Hutson Considers Maintenance Treatment for Bladder Cancer Post Chemotherapy

Thomas Hutson, DO, PharmD

During a a Targeted Oncology Case Based Peer Perspectives event, Thomas Hutson, DO, PharmD, the director, Urologic Oncology Program cochair, Urologic Cancer Research Center, at Baylor University Medical Center in Dallas, TX, discussed the case of a 66-year old woman with bladder cancer that presented post chemotherapy.

Targeted Oncology™: When do you give platinum-based chemotherapy in the frontline setting for patients with bladder cancer? Which regimen do you use?

HUTSON: We generally feel that creatinine clearances above 45 mL/min would be good for platinum chemotherapy. When you start getting below 40 to 45 mL/min, the ability to give cisplatin reliably becomes challenging in that setting. It’s dealer’s choice; it really becomes about your own comfort level.

But looking at the cisplatin-based [regimens in a presentation of cross-trial comparisons from the 2020 American Society of Clinical Oncology (ASCO) Annual Meetin], you see the 2 [regimens]: the dose-dense MVAC [methotrexate, vinblastine, doxorubicin hydrochloride, and cisplatin] and [gemcitabine and cisplatin].¹ From the EORTC trials, there was a 72% objective response rate [ORR], a 25% complete response [CR] rate, and a median overall survival [OS] of 15.1 months [with MVAC]. Then gemcitabine and cisplatin [had a lower response], with a 49% ORR, a CR rate of 12%, and a median OS of 14 months.

Another trial compared MVAC versus gemcitabine and cisplatin. It was a noninferiority study, and it showed that gemcitabine and cisplatin was close to dose-dense MVAC in activity. The trial wasn’t completed, so it was underpowered, but that allowed people to feel more comfortable using gemcitabine and cisplatin.

For the median OS, there was about a month difference between the 2 [regimens].¹ But when you’re looking at tumor ORR, I feel that dose-dense MVAC gives you a better [response].

So, if I have a younger patient, I would generally lean that way. But those are the regimens we’ve used.

Then, for the patients who were cisplatin ineligible, there was definitely a reduction in benefit [with gemcitabine and carboplatin]. The median OS dropped off by 5 or 6 months, and the CR rate dropped, and the response rate dropped. So that’s clearly an inferior regimen.

What are the drawbacks of comparing trials in this way?

Because we’re [discussing] cross-trial comparisons, if you look at the cisplatin-ineligible population, you’re going to find a greater population that will have more comorbidities, impaired kidney function, and they’re going to have [a greater] volume of cancer. Really, the only way to compare them adequately would be to stratify for those factors in a randomized trial, but we don’t have that. But truly, the response rates are noticeably different, and that’s the bias that’s built into this kind of discussion; there’s a bias there. I think we agree that carboplatin is inferior, but the degree of inferiority could be questioned.

Would you give these regimens as adjuvant or neoadjuvant therapy?

A lot of people think of dose-dense MVAC in the neoadjuvant setting. Everything we use in the neoadjuvant setting is an extrapolation from the metastatic setting. We often think about [the scenario that] if someone was presenting to you with a curative-intent therapy goal, then give them dose-dense MVAC if they’re young and if it makes sense. I think we’re reminding ourselves that there’s a small group of patients who come in with metastatic disease that has spread beyond the lymph nodes or have lymph node metastases, who historically wouldn’t be offered surgery unless they had some type of response or CR to up-front chemotherapy. You would try to use dose-dense MVAC in that situation.

When do you offer surgery to patients in this setting?

At Baylor [University Medical Center], we tend to be a little bit more aggressive than our colleagues down in Houston. My colleagues there will sample anything suspicious, and if they find that there’s cancer or lymph node involvement, they will not plan on curative surgery; they will treat with 2 or 3 cycles of a chemotherapy regimen such as dose-dense MVAC or gemcitabine and cisplatin, and then they’ll sample the lymph nodes. If the lymph nodes still have any viable cancer, even if it’s microscopic, they will not proceed with surgery.

