Kyriakopoulos Reviews the Treatment Approach for Patients With Metastatic Bladder Cancer

During a Targeted Oncology Case-Based Roundtable event, Christos Kyriakopoulos, MD,, as associate professor at the University of Wisconsin Carbone Cancer Center in Madison, WI, discussed the case of a 66-year-old patient with metastatic bladder cancer.

Targeted OncologyTM: What is the best treatment approach for this patient? How many cycles of frontline cisplatin-based chemotherapy do you typically plan to use?

KYRIAKOPOULOS: Cisplatin-based chemotherapy remains the preferred first-line standard-of-care therapy for patients with metastatic urothelial carcinoma [mUC]. The overall response rates [ORRs] with dose-dense [DD] MVAC [methotrexate (Rheumatrex, Trexall), vinblastine (Velban), doxorubicin (Adriamycin), and cisplatin (Platinol)] compared with gemcitabine [Gemzar] and cisplatin, appear somewhat better. The ORR is 72% [for DD MVAC] vs 49% [for gemcitabine and cisplatin]. The complete response [CR] rate is 25% for DD MVAC vs 12% for gemcitabine plus cisplatin. The median overall survival [mOS] for both are not significantly different, ranging between 14 and 15 months.¹

It appears that for patients who receive cisplatin-based chemotherapy, there is a long tail in the Kaplan-Meier curves, even with prolonged follow-up. This means some of these patients will eventually achieve long-term remission. [On the other hand], carboplatin [Paraplatin] is considered an inferior regimen. The ORR is lower at 36%, the CR is 3%, and the mOS is 9.3 months. Patients who receive carboplatin-based chemotherapy have no long tail in their Kaplan-Meier curves.¹

How does the site of metastatic disease affect the decision of drug choice?

It appears that patients with visceral disease likely have a worse outcome. The question is whether we want to be more aggressive for patients who have poor-risk disease; otherwise chemotherapy works everywhere. It’s not like chemotherapy works better in visceral disease vs lymph node disease only.

Please discuss the poll results.

Preliminary data from phase 3 studies assessing immune checkpoint inhibitor [ICI] monotherapy, as well as in combination with chemotherapy vs chemotherapy either with cisplatin or carboplatin alone, in advanced UC showed a shorter OS with ICIs alone for the PD-L1–negative patients. For that reason, in this patient population, we tend not to offer them treatment with ICIs in the first-line setting. Full results from these studies also showed that neither pembrolizumab [Keytruda] nor atezolizumab [Tecentriq] monotherapy significantly improved the OS in the overall patient population, as well as for patients who receive ICI monotherapy alone.²

Another small phase 2 study, led by Matthew Milowsky, MD, and conducted through the Hoosier Cancer Research Network, randomized patients to chemotherapy plus pembrolizumab vs chemotherapy plus placebo. It showed an improved ORR for the patients who received pembrolizumab at 23% vs 10% for placebo and an improved progression-free survival [PFS] at 5.4 months vs 3.0 months, which was statistically significant. However, that was a relatively small study and it was underpowered, [which gave] a benefit to the mOS.³

What is the rationale for use of ICI maintenance after frontline chemotherapy for mUC?

Overall, the cytotoxic and immunogenic effects of chemotherapy, along with the antitumor activity, favorable safety profile of ICIs, and the immunogenic nature of bladder cancer, provide an excellent rationale for exploring ICIs as first-line maintenance therapy in locally advanced or mUC.⁴

The study schema of the landmark JAVELIN Bladder 100 study [NCT02603432] had avelumab [Bavencio] maintenance after first-line platinum therapy for advanced UC. Patients who received either cisplatin- or carboplatin-based chemotherapy with gemcitabine and achieved either CR, PR [partial response], or stable disease [SD] after 4 to 6 cycles were allowed to enroll, so this was a big study. They enrolled about 700 patients that were randomized 1:1 to avelumab maintenance plus best supportive care [BSC] vs BSC alone.

Patients were stratified based on the response to first-line chemotherapy into CR, PR, or SD, and based on the location of the metastatic tumor, either visceral or nonvisceral. Patients continued treatment until disease progression, acceptable toxicity, or withdrawal.

The primary end point of the study was OS, and there were 2 populations with all randomized patients as well as patients who were PD-L1 positive. In addition, there were several secondary end points, such as PFS [and] objective response for disease, safety, and tolerability, as well as patient-reported outcomes. In this study, no crossover was allowed.⁵ The avelumab plus BSC group had a mOS of 21.4 months vs 14.3 months for the BSC group alone. This was found to be statistically significant [HR, 0.69; 95% CI, 0.56-0.86; P < .001].⁵

From the other efficacy outcomes, I would like to focus on the PFS, both for the overall population [and] for patients who were PD-L1 positive. For the overall population, the PFS was 3.7 months for the avelumab group vs 2 months for the BSC alone group, which was statistically significant [HR, 0.62; 95% CI, 0.52-0.75; P < .001]. For the PD-L1–positive patients, the median PFS was 5.7 months vs 2.1 months, which, again, was statistically significant [HR, 0.56; 95% CI, 0.43-0.73; P < .001].⁵

The disease control rates for the avelumab arm [were] 41.1% vs 27.4% [for BSC] alone in the overall population, as well as 43.9% vs 27.8% for the PD-L1–positive patients. For disease control rate, it appears there’s no significant difference between the overall population and the PD-L1–positive patients.⁵ Patients who received avelumab did better, even though it appears that was not statistically significant [in some cases].

