage to using maintenance avelumab as opposed to waiting for second line, with median OS of 21.4 months in the avelumab arm versus the best supportive care alone, which was 14.3 months—a very strong result with a hazard ratio of 0.69 [95% CI, 0.56-0.86; P < .001].

The [Kaplan-Meier] curve showed that [61%] of patients [were] still alive [at 18 months]. About 40% of patients were still alive at 3 years…so [these were] strong data.

In the subgroup analysis, there was benefit [with avelumab] in every subgroup. The impact of PD-L1 status positive versus negative [showed that] even in the negative group, there still was an advantage favoring avelumab versus best supportive care alone. The hazard ratio was still strong. [Some in the negative subgroup hazard ratio] did cross 1.00 but…in a subgroup analysis there are no exceptions as far as you know for the various groups, whether it be age, performance status, creatinine clearance, etc.

These were encouraging results all the way around.

DRONCA: I would also comment that elderly patients, or patients [older than] 65 years, derived some benefit, and it is similar to what we see in our practice. I think going back 10 years ago, all of us had the idea that maybe elderly patients would not respond that well to immunotherapy because of the aging of the immune system and the immune response, but we see quite robust [efficacy] both in melanoma and gastrointestinal cancers for patients over [the age of] 65. I think this trial showed this, as well. I think this mirrors what we see in practice. Also, patients with lymph node–only disease respond quite well and with long duration of response, at least in my experience.

How did patients with PD-L1 expression of 25% or greater do with avelumab maintenance?

BRYCE: This is the idea of switch maintenance in patients with PD-L1 expression—in the first line, PD-L1 expression matters, but in the switch maintenance population, it really doesn’t matter. Whether it’s the overall population or the PD-L1 positive or negative, there was OS benefit seen in all groups. So, [determining] PD-L1 expression is not necessary to make the decision to put a patient on switch maintenance. It’s appropriate regardless [of whether the patients have expression].

The PFS improved [with avelumab], as one would expect. There is a stronger result in those with PD-L1 positivity [than the overall population], but it’s positive in both groups with good hazard ratios [overall HR, 0.62; PD-L1 positive HR, 0.56]. There [was] an improved response rate and more complete responses [in patients with] greater PD-L1 expression, but there was an advantage to [using] switch maintenance over best supportive care in the disease control rates [for both].

What were the adverse events (AEs) in JAVELIN Bladder 100?

BRYCE: The toxicities…were some fatigue, some cutaneous toxicity, and some pruritus. There was gastrointestinal toxicity, but it was largely grade 1/2. There was not a lot of grade 3 or greater toxicity. The strongest signal we see here is for UTIs [urinary tract infections], but that is only 4.4%, and even in the best supportive care population that was 2.6%. This is something that happens frequently in this population of patients. So, there were really no surprises in the toxicity data. It was consistent with what we know about PD-L1 inhibition and avelumab.

The immune-related AEs [included] hypothyroidism and endocrinopathies. These are the AEs that tend to be more lasting, but the other concerning ones are pneumonitis and colitis. There were low rates of grade 3 toxicities, only 7% overall. In this study, 9% of patients required high-dose cortical steroids for a time, but this is familiar [to most oncologists] and not out of bounds or unusual or difficult to deal with.

DRONCA: I think for avelumab, we do premedicate the first 4 cycles because of infusion reactions, but rarely do these lead to discontinuation of treatment or the patient’s inability to last between the second or third cycle. In general, they are manageable.

Has avelumab maintenance become a part of standard practice?

BRYCE: This regimen is FDA approved.2 Avelumab is now the only approved switch maintenance option for metastatic urothelial carcinoma [after] advanced chemotherapy.

It’s now also in the National Comprehensive Cancer Network guidelines.3 So, first-line therapy preference is to do a cisplatinbased regimen. If a patient is cisplatin ineligible, one could now consider the other checkpoint inhibitors, but only based on PD-L1 expression. The alternative is to go with carboplatinbased chemotherapy and then go into avelumab maintenance. In my experience so far, we haven’t seen any difficulty at all with the insurance approvals; the support for this was quick.