At Baylor, we don’t sample the lymph nodes. If we see enlarged lymph nodes, we will give something like 3 cycles of dose-dense MVAC or 3 or 4 cycles of gemcitabine and cisplatin. If we see some type of response there, we don’t sample; we go in and remove it. We cut it all out because we think that’s the only way to give the patient, in our opinion, the best chance of having the best disease control moving forward. I think that we see a difference in practice pattern there.

An example for me would be doing an evaluation before you give neoadjuvant chemotherapy and get scans done. Usually the urologist has only done an abdomen, pelvis, or chest x-ray, and you’re getting a CT chest and a bone scan, and you pick up some [small] nodules in the lung with uncertain significance, maybe some lymph nodes in the pelvis. [I would] move forward with chemotherapy and follow those [patients]. But I’m not going to play games with trying to do biopsies of the lung nodules after chemotherapy or try to base things on any type of response. I go forward [with surgery] if it’s an otherwise fit person. I let them know that [there is a concern with this], but if we don’t go for [it], we’re never going to get them to a good outcome.

If it looks like metastatic spread, then that’s a different story; we would go forward with chemotherapy, and we’re reassessing. If they have a great response or it’s a CR, then [we have to] make some type of decision about how to proceed forward at that point.

How have immunotherapies changed the landscape for bladder cancer?

I think there’s been some thought among the pharmaceutical companies and maybe in practice pattern that because we have immune therapy—because cisplatin can be so difficult to give, and you have drugs like pembrolizumab [Keytruda] and others that are approved for cisplatin-ineligible patients—that everyone is moving away from chemotherapy altogether and not even trying to give chemotherapy. They’re jumping right into immune therapy, but what I’m hearing in the community setting is that that’s not necessarily the case. [They are] still thinking about giving platinum-based chemotherapy up front and thinking about giving cisplatin if they can.

Do you agree with how this patient was treated?

She had 4 cycles. I only give 4; some people like to give 6. I’ve seen people give 8 cycles of therapy, but I think the standard generally is 4 [cycles].

What do you think of the responses to this poll?

Eighty percent are jumping into avelumab [Bavencio] maintenance therapy after 4 cycles of platinum chemotherapy. That’s the new standard of care we want to review. The other 20% said clinical trials, but no one is just doing observation. I think in the past, prior to ASCO this year and the plenary presentation [with] these data, we would have just observed. Unless you had a clinical trial, there was nothing. You would [hope] that your patient would have 4 to 8 months before they would have progression that would warrant more treatment.

Which factors influence your decision to use avelumab maintenance?

Chemotherapy regimens should not influence that....If these patients are platinum refractory, which is going to be a small percentage of patients, that is a negative prognostic sign. You would generally be moving them into second-line therapy, which is checkpoint inhibition. The number of cycles of first-line chemotherapy completed is unlikely an exclusionary component. We don’t test PD-L1 expression levels in bladder cancer. And then, for comorbidities, the only ones that we know about with the checkpoint inhibitors tend to be the autoimmune diseases. You would apply your normal criteria for using checkpoint inhibitors for this patient population.

Please describe the methods for the data presented at ASCO for avelumab maintenance.

The reason we’re all excited is because that, for the first time, are affecting survival in our patients and [achieving] recurrence free or disease control in our patients. The JAVELIN Bladder 100 trial [NCT02603432] was the avelumab maintenance trial after frontline platinum chemotherapy for patients with advanced 2 arms from each other to really figure out what the additive benefit of the treatment is.

My first take-home [message] when I look at [the treatment-emergent AE profile] is the high amount of toxicity from being on [best supportive care alone]. A lot of it seems to be grade 1 or 2, things like fatigue, urinary infections, and blood in the urine. It seems like patients who are receiving avelumab are having a greater incidence of grade 1 or 2 toxicities and even greater than or at least grade 3 than they are on best supportive care, so we would attribute an incremental increase of a variety of AEs to immune therapy.

