During a virtual Targeted Oncology Case-Based Roundtable event, Anish B. Parikh, MD, discussed front-line treatment options for metastatic urothelial cancer as well as the data supporting avelumab maintenance.
During a virtual Targeted Oncology Case-Based Roundtable event, Anish B. Parikh, MD, an assistant professor in the Division of Medical Oncology at The Ohio State University College of Medicine in Columbus, OH, discussed front-line treatment options for metastatic urothelial cancer as well as the data supporting avelumab maintenance.
Targeted OncologyTM: What are the frontline treatment options for patients such as this?
PARIKH: Cisplatin-based chemotherapy remains the preferred frontline standard of care for metastatic urothelial cancer. The most commonly used cisplatin-eligible regimens [are] dose-dense MVAC [methotrexate, vinblastine, doxorubicin, and cisplatin] and gemcitabine/cisplatin. The response rate and complete response [CR] rate [are higher] with dose-dense MVAC, although [there is a] relatively similar survival rate [15.1 vs 14 months].1,2
For the cisplatin-eligible patients, the 2 survival curves with the tail at the end of the curve suggest that with many years of follow-up in these larger phase 3 studies, there are some patients—not a lot, but some—[with] a more durable response.3
For the cisplatin-ineligible patients, the general preferred regimen is gemcitabine and carboplatin, which is [a regimen] associated with lower response rates, quite a bit lower in terms of CR, and also inferior survival [9.3 months]. And there is, you’ll note, no tail to that curve.
What other options should be considered?
Another thing that’s being looked at and was reported on earlier this year is chemoimmunotherapy. [Similar to] what’s being done in many other cancers, this combines platinum chemotherapy with an immune checkpoint inhibitor in the frontline setting. It’s still an investigational approach, but it is being studied as another possibility. So, there are a lot of unanswered questions, and I think that’s 1 of them.
Why is avelumab maintenance therapy preferred here?
JAVELIN Bladder 100 [NCT02603432] was the large phase 3 randomized study of avelumab [Bavencio] maintenance after first-line platinum chemotherapy for advanced urothelial cancer. Patients had to have had unresectable locally advanced or metastatic urothelial cancer, and they had to have received first-line chemotherapy, anywhere from 4 to 6 cycles of either cisplatin/gemcitabine or carboplatin/gemcitabine. And they had to have achieved either CR, partial response, or stable disease. So essentially, they had to have just not progressed during or after chemotherapy.4
The treatment-free interval was 4 to 10 weeks, so after chemotherapy, there was a 4- to 10-week period during which they were randomized. It was a 1:1 randomization to avelumab maintenance plus best supportive care versus best supportive care alone. The avelumab maintenance was 10 mg/kg intravenously [IV] every 2 weeks, and that was continued until progression, toxicity, or withdrawal.
The primary end point was overall survival [OS], and the secondary end points were PFS [progression-free survival] and objective response, as well as safety, tolerability, and some patient-reported outcomes. There was no crossover allowed.
The Kaplan-Meier curve for OS in the overall study populations [show] avelumab plus best supportive care [is] clearly superior to best supportive care alone, with a nice separation of the curves. These are some of the landmark analyses: at 1 year, the OS [rate was] 71% versus 58%, and at 18 months, the OS rate was 61% versus 44%. The median OS for avelumab maintenance was 21.4 months versus 14.3 months with supportive care alone, and there was a nice hazard ratio for survival with a very low P value [HR, 0.69; 95% CI, 0.56-0.86; P <.001].
[In terms of] the other efficacy outcomes that they looked at—PFS and response rate—overall, minimal but some benefit. I think [these] response rate data are difficult to interpret, because a lot of these patients were already in a deep response at the end of the study, which is not accounted for here….I would make the argument that, in my opinion, these other efficacy outcomes are not nearly as important, and I’m not sure how relevant they are. I think that a more meaningful end point is probably something [such as] maintenance of initial response.
Would any groups of patients benefit from avelumab maintenance therapy?
