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Key Studies in Genitourinary Cancers: CCO Independent Conference Highlights of the 2021 ASCO Annual Meeting
  • CME

Daniel P. Petrylak, MD
Elizabeth R. Plimack, MD, MS
Released: September 7, 2021

Key Studies in Urothelial Cancer

KEYNOTE-052 5-Year Update: Study Design

Elizabeth R. Plimack, MD, MS:
KEYNOTE-052 was a critical study for our patients with urothelial cancer. This was one of the first studies looking at a single-agent immune checkpoint inhibitor for metastatic urothelial cancer.13-16 KEYNOTE-052 was a single-arm, open-label phase II trial, and patients (N = 370) had locally advanced/metastatic urothelial cancer with no prior systemic therapy and were cisplatin ineligible. This is a tough population of patients to treat. Patients in this study received pembrolizumab for up to 2 years of treatment or until disease progression, withdrawal, or noncompliance with trial procedures.

The primary endpoint in KEYNOTE-052 was confirmed ORR per Response Evaluation Criteria in Solid Tumors v1.1, and key secondary endpoints were PFS, DoR, OS, and safety.

At ASCO 2021, data from the 5-year follow-up for these patients were presented.13 These are the first data that give us a glimpse of that long-term survival, and we hope that we are curing some people in the metastatic setting with pembrolizumab.

KEYNOTE-052 5-Year Update: Baseline Characteristics

Elizabeth R. Plimack, MD, MS:
The patient population in KEYNOTE-052 reflects the population of cisplatin-ineligible patients with urothelial cancer whom I treat in clinical practice. The median age of patients in this trial was 74 years, and most patients (77%) were male. Also, approximately one third of the patients in this trial had a PD-L1 CPS ≥10.

In this trial, pembrolizumab infusions ended at 2 years. Here, 88% of patients discontinued treatment before Year 2 for reasons such as disease progression (59.5%), AEs (16.8%), and withdrawal (5.4%). So, only approximately 12% (n = 44) of patients completed the whole 2 years of therapy.

KEYNOTE-052 5-Year Update: OS

Elizabeth R. Plimack, MD, MS:
The median OS for the overall population in the KEYNOTE-052 trial was 11.3 months (95% CI: 9.7-13.1), and patients with CPS ≥10 (n = 110) had improved survival compared with patients with CPS <10 (n = 251). The median OS for those with a PD-L1 CPS ≥10 was 18.5 months (95% CI: 12.2-28.5) vs 9.7 months (95% CI: 7.6-11.5) for those with a PD-L1 CPS <10.

However, keep in mind that this is a discovery set and that the CPS scoring and cutoff, in particular, were developed based on the dataset generated by this trial in this group of patients. The validation set was built in, so we expect the biomarker to perform well in this study. Indeed, as we show here, it did.

KEYNOTE-052 5-Year Update: Response

Elizabeth R. Plimack, MD, MS:
At 5-year follow-up, the response data have not changed much. For all patients, the response rate was 28.9%. Again, we see a better response in patients with a PD-L1 CPS ≥10. ORR was 47% in patients with a higher CPS score compared with 21% in patients with a lower CPS score. The median DoR was 33.4 months (range: 1.4+ to 60.7+) for all patients and 21.2 months (range: 1.6+ to 59.7+) for patients with a CPS <10, and it was not reached for patients with a CPS ≥10.

KEYNOTE-052 5-Year Update: Safety

Elizabeth R. Plimack, MD, MS:
Single-agent pembrolizumab has been evaluated in many different malignancies and has been given to thousands of patients. The AE profile here is no different from previous reports. In total, 67% of patients experienced a treatment-related AE, with 21% experiencing a grade 3-5 treatment-related AE and 11.6% having a serious treatment-related AE. In this trial, 9.5% of patients discontinued treatment due to a treatment-related AE. The most common treatment-related AEs reported in KEYNOTE-052 were pruritis (18.4%), fatigue (18.1%), and rash (12.2%).

KEYNOTE-052 5-Year Update: Conclusions

Elizabeth R. Plimack, MD, MS:
One of the most compelling pieces of data from this longer-term follow-up of the KEYNOTE-052 trial is that, in the total population of patients who responded to therapy, 45% remained in response at 36 months, and 57% of those with a CPS ≥10 remained in response at 36 months.

This is why many oncologists are still leaning toward giving immune checkpoint inhibitor therapy early. We have patients who have been treated and responded, and are still alive and responding to an immune checkpoint inhibitor. The DoR data are a little less compelling than the OS data, but >20% of patients are surviving until 36 months—and that is something we have not previously seen in a cisplatin-ineligible population. This is a true breakthrough in treating urothelial cancer and has greatly improved outcomes for our patients who are ineligible for cisplatin-based therapy.

One caveat is that during the 5 years that we were following the KEYNOTE-052 cohort of patients, the JAVELIN Bladder 100 trial reported data showing that following either cisplatin- or carboplatin-based chemotherapy with maintenance avelumab resulted in impressive OS for patients with metastatic urothelial cancer who achieved a response to chemotherapy. But again, it behooves us to follow those data long term as well to better understand what the optimal approach should be.

