NICE Rejects Pembrolizumab for Urothelial Carcinoma

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The United Kingdom’s National Institute for Health and Care Excellence (NICE) has chosen not to recommend pembrolizumab (Keytruda) as a treatment for patients with locally advanced or metastatic urothelial carcinoma who have previously received platinum-containing chemotherapy.¹

The agency agreed that clinical trial evidence, some of which has been collected through the Cancer Drugs Fund, shows that pembrolizumab significantly improves overall survival (OS) compared with docetaxel and paclitaxel, which has been a standard treatment, for this patient population. However, no clinical or cost-effectiveness data are available to show the comparison between pembrolizumab and best supportive care in this population.

Additionally, it was determined that pembrolizumab meets NICE’s criteria to be considered a life-extending treatment at end of life, but that the cost-effectiveness estimates are uncertain since it’s unclear which model of OS is most appropriate, or how long pembrolizumab’s benefit will continue.

“Even when pembrolizumab is offered with its agreed discount, the most plausible cost-effectiveness estimate remains above what NICE normally considers acceptable for end-of-life treatments,” NICE stated in its appraisal consultation document.

The decision is not intended to affect treatment with pembrolizumab that was initiated in the Cancer Drugs Fund (CDