Recap: Clinical Practice Experience With Avelumab First-Line Maintenance in Urothelial Carcinoma

For clinicians treating patients with locally advanced or metastatic urothelial carcinoma, merely considering the best first-line therapy is not enough; they also consider what can be done to extend responses and subsequent therapies in the natural course of the disease. Recent evidence supports use of first-line switch maintenance therapy, or “line 1.5,” with immunotherapeutic agents such as avelumab (Bavencio) that can lead to strong results in patients whose cancer responds to or remains stable following chemotherapy.

Daniel P. Petrylak, MD, professor of medicine (medical oncology) and urology at Yale School of Medicine and coleader of the Cancer Signaling Networks at Yale Cancer Center in New Haven, Connecticut, and Donald Barry Boyd, MD, MS, assistant professor at Yale School of Medicine, discussed the latest evidence surrounding avelumab maintenance for urothelial carcinoma during a recent edition of Between the Lines, hosted by CancerNetwork^®.

Current State of Treatment

Petrylak and Boyd began by reviewing treatment with cisplatin-based chemotherapies, including MVAC (methotrexate, vinblastine, doxorubicin [Adriamycin], and cisplatin) and cisplatin plus gemcitabine, which led to responses in about two-thirds of patients. However, Petrylak said responses tend to be short-lived. “Certainly, there is a need for second-line treatments, as well as treatments that may prolong the responses that are seen with either MVAC or gemcitabine and cisplatin,” he said.

The first immunotherapies for urothelial carcinoma were atezolizumab (Tecentriq) and pembrolizumab (Keytruda), which were approved by the FDA as second-line agents in 2016 and 2017, respectively.^1,2 They were later approved as first-line treatments for platinum-ineligible patients.^3,4

Boyd said many patients do not make it to second-line therapy because patients with urothelial carcinoma are often older with poor performance status and multiple comorbidities. By the time many patients experience progression, they are considered ineligible for second-line therapy. “We lose those patients to mortality, then we go on to supportive care,” he said.

Adding Avelumab as Maintenance Therapy

One strategy for boosting the number of patients who benefit from chemotherapy is to offer first-line switch maintenance with immunotherapies such as avelumab. “By giving checkpoint inhibition agents in this clinical setting within the time that these patients are having a response, you may actually receive more of a benefit from checkpoint treatment,” Petrylak said.

Boyd said chemotherapy and immune checkpoint inhibitors can work in synergy because chemotherapy can also have immunogenic effects. As chemotherapy damages tumor cells, it sparks enhanced expression of PD-L1, boosting sensitivity to PD-L1 inhibitors like avelumab. Chemotherapy also downregulates the cellular immune suppressive network, including T-regulatory cells and myeloid suppressor cells, which he said tend to be highly sensitive to gemcitabine.

“The regimens we’re giving [may be] downregulating numerous components of the checkpoints that block the immune response,” he said. “Then, you come in with avelumab, and you now have enhanced the sensitivity to the immune response.”

Assessing Outcomes

The phase 3 JAVELIN Bladder 100 trial (NCT02603432) studied avelumab plus best supportive care vs best supportive care alone in 700 patients with locally advanced or metastatic urothelial carcinoma.⁵ The study led to FDA approval of avelumab as first-line maintenance therapy following frontline platinum-based chemotherapy.⁶

In the study, patients received 4 to 6 cycles of either cisplatin plus gemcitabine or carboplatin. Those with complete or partial responses, or whose disease remained stable, were randomized to either treatment arm of intravenous avelumab at 10 mg/kg every other week along with best supportive care or best supportive care alone.

The avelumab arm had enhanced median overall survival compared with the control group at 21.4 months vs 14.3 months (HR, 0.69; 95% CI, 0.56-0.86;
P = .001). The benefit was seen in the PD-L1–positive subgroup as well (HR, 0.56; 95% CI, 0.40-0.79; P < .001).

In terms of safety, 77.3% of patients experienced treatment-related adverse effects (TRAEs) with avelumab, only 16.6% of which were grade 3 or above. Pruritus (13.7%), hypothyroidism (10.5%), diarrhea (10.2%), and infusion-related reactions (10.2%) were the most common TRAEs.

In their discussion, Petrylak and Boyd considered the implications of the study for clinical practice, a topic that was the subject of a 2021 review article in Cancer Treatment Reviews. Boyd said the study upends much of the thinking about therapy in this patient population, including the perceived superiority of cisplatin and gemcitabine vs carboplatin and gemcitabine.⁷ He added that it was exciting to see the regimen benefitting patients even if they were over 65 years and negative for PD-L1 expression. “We’re still coming to grips with the idea that some patients who are PD-L1 negative may still have an immune response,” Boyd said.

Petrylak said although clinicians might disagree about which chemotherapy regimen is best, the most important finding of the study is that first-line maintenance therapy should be part of the conversation. “When you get there, maintenance therapy is something we want to think about,” he said.

Advantages of Avelumab

Petrylak said one of the key advantages of “line 1.5” maintenance therapy is that it lowers the risk of patients dropping out of therapy. He noted that most patients who begin first-line therapy for metastatic urothelial carcinoma do not continue to second-line therapy.⁶

“By giving [maintenance therapy] earlier, you don’t have those [patients] drop out,” he said.

On the other hand, Petrylak notes that this strategy means subjecting some
patients to immune toxicities when they will not benefit from the therapy. He said that better understanding of this relationship is crucial and will allow patients to benefit from treatment.

Boyd said he was encouraged that the data suggest toxicities are usually minor.

“This is one of the therapies that is generally well tolerated with older patients.”

For Boyd, a major question going forward is just how long the treatment benefit will last. He said early indications are very promising. “We’re seeing extended potential long-term remissions in patients who get this. We can’t discount how important that is.”

Continuing Evolution in the Field

With checkpoint therapies presumably being moved into earlier stages of treatment, Petrylak said clinicians will need to grapple with the question of whether to use the same maintenance therapy if or when these patients become metastatic. “That really shifts your whole treatment paradigm, in terms of reinducing a patient with a checkpoint [inhibitor] after a certain period of time,” Petrylak said.

Boyd noted that evidence from lung cancer shows patients with limited disease in nodal areas can be successfully returned to checkpoint inhibitors following targeted therapy. “It depends on the nature of the response, whether you can control local disease through other means and then go back onto the checkpoint.”

Future bladder cancer treatment strategies may depend significantly on the results of ongoing clinical trials. A recent trial (NCT02500121) of pembrolizumab as a maintenance therapy yielded positive results, although Petrylak noted that its primary end point was progression-free survival, not overall survival.⁸

He added that a greater role for switch maintenance therapy will also have
implications for options like enfortumab vedotin (Padcev), erdafitinib (Balversa), or sacituzumab govitecan (Trodelvy), which can be used if patients progress on switch maintenance. “These will now be used earlier, and we need to make sure that physicians are aware that these treatments are available,” he said.

Both Petrylak and Boyd said this potential paradigm shift in bladder cancer also raises broader questions about the interplay between the immune system, tumor cells, and therapeutic agents.9 “[We] have to think bigger about how the immune response works,” Boyd said. “There [are] growing data and a lot of contributors.”

In the meantime, Petrylak said investigators and clinicians will have to be more forward thinking when sequencing agents. He likened it to planning for a trip to the moon.

“You don’t aim where the moon is now,” he said. “You aim where it’s going to be in 4 days. That’s where we have to start going with the field—thinking ahead about how we’re going to sequence these agents.”

References

1. Atezolizumab for urothelial carcinoma. FDA. May 19, 2016. Accessed April 15, 2022. https://bit.ly/3uIqYSr
2. Pembrolizumab (Keytruda): advanced or metastatic urothelial carcinoma. FDA. May 19, 2017. Accessed April 15, 2022. https://bit.ly/3rtaFHg
3. FDA grants Genentech’s Tecentriq (atezolizumab) accelerated approval as initial treatment for certain people with advanced bladder cancer. News release. Genentech. April 17, 2017. Accessed April 18, 2022. https://bwnews.pr/37mVx7s
4. FDA approved updated indication for Merck’s Keytruda (pembrolizumab) for treatment of certain patients with urothelial carcinoma (bladder cancer). News release. Merck. August 31, 2021. Accessed April 18, 2022. https://bit.ly/3Om4myG
5. Powles T, Park SH, Voog E, et al. Avelumab maintenance therapy for advanced or metastatic urothelial carcinoma. N Engl J Med. 2020;383(13):1218-1230. doi:10.1056/NEJMoa2002788
6. FDA approves avelumab for urothelial carcinoma maintenance treatment. FDA. July 1, 2020. Accessed April 15, 2022. https://bit.ly/36i6G8Z
7. ‌Grivas P, Agarwal N, Pal S, et al. Avelumab first-line maintenance in locally advanced or metastatic urothelial carcinoma: applying clinical trial findings to clinical practice. Cancer Treat Rev. 2021;97:102187. doi:10.1016/j.ctrv.2021.102187
8. Simeone JC, Nordstrom BL, Patel K, Mann H, Klein AB, Horne L. Treatment patterns and overall survival in metastatic urothelial carcinoma in a real-world, US setting. Cancer Epidemiol. 2019;60:121-127. doi:10.1016/j.canep.2019.03.013
9. Galsky MD, Mortazavi A, Milowsky MI, et al. Randomized double-blind phase II study of maintenance pembrolizumab versus placebo after first-line chemotherapy in patients with metastatic urothelial cancer. J Clin Oncol. 2020;38(16):1797-1806. doi:10.1200/JCO.19.03091