About 12% of patients who were put on maintenance avelumab discontinued it because of treatment-emergent AEs. There was death attributed to 2 patients in the avelumab arm; 1 was due to sepsis at cycle 10, and another was ischemic stroke.

When we look at some of the immune-related AEs, which I know a lot of us focus on, none were grade 4 or 5. High-dose corticosteroids, which [the investigators] defined as greater than or equal to 40 mg of total prednisone daily or equivalent for modulation of an immune-related AE, was 9% of avelumab-treated patients. Avelumab has one of the lowest amounts of immune-related AEs that require steroid use. We know drugs such as pembrolizumab are a bit higher in corticosteroid usage. Avelumab is lower at 9%. And, if we look at the grade 3 AEs that are immune related, it’s pretty low; most of them are grade 1 or 2. There’s the traditional breakdown of thyroid, skin rash, low incidence of pneumonitis, colitis, liver transaminase, and myositis.

Is avelumab approved for use in this patient population?

Based upon this plenary presentation—it was late-breaking abstract number 1, so it was the highest-ranked abstract at ASCO this year—the FDA approved avelumab for urothelial cancer as maintenance on June 30, 2020.³ It was for patients who had unresectable locally advanced or metastatic disease that had not progressed with 4 to 6 cycles of first-line platinum therapy, which could have included carboplatin, based upon this trial. They needed to initiate therapy within 4 to 10 weeks of their last chemotherapy dose, and they were continued on the avelumab therapy until progression or unacceptable toxicity.

[Because of] the FDA approval, there was rapid uptake into the NCCN [National Comprehensive Cancer Network] guidelines.⁴ We have it listed on our McKesson guidelines now. It is listed as a preferred therapy following platinum-based chemotherapy with category 1. It’s even listed as preferred following dose-dense MVAC with growth factor support. For cisplatin-ineligible patients, they now have gemcitabine and carboplatin listed, followed by avelumab maintenance therapy as an arm that you could use. They also list the immunotherapies that could be utilized by themselves in that situation. This is the current guideline as of June 2020.

Based upon this, we would say that the new standard of care in this setting becomes maintenance therapy with avelumab for what appears to be a 4-to-5-month improvement in survival.

How does this switch maintenance approach compare with other options in bladder cancer, such as second-line treatment?

For the JAVELIN 100 pivotal trial versus KEYNOTE-045 [NCT02256436]…the OS curves showed that there was a 21.4- month median for all-comers [vs median OS of 10.1 months].1 [KEYNOTE-045 looked at] pembrolizumab versus chemotherapy postplatinum therapy after progression.

Looking at a sequence that yields the longest median OS, there are a couple of scenarios that I think will help solidify the benefits of doing maintenance therapy. If you go with your first-line platinum chemotherapy and then have progressive disease, you’re going into the checkpoint second line.

[As seen] from the pembrolizumab trial, patients are getting 10 months with pembrolizumab and 11.1 months for atezolizumab, [according to the IMvigor 211 (NCT02302807) data]. Adding up the estimated median OS is 14 months; if you’re sitting with first-line platinum 4 to 6 cycles, you get randomized then because you’ve had at least stable disease. For maintenance therapy, you’re getting 21.4 months with JAVELIN and 22 months in the pembrolizumab Hoosier Cancer Research Network GU14-182 trial [NCT02500121]. So it’s about a 25-month median OS.

_References:

_{1. 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. Accessed August 25, 2020.}

_{2. 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}

_{3. FDA approves avelumab for urothelial carcinoma maintenance treatment. FDA. Updated July 1, 2020. Accessed August 26, 2020. https://bit.ly/2YENV8t}

_{4. NCCN. Clinical Practice Guidelines in Oncology. Bladder cancer, version 6.2020. Accessed August 26, 2020. https://bit.ly/2EC6Nhw}