Daniel P. Petrylak, MD:
I agree. Another question here is patient selection: For patients with a CPS <10, there is a 34% DoR at 36 months, and that is still pretty good. The question now is who are those patients who achieve a durable response? Do they have some defining characteristic, such as more disease or visceral disease?

From other immune checkpoint inhibitor studies in the second-line setting, we know that patients with visceral disease tend not to do as well as patients without visceral disease. So, I think we need a multivariate analysis of clinical characteristics and CPS score to determine which patients benefit from receiving an immune checkpoint inhibitor up front vs after chemotherapy to gain disease control.

Because of these data, I have more confidence in giving an immune checkpoint inhibitor to a patient with a PD-L1 CPS ≥10 up front. Although other patients also might benefit from this approach, I typically recommend chemotherapy for patients with a PD-L1 CPS <10 based on how quickly these patients can progress in various sites of disease.

KEYNOTE-045 5-Year Update: Study Design

Daniel P. Petrylak, MD:
The KEYNOTE-045 trial was a randomized, open-label phase III study that enrolled patients (N = 542) who had progression after 1-2 lines of platinum-based chemotherapy or disease recurrence <12 months after perioperative platinum-based chemotherapy.17-18 Patients were randomized to receive either pembrolizumab or single-agent chemotherapy with paclitaxel, docetaxel, or vinflunine.

The coprimary endpoints of KEYNOTE-045 were OS and PFS, and the key secondary endpoints were ORR, DoR, and safety.

KEYNOTE-045 5-Year Update: PFS

Daniel P. Petrylak, MD:
At the 5-year update, the KEYNOTE-045 PFS data are consistent with what we have seen before.17,19-20 At 12 months, the rate of PFS with pembrolizumab was 19% vs approximately 11% with chemotherapy. The median PFS with pembrolizumab was 2.1 months (95% CI: 2.0-2.2) and 3.3 months (95% CI: 2.4-3.5) with chemotherapy, with an HR of 0.95 (95% CI: 0.79-1.14). There was not a huge difference in PFS, and this was not unexpected with immune checkpoint inhibitor therapy. However, there is a small subset of patients who remain progression free for the remainder of follow-up.

KEYNOTE-045 5-Year Update: OS

Daniel P. Petrylak, MD:
The OS with pembrolizumab in the KEYNOTE-045 trial is impressive. At 36 months, the OS rate was 20.7% with pembrolizumab vs 11.0% with chemotherapy. The median OS was 10.1 months (95% CI: 8.0-12.3) vs 7.2 months (95% CI: 6.1-8.0) for pembrolizumab vs chemotherapy, respectively, with an HR of 0.71 (95% CI: 0.59-0.86).

Remember that when we think about cisplatin-based chemotherapy from the historical data, the OS rate after 5 years is approximately 5% to 10%. So, compared with that, these are impressive data.

KEYNOTE-045 5-Year Update: Response and OS by Best Response

Daniel P. Petrylak, MD:
With this update, the response patterns are consistent with what we have seen in previous reports.17, 19-20 The ORR was 21.9% (95% CI: 17.1%-27.3%) for pembrolizumab vs 11.0% (95% CI: 7.6%-15.4%) with chemotherapy. With pembrolizumab, 10% of patients achieved complete response, and 11.9% achieved partial response. In total, 17% of patients receiving pembrolizumab had stable disease. With chemotherapy, 3% of responding patients had a complete response, 8% had a partial response, and 34% had stable disease. Again, the results with chemotherapy are as would be expected.

The median DoR with pembrolizumab was almost 6 times that of chemotherapy at 29.7 months (range: 1.6+ to 60.5+) compared with 4.4 months (range: 1.4+ to 63.1+)

KEYNOTE-045 Update: Conclusions

Daniel P. Petrylak, MD:
In the KEYNOTE-045 study, the median OS was 10.1 months with pembrolizumab vs 7.2 months with chemotherapy. The ORR also was superior at 21.9% with pembrolizumab vs 11% with chemotherapy, with a DoR of nearly 30 months with pembrolizumab vs 4.4 months with chemotherapy. Also, no new safety signals with pembrolizumab emerged with the longer follow-up.

Here, I think the survival benefit is predicated on the longer DoR.

Elizabeth R. Plimack, MD, MS:
I agree. I think it is important to continue following the long-term outcomes. We give these immune checkpoint inhibitors more so for the long-term benefit than for the short-term benefit. We know that we can get better response rates, in some cases, with chemotherapy than with an immune checkpoint inhibitor, but we give pembrolizumab for the possibility that patients will do well for a long time. This follow-up shows that even in the platinum-resistant or refractory setting, we are achieving long-term benefit for a small subset of patients. I think KEYNOTE-045 is an important contribution to the field and again underscores the use of immune checkpoint inhibitor therapy after prior chemotherapy.

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