Immunotherapy Agents Leading Advancements in Metastatic Bladder Cancer

Joaquim Bellmunt MD, PhD

The therapeutic landscape is rapidly being altered by clinical trials of immunotherapy for patients with metastatic urothelial carcinoma (mUC), but simply changing the way quality of life (QoL) is monitored could provide dramatic improvements in overall survival (OS), according to findings presented at the 2017 Global Congress on Bladder Cancer.

Immunotherapy concerns regarding atypical responses and immune-related adverse events (AEs) must also be taken into account, experts added.

“The current standard of care in metastatic urothelial cancer is cisplatin-based chemotherapy, which provides a high initial response rate; however, these responses are rarely durable and the median OS is approximately 12 to 15 months,” said Joaquim Bellmunt MD, PhD, an associate professor of medicine at Harvard Medical School and director of the Bladder Cancer Center at Dana-Farber Cancer Institute.

“The 5-year OS rate with cisplatin regimens is only around 13%, indicating a high unmet need for new treatments,” he continued. “Furthermore, there is little consensus on how to treat metastatic urothelial cancer that has relapsed or is refractory to first-line platinum-based chemotherapy.”

Bellmunt added that taxanes are currently used in the United States, while vinflunine is commonly used in Europe. However, neither shows a statistically significant improvement in OS over best supportive care.

Bellmunt discussed the promising treatment of inhibiting the pathway regulated by PD-L1 and PD-L2, which are expressed on tumor cells and allow immune escape by binding to activated T cells. “Targeting PD-1 and PD-L1 has shown clinically meaningful antitumor activity,” said Bellmunt, adding that immunotherapeutic agents pembrolizumab (Keytruda), nivolumab (Opdivo), and atezolizumab (Tecentriq) are approved in the European Union for treatment of patients with mUC. During the congress, he provided an overview of second-line immunotherapy clinical trials, referencing the IMvigor210 trial of atezolizumab and the CheckMate-032 and CheckMate-275 trials of nivolumab, which have demonstrated objective response rates (ORR) of 15%, 25%, and 19.6%, respectively.^1,2,3

The issue of prognostic markers of response remained a major issue, citing IMvigor211 where an OS advantage was demonstrated for atezolizumab over chemotherapy in the overall population. However, this primary endpoint was not met in the subgroup of patients with higher PD-L1 expression on immune cells (IC2/3) as expected.

He explained that PD-L1 expression may be an unreliable marker for immunotherapeutic response and advised using the more traditional markers of ECOG performance scores of 0 to 1 versus 2, hemoglobin levels <10 versus ≥10, the presence of liver metastasis, and the time from last chemotherapy dose of <3 versus ≥3 months as better indicators of response. A combined positive score (CPS) of these factors that is indicative of poorer response was developed by his group. Regarding efficacy with pembrolizumab, mature results of the KEYNOTE-045 trial demonstrated an OS benefit with the PD-1 inhibitor over chemotherapy at a median follow-up of 22.5 months in both arms. The median OS was 10.3 versus 7.4 months with pembrolizumab and chemotherapy, respectively (HR, 0.70; P = .0003).⁴

Additionally, significantly improved OS was observed regardless of the level of PD-L1 expression, as measured by CPS, with patients having CPS ≥10% demonstrating a median OS of 8.9 with pembrolizumab versus 5.2 months with chemotherapy (HR, 0.58; P = .003).

KEYNOTE-045 also demonstrated a superior safety profile for pembrolizumab over chemotherapy, with 62.0% versus 90.6% of patients experiencing a treatment-related AE (TRAE), and 16.5% versus 50.2% of patients experiencing grade ≥3 AEs, respectively. Pembrolizumab was associated with a low rate of immune-related AEs, with hypothyroidism being the most often reported any grade (<10%) and colitis grades 3 to 5 being reported by <3% of patients.

In discussing trials of immunotherapy as first-line therapy in cisplatin-ineligible patients, Bellmunt noted that atezolizumab demonstrated median OS of 15.9 months overall in the IMvigor210 trial, but 12.3 versus 19.1 months, respectively, in the IC2/3 versus IC0/1 subgroups. He noted that the tumor mutation load (TML) was higher in responders versus non-responders across all subgroups, and patients with high TML also showed prolonged OS.⁵

“Data from studies of immunotherapy in the first- and second-line [setting] for treatment of patients with mUC are available and support immunotherapy as a promising new treatment for these patients,” Bellmunt concluded.

Robert Jones, professor of clinical cancer research, Institute of Cancer Sciences, Cancer Research UK Beatson Laboratories in Glasgow, Scotland shared insight on QoL considerations in patients with mUC by polling the audience on the methods used to assess QoL, with 85% responding that they made their own assessment during consultation, and just 6% said that they used trial-type questionnaires—such as EORTC or FACT&mdash;or patient-reported outcomes (PROs).

