There are currently 5 ICI’s approved for UC at this time, and he had a beautiful graphic demonstrating their targets and the clinical studies leading to their approval – and noted that Pembrolizumab and Atezolizumab had phase III trials completed.
He made an interesting point up front. While everyone tries very hard to find differences between the agents, in reality they are likely looking so hard into the data that they may be finding statistical differences where none truly exists. He noted that, in platinum-refractory advanced/metastatic UC, when taking into account 95% confidence intervals, all the agents had a relatively similar ORR of 15-25%. Ultimately, all we can tell is that these agents all seem to work, with a relatively similar ORR. And more importantly, the response rate of chemotherapy in platinum-refractory UC is lower at 10-15%.
He reviewed the two phase III trials for Pembro (Keynote-045) and Atezo (IMVIGOR 211), highlighting the primary endpoints and outcomes. He noted, as many have, that the Atezo study was a negative study for its primary outcome because it linked its primary outcome to PD-L1 positivity (based on phase 1/2 results), but this doomed the phase III study to failure – even though there is evidence that it is equally effective in the absence of PD-L1 staining.
In the setting of platinum-refractory mUC, the main take-home points:
1) All 5 agents likely have similar activity and should be considered first-line therapy
2) Pembro is the only study with Phase III data
3) The PD-L1 biomarker has no role
In the setting of platinum-naïve metastatic or advanced UC, the bar is much higher. Why? Because first line chemotherapy has much higher success in this setting – response rates between 40-60%. However, it has been demonstrated to be useful in cisplatinum-ineligible patients; as Dr. Powles indicated, carboplatin is not considered equivalent to cisplatin. Atezo (IMVIGOR 210) and pembro (Keynote-052) have both demonstrated success in this disease space. However, after reviewing the primary outcomes, he again noted that slight differences in the study population led to slight differences in outcomes – therefore, it is hard to choose one over the other.
In this setting, the main take-home point:
Carboplatin-based chemotherapy or ICI (pembro or atezo) are reasonable choices for cisplatin inelible patients. However, lack of data means that strong recommendations cannot be given.
His last talking points focused on the immune checkpoint inhibitor biomarkers. He reviewed the literature demonstrating inconsistencies between these biomarkers:
1) All the trials utilize their own assay and set their own cutoffs
2) In general, ORR to all-comers in these trials has been 15-25%, while ORR in PD-L1 positive tumors has been just slightly higher.
3) Even using the same drug / same assay, the results are not always reproducible
4) The same assay between disease sites (lung, bladder, head & neck) has sometimes between positive and has sometimes been negative
Main take-home point: The biomarkers are consistently inconsistent.
Presented by: Thomas Powles, MD Barts Cancer Institute, Longdon UK
Written by: Thenappan Chandrasekar, MD, Clinical Fellow, University of Toronto | @tchandra_uromd at the 2018 American Society of Clinical Oncology Genitourinary (ASCO GU) Cancers Symposium, February 8-10, 2018 - San Francisco, CA