What are your opinions on the [JAVELIN Bladder 100] subgroups analyses? Is age an important factor, based on these results? If somebody is younger than 65 years, would you offer them avelumab maintenance based on these results?

It’s a small subgroup of patients. Again, it’s a positive study, so I’m not sure if looking at age-specific subgroups would [help us] make any sort of decision.

What about the PD-L1 studies? Would those affect your decisions?

The study was positive for the total patient population, and all-comers were allowed to enroll. It is important to mention that one of the interesting findings in the JAVELIN study was that the percentage of patients who were PD-L1 positive was higher compared [with] other studies with avelumab, or even other studies with immunotherapy.

Would you use the same data in the patients who have received DD MVAC rather than cisplatin therapy?

I know DD MVAC was not one of the regimens in the study. I think the rationale remains the same, meaning there are a lot of patients who receive first-line chemotherapy, and they end up not receiving maintenance therapy because we miss the window to offer them an active treatment. Basically, I don’t think there is any reason to make me think that patients who receive DD MVAC up front will not get the same benefit from maintenance avelumab as patients who receive cisplatin or carboplatin plus gemcitabine in the first-line setting.

What were the efficacy results for patients on this treatment?

The results of the PFS for the PD-L1–positive patients for the avelumab group [were] 5.7 months vs 2.1 months for the BSC group. At the time of the initial report, [the OS] was not reached for the avelumab arm vs 17.1 months for the BSC group, which was statistically significant [HR, 0.56; 95% CI, 0.40-0.79; P < .001].⁵

At the time of the report, 24.3% of patients who received avelumab were still on treatment, whereas 75.7% had discontinued that because of PD. [Of] these patients, 148 patients, which is 42.3% of the total study population, ended up receiving additional therapy, and small numbers received a different PD-1 or PD-L1 inhibitor. A few patients received an FGFR inhibitor based on molecular testing. About 40% of patients received different treatments, including chemotherapy, as well as investigational therapies.⁵ About 33.4% of the patients who received avelumab ended up not receiving subsequent therapy. However, in the patients who received BSC, at the time of the report, 92.6% had come off the study. Most of these patients ended up getting either a PD-1 or a PD-L1 inhibitor, and almost 31% of these patients ended up not receiving any subsequent therapy. About 60% or more of patients who received first-line treatment for metastatic disease ended up not receiving subsequent therapies.

What were the safety results?

The safety population included all patients in the avelumab group [and] patients in the control group that completed cycle 1 during a day 1 assessment. There were different adverse events [AEs], but it is important to mention that treatment-emergent AEs led to discontinuation of avelumab in only 11.9% of cases. There were 2 deaths attributed by the investigators to avelumab. One was due to sepsis and the other was due to ischemic stroke.5 Immune-related AEs [irAEs] are often seen with ICIs. Most common irAEs were related to either hypothyroidism or hyperthyroidism [and] skin reactions.

The scariest [AEs] from immunotherapy, such as pneumonitis, colitis, hepatitis, diabetes, and myositis, were very uncommon, especially the grade 3 AEs, which were less than 1% of AEs. No grade 4 or 5 irAEs were noted, and 9% of patients in the avelumab arm ended up receiving high-dose steroids.

Based on the results of the JAVELIN Bladder 100 study, avelumab maintenance is a category 1 treatment option [in the National Comprehensive Cancer Network guidelines] for patients with mUC who have received either cisplatin or carboplatin-based chemotherapy and have achieved at least SD. DD MVAC is included as one of the initial chemotherapy regimens for these patients.⁶

Does duration/number of cycles of frontline chemotherapy matter?

Based on the recent analysis of the JAVELIN Bladder 100 study, it appears the number of prior cycles of chemotherapy does not play a significant role in terms of benefits from maintenance avelumab.⁷

_REFERENCES:

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_{2. Galsky MD, Arija JÁA, Bamias A, et al. Atezolizumab with or without chemotherapy in metastatic urothelial cancer (IMvigor130): a multicentre, randomised, placebo-controlled phase 3 trial. Lancet. 2020;395(10236):1547-1557. doi:10.1016/ S0140-6736(20)30230-0}

_{3. 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}

_{4. 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}

_{5. Powles T, Park SH, Voog E, at al. Avelumab maintenance therapy for advanced or metastatic urothelial carcinoma. N Engl J Med. 2020;383(13):1218-1230. doi:10.1056/NEJMoa2002788}

_{6. NCCN. Clinical Practice Guidelines in Oncology. Bladder cancer, version 6.2020. Accessed October 21, 2021. https://bit.ly/3EXoOAw}

_{7. SA Hussain, JF Lester, R Jackson, et al. Phase II randomized placebo-controlled neoadjuvant trial of nintedanib or placebo with gemcitabine and cisplatin in locally advanced muscle invasive bladder cancer (NEO-BLADE). J Clin Oncol. 2020;38(suppl 6):438. doi:10.1200/JCO.2020.38.6_suppl.438}