Jones said physician assessment offered the advantage of being quick and familiar, while pointing out that formal questionnaires are thought to be time consuming, and may not reveal the truth due to large inter-observer variability and imposed physician values. Questionnaires used in trials referred directly to the trial data, could be validated, and were quantitative, he added; whereas, they also had the disadvantage of being cumbersome for both patients and physicians and were not designed for routine care as they may impose research values.

Findings from a randomized trial of patients receiving chemotherapy for metastatic breast, lung, genitourinary, and gynecological cancer showed that patients using verbal or bespoken self-reporting (SR) had improved QoL at 6 months of 34% compared with 18% in patients having standard care (SC) physician assessments; QoL was unchanged in 23% versus 29%, and QoL was worsened in 38% versus 53% of SR versus SC patients, respectively. At 5 years, the SR group had also received fewer emergency rooms visits compared with the SC arm (P = .02). OS was improved by self-reporting; at over 8 years of follow-up, the median OS was 31.2 versus 26.0 months with SR and SC (HR, 0.832; 95% CI, 0.696-0.995; P = .03).⁶

“An OS improvement like this in a drug clinical trial would be significant and would cause quite a bit of excitement,” Jones noted.

Jones presented additional QoL data using the EORTC QLQ-C30 Global Health Scale from the KEYNOTE-045 trial, which revealed a significant improvement in time to deterioration with pembrolizumab over chemotherapy (P = .0012). Using the same scale, IMvigor showed improved QoL with atezolizumab, and CheckMate-275 showed improvements across the majority of QoL parameters by least means change from baseline with nivolumab.

“Improving and maintaining QoL is a primary treatment aim in mUC and immune checkpoint inhibitors have shown the potential to improve QoL outcomes; closer attention to PRO measures in routine practice may yield even better outcomes,” Jones summarized.

Methods to determine prognosis with treatment using immunotherapy in mUC were discussed by Shahrokh F. Shariat, MD, PhD, chairman, Department of Urology, Vienna Medical University General Hospital, in Vienna, Austria.

“Immunotherapy has changed our perception of mUC, which was a uniformly lethal disease to one with the hope of successful treatment; however, immunotherapy strategies might not be appropriate in the context of certain comorbidities or disease-related conditions,” Shariat said, adding that awareness of potential of immune-related AEs is crucial, as they can be severe enough to interrupt or end treatment.

Toxicity management requires response assessment and the recognition of unconventional responses, such as late response, psuedoprogression, and hyperprogressive disease (HPD), according to Shariat, who pointed out that biopsy reveals evidence of tumor growth in disease progression but will show evidence of T-cell infiltration with an unconventional response.

“Although clinical considerations currently driving our treatment decisions largely favor immunotherapy over chemotherapy, immune escape is an issue in successful immunotherapy. The future of overcoming immune escape is identification of a patient’s individual immunotype, which can affect treatment decisions to use immunotherapy alone or in combination,” said Shariat.

References

1. Hoffman-Censits JH, Grivas P, Van Der Heijden MS, et al. IMvigor 210, a phase II trial of atezolizumab (MPDL3280A) in platinum-treated locally advanced or metastatic urothelial carcinoma (mUC). J Clin Oncol. 2016;34(suppl 2S; abstr 355).
2. Sharma P, Bono P, Kim JW, et al. Efficacy and safety of nivolumab monotherapy in metastatic urothelial cancer (mUC): results from the phase I/II CheckMate 032 study. J Clin Oncol. 2016;34(suppl; abstr 4501).
3. Galsky MD, Retz M, Siefker-Radtke AO, et al. Efficacy and safety of nivolumab monotherapy in patients with metastatic urothelial cancer (mUC) who have received prior treatment: Results from the phase II CheckMate-275 study. In: Proceedings from the 2016 ESMO Congress; October 7-11, 2016; Copenhagen, Denmark. Abstract LBA31.
4. De Wit R, Vaughn DJ, Fradet Y, et al. Pembrolizumab (pembro) versus paclitaxel, docetaxel, or vinflunine for recurrent, advanced urothelial cancer (UC): mature results from the phase 3 KEYNOTE-045 trial. Abstract presented at: 2017 ESMO Congress; September 8-12; Madrid, Spain. Abstract LBA37.
5. Balar AV, Galsky MD, Rosenberg JE, et al. Atezolizumab as first-line treatment in cisplatin-ineligible patients with locally advanced and metastatic urothelial carcinoma: a single-arm, multicentre, phase 2 trial. Lancet. 2017;389(10064):67-76.
6. Basch E, Deal AM, Dueck AC, et al. Overall survival results of a randomized trial assessing patient-reported outcomes for symptom monitoring during routine cancer treatment. J Clin Oncol. 2017;35 (suppl; abstr LBA2).