During a Targeted Oncology Case Based Peer Perspectives event, Bradley G. Somer, MD, discussed the case of a 30-year-old patients with bladder cancer.
Bradley G. Somer, MD
During a Targeted Oncology Case Based Peer Perspectives event, Bradley G. Somer, MD, a hematologist and medical oncologist at the West Cancer Center & Research Institute in Germantown, Tennessee, discussed the case of a 30-year-old patients with bladder cancer.
Targeted Oncology™: How do the treatments for bladder cancer compare?
SOMER: The dose-dense MVAC [methotrexate, vinblastine, doxorubicin hydrochloride, and cisplatin] has a high response rate at 72%, 25% complete response [CR], but an overall survival [OS] of 15.1 months.1 Gemcitabine and cisplatin [has an overall response rate of] 49%—also a good response—CR at 12% and 14 months OS. With gemcitabine and carboplatin, [there was] a reasonable response, but it’s never durable. Generally speaking, it’s 9.3 months. The [data have] high selection bias between these studies, and they’re not compared head-to-head. The patients on gemcitabine and carboplatin are going to be less [responsive], but it’s a different patient population.
Some patients have durable responses with cisplatin, and so when you can give it, cisplatin is the one where we ought to be headed. That being said, some [physicians] may modify or fix their renal function first if there’s an obstruction or split those cisplatin doses at times. But that is the way to go. You have to sacrifice between MVAC and gemcitabine plus cisplatin…they basically [have] overlapping efficacies.
What data support these responses?
The JAVELIN 100 study [NCT02603432] for the bladder cohort was an interesting trial.2 These patients had to have frontline platinum-based therapy of either gemcitabine and cisplatin or gemcitabine and carboplatin. Then they had to have either a CR, partial response [PR], or stable disease and 4 to 6 cycles after. All patients had unresectable locally advanced or metastatic urothelial carcinoma.
This is a big study for bladder cancer, 700 patients. As long as they didn’t have progressive disease, they were randomized 1:1 to avelumab [Bavencio] maintenance therapy with 10 mg/kg every 2 weeks and best supportive care [BSC] versus BSC alone. They stayed on avelumab until progression, [unacceptable toxicity], or withdrawal. The patients were stratified by the degree of response and whether or not there was visceral metastasis. The primary end point was OS, and there were 2 populations that were analyzed. One was all-comers and the second was specifically the PD-L1–positive population. There were secondary end points of progression-free survival [PFS], safety and tolerability, and patient-reported outcomes data.
In the overall population, the OS hazard ratio was 0.69 [95% CI, 0.56-0.86; P < .001]. The median OS was 14.3 months in the BSC arm versus 21.4 months in the avelumab arm. The 18-month survival increased from 44% to 61% with avelumab.
If you look at all the prespecified subgroup analysis, it favored avelumab in all these prespecified subgroups, whether it was older or less than 55 years old, performance status, cisplatin or carboplatin; whether or not there was a PR or CR or stable disease; whether or not visceral or nonvisceral metastases; and what the creatinine clearance level was. They all favored avelumab. In addition, if you looked at PD-L1, whether the patient’s disease was PD-L1 positive or negative, there was clearly benefit with avelumab.
Does PD-L1 status influence in switch maintenance?
If you look at the OS in the PD-L1–positive group, the hazard ratio was 0.56 [95% CI, 0.40-0.79; P < .001]. In the avelumab arm, the median OS was not reached by the time of the study analysis. In the BSC arm, for the PD-L1–positive population, OS was 17.1 months. So, [this is] potentially prognostic information, but it doesn’t necessarily change the impact or the decision on whether to use avelumab.
What were the outcomes for the secondary end points?
The PFS was improved from 2.0 months to 3.7 months in the overall population and 2.1 to 5.7 months in the PD-L1–positive population [with BSC vs avelumab, respectively]. The hazard ratio was not too far off in each of those populations [HR, 0.62 in the overall group and 0.56 in the PD-L1–positive group].
The response rate, CR, and PR were higher in the avelumab arm. However, the question is: What is the role of response in this patient population? Because remember, we’re talking about maintenance therapy, and these are patients who have already seen a response from platinum-based therapy. In addition, the disease control rate was better and was also improved with avelumab over BSC in the overall and PD-L1–positive populations.
Treatment-emergent adverse events [AEs] caused the discontinuation of avelumab in 12% of patients, and 2 deaths were contributed to avelumab, 1 because of sepsis and 1 because of stroke. But, for the most part, it was relatively well tolerated. [There were] grade 1/2 toxicities, with grade 3 a bit higher [for avelumab] than BSC. These were patients who have a lot of comorbidities, and they are prone to other health situations. But there was a higher grade 3 urinary tract infection rate, as well as fatigue, anemia, and hematuria in the avelumab arm.
There were no grade 4 or 5 immune-related AEs, and there was a 7% [rate of] grade 3 immune-related AEs. That included thyroid dysfunction, rashes, colitis, increased alanine transaminase level, hyperglycemia, and myositis. For the most part, just 9% required high-dose steroids.
How does the National Comprehensive Cancer Network (NCCN) suggest using avelumab?
Based on the efficacy data and the reasonable toxicity profile, it resulted in FDA approval on June 30, a month after the American Society of Clinical Oncology Virtual Scientific Program.3 It was based on the efficacy of avelumab for maintenance therapy following platinum-based therapy.
The NCCN quickly updated their protocol and their recommendations, and it became standard.4 For cisplatin-eligible patients, it would either be gemcitabine and cisplatin or dose-dense MVAC followed by avelumab; for the platinum ineligible, gemcitabine and carboplatin followed by avelumab maintenance.
In the PD-L1–positive patient population, some studies show some efficacy for atezolizumab [Tecentriq] and pembrolizumab [Keytruda] as alternative possibilities. And then also, there are other chemotherapy regimens that are a possibility. Even in the platinum-cisplatin ineligible, gemcitabine and carboplatin followed by avelumab maintenance was also an option given.
Was there a reason avelumab was used as switch maintenance instead of in the front line or second line?
When you have a whole bunch of other immunotherapy checkpoint inhibitors that were already FDA approved, to get avelumab in, [the manufacturer had to] leapfrog it upstream. We designed this study to basically leapfrog it, and I think in this similar population, you had a similar situation where there are multiple checkpoint inhibitors; 5 different FDA-approved drugs.
If you look at JAVELIN 100, in the avelumab arm after chemotherapy, there was a 21.4-month survival [rate]. If you look at KEYNOTE-045 [NCT02256436], a phase 3 study after platinum progression—patients could have either responded and then had a chemotherapy holiday and then progressed or they progressed on platinum-based therapy—patients were randomized through either second-line chemotherapy or pembrolizumab. In the pembrolizumab arm, patients survived 10.1 months in that situation.1
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.
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