For almost all subgroups, the OS was improved with avelumab versus supportive care alone. This is based on age, performance status, chemotherapy regimen, response to chemotherapy, and creatinine clearance. There are a few areas where it’s a little less clear how much benefit there was. I think the most notable is PD-L1 status.
So, in PD-L1–positive patients, there was clearly an improvement in survival with avelumab. The hazard ratio was 0.56 versus the negative patients, [where the] hazard ratio was 0.86, with a confidence interval crossing 1, suggesting less significance. I think that’s interesting to see. But regarding the other subgroups and much of what we initially talked about in patients, regardless of their age, performance status, chemotherapy regimen they used, or the response to chemotherapy, there doesn’t seem to be any lack of benefit with maintenance avelumab. It seems to benefit everyone, regardless of those subgroups.
The question remains: Does PD-L1 matter in this approach? And, if so, how much and why? [In the] OS curves for the overall population compared with OS for the PD-L1–positive population, there was more separation between the curve and better numbers for the PD-L1–positive population.4,5 At [approximately] 36 months, median OS had not been reached for maintenance avelumab. But I think a thing that’s important to note, and we know this with some other cancers, is that the PD-L1–positive population seems to do better than the overall population, which includes PD-L1– negative patients, as well. Patients with PD-L1 positivity, even if they just received best supportive care, did better than the overall population.
What did the JAVELIN Bladder 100 trial show in terms of toxicity?
In terms of any-grade toxicity, 98% [of patients in the avelumab plus best supportive care] arm versus 77% in the best supportive care arm [had adverse events (AEs)].4 But if we’re talking about more serious grade 3 or higher AEs, [the results showed 47.4%] for avelumab and 25.2% for best supportive care. The most common grade 3 or higher AEs were urinary tract infection, back pain, hematuria, anemia, pruritis, and fatigue, and [they were] not profoundly different than what you see for best supportive care.
Interesting to note is that there is [approximately] a 10% rate of any-grade infusion-related reaction, which I haven’t seen with other immunotherapy agents nearly as commonly as with avelumab. These events led to discontinuation of the study drug, avelumab, in 12% of patients.
There were 2 deaths [grade 5 AEs] that were attributed to the study treatment in the avelumab arm. One patient died due to sepsis in cycle 10, and another patient had an ischemic stroke, which was 100 days after a single dose of avelumab.
For avelumab, the most common immune-related AEs are what are typical for immune checkpoint inhibitors. Thyroid disease, rash, colitis, pneumonitis, hepatitis—those are the most common of any grade but also of grade 3. There were no grade 4 or 5 immune-related AEs in this study. High-dose steroids were administered for an immune-related AE in 9% of patients who received avelumab.
How is avelumab now used in clinic?
The announcement from the FDA came in June 2020 that avelumab [was approved] for urothelial carcinoma maintenance treatment.6 This was based off the JAVELIN 100 study that was [presented at] an ASCO [American Society of Clinical Oncology] plenary presentation. It is approved for maintenance therapy for patients with locally advanced, or metastatic, urothelial carcinoma that has not progressed on first-line platinum chemotherapy. So, that is the official label.
Because of that, this is now in the NCCN [National Comprehensive Cancer Network] guidelines for first-line systemic therapy for advanced or metastatic disease, for cisplatin-eligible or ineligible patients, as long as they’re getting platinum-based chemotherapy, whether that's gemcitabine/cisplatin or dose-dense MVAC, or carboplatin/gemcitabine for cisplatin-ineligible patients. It is now approved as maintenance after chemotherapy in the NCCN guidelines.7
Why would you recommend a switch maintenance approach over a second-line therapy?
[I would recommend it because of] how it compares [with] saving the checkpoint inhibitor for the second-line setting, should the patient get there, in terms of OS. The survival curves [look better for the JAVELIN 100 study compared with KEYNOTE-045 (NCT02256436), the second-line pembrolizumab (Keytruda) study versus chemotherapy after progression on first-line chemotherapy]. The avelumab median OS was around 21 months, and for pembrolizumab in this study, [OS] is around 10 months.4,8
So, which treatment approach helps people live the longest? As many [individuals have] pointed out, this is oncology—OS is our gold standard end point. How do we choose among the different treatment approaches? How do we choose what’s best in terms of OS?