Do you see more patients going on switch maintenance as opposed to consolidation, or does consolidation still have a role in this setting?

BRYCE: These data involve patients with metastatic disease…. For symptomatic palliation you might treat it [differently], but apart from that in metastatic disease, I am largely going to avoid introducing any toxicity from surgery or radiation on the bladder, because I don’t think that it is going to [affect] OS. It is going to be a palliative measure, as is the case with all metastases. But if you are just talking about [a patient] with localized disease, we are still then talking about primary therapy, local therapy, surgery, radiation. We are not proposing at this point that systemic therapy is curative and using [systemic] therapy for the patients with localized disease.

DRONCA: I would say a scenario where I would consider radiation or surgery—and you still see this in other tumor types as well—[is] where a number of lesions respond to immunotherapy and 1 or 2 do not. Whether it’s penetration in the tumor or the microenvironment that is different in 1 metastatic site versus another, in the liver versus the lung [for example], we do at times go in and radiate that 1 lesion that doesn’t [respond] if there is overall a good response otherwise.

I wouldn’t completely exclude additional therapies, especially radiation plus immunotherapy. There is a bit of evidence of an abscopal effect for metastatic disease. I think it’s still possible in advanced [stages]. I would do it for palliation or for extraordinary responses if we are to truly consolidate.

How would you treat this patient if she progressed?

BRYCE: The issue of switch maintenance versus the second line…in the second line you start talking about an OS of about 10 months.4 When we talk about the switch maintenance, a majority of the patients [who received it] just after chemotherapy relapse within [21 months]....The sense is that there is a much greater benefit from introducing therapy earlier. The [OS] advantage of switch maintenance over best supportive care is on the order of 7 months as opposed to 3 for doing it in the second line….[Keep] in mind that [most] patients on the best supportive care in the JAVELIN study will go on to get immunotherapy later.

DRONCA: Putting all these data together for patients who respond to first-line platinum therapy and continue on immune checkpoint [inhibition], the survival of 21 months that we saw [with avelumab maintenance] plus the [2 to 5 months] of chemotherapy gives us an OS of 25 months for patients who are resistant to platinum-based therapy. There are 15% of patients who progress straight through treatment. [Looking] at the KEYNOTE-045 [NCT02256436] data in patients who relapse, the median OS of 10 months plus adding the [2 to 5] months of chemotherapy leads us to a survival of 14 months.

For the patients who progress or are ineligible for platinum-based therapy, the OS is much less. Atezolizumab [Tecentriq] in IMvigor130 [NCT02807636] was 16 months’ OS for patients who were ineligible for cisplatin with PD-L1 negative disease. In the KEYNOTE-052 trial [NCT02335424], the OS was 18.2 months.

_References:

_{1. Powles T, Park SH, Voog E, et al. Maintenance avelumab + best supportive care (BSC) versus BSC alone after platinum-based first-line (1L) chemotherapy in advanced urothelial carcinoma (UC): JAVELIN Bladder 100 phase III interim analysis. J Clin Oncol. 2020;38(suppl 18):LBA1. doi:10.1200/JCO.2020.38.18_suppl.LBA1}

_{2. FDA approves avelumab for urothelial carcinoma maintenance treatment. FDA. Updated July 1, 2020. Accessed December 1, 2020. https://bit.ly/2YENV8t}

_{3. NCCN. Clinical Practice Guidelines in Oncology. Bladder cancer, version 6.2020. Accessed December 1, 2020. https://bit.ly/2EC6Nhw}

_{4. Plimack ER. Checkpoint inhibition in metastatic urothelial carcinoma: timing is everything. Plenary session presented at: 2020 American Society of Clinical Oncology Virtual Scientific Program; May 29-June 2, 2020.}