Elizabeth Plimack, MD, MS, presented at ASCO [and compared] a lot of these different regimens. [If] a patient gets first-line platinum-based chemotherapy, anywhere from 4 to 6 cycles, let’s say that takes 2 to 4 or 5 months. We know that [approximately] 15% of patients will immediately progress, either during or right after chemotherapy. And so, if they were to go on a second-line checkpoint inhibitor— be it pembrolizumab, atezolizumab [Tecentriq], any of the other checkpoint inhibitors—based on the studies, in terms of OS, those second-line checkpoint inhibitors have OS around 10 to 11 months, as a median. So, if you add that 10 to 11 months to this initial few months of chemotherapy, then an estimate for these patients, in terms of OS, is [approximately] 14 months.
Now, if you instead gave all the patients who did not progress initially—so, they either had stable disease or responded—maintenance checkpoint inhibitor with avelumab, you can see that the OS for that is another 21 to 22 months.
And so, if you add that to the initial duration of chemotherapy, then you’re talking an OS of 10 to 11 months longer [than without maintenance]. I think that [this] leaves out a potentially substantial number of patients, because these aren’t really the only 2 options we have. So, what this [comparison] is not talking about is the patients who had first-line chemotherapy and did not progress—they responded or had stable disease. They were on a period of observation, and then they started second-line therapy. Now, obviously, there are many patients who never get to second-line therapy. But, even if it’s 50% of your patients who do get second-line therapy, that’s a substantial proportion whose OS is going to be longer than this 14-month estimate, perhaps less than the 25 months on [avelumab], but those patients are likely somewhere in the middle. We know from studies using the median PFS from the initial chemotherapy studies that it could be anywhere from 3 to 10 months in addition to this 14 months, potentially.
1. von der Maase H, Sengelov L, Roberts JT, et al. Long-term survival results of a randomized trial comparing gemcitabine plus cisplatin, with methotrexate, vinblastine, doxorubicin, plus cisplatin in patients with bladder cancer. J Clin Oncol. 2005;23(21):4602-4608. doi:10.1200/JCO.2005.07.757
2. Sternberg CN, de Mulder P, Schornagel JH, et al; EORTC Genito-Urinary Cancer Group. Seven year update of an EORTC phase III trial of high-dose intensity M-VAC chemotherapy and G-CSF versus classic M-VAC in advanced urothelial tract tumours. Eur J Cancer. 2006;42(1):50-54. doi:10.1016/j.ejca.2005.08.032
3. De Santis M, Bellmunt J, Mead G, et al. Randomized phase II/III trial assessing gemcitabine/carboplatin and methotrexate/carboplatin/vinblastine in patients with advanced urothelial cancer who are unfit for cisplatin-based chemotherapy: EORTC study 30986. J Clin Oncol. 2012;30(2):191-199. doi:10.1200/JCO.2011.37.3571
4. 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):LBA1. doi:10.1200/JCO.2020.38.18_suppl.LBA1
5. Plimack E. Discussion of LBA1. Presented at: 2020 American Society of Clinical Oncology Virtual Scientific Program; May 29-31, 2020.
6. FDA approves avelumab for urothelial carcinoma maintenance treatment. FDA. June 30, 2020. Accessed February 1, 2021. https://bit.ly/3jaforD
7. NCCN. Clinical Practice Guidelines in Oncology. Bladder cancer, version 6.2020. Accessed February 1, 2021. https://bit.ly/39PQGtI
8. Necchi A, Fradet Y, Bellmunt J, et al. Three-year follow-up from the phase III KEYNOTE-045 trial: pembrolizumab (pembro) versus investigator’s choice (paclitaxel, docetaxel, or vinflunine) in recurrent, advanced urothelial cancer (UC). Ann Oncol. 2019;30(suppl 5):v336-v367. doi:10.1093/annonc/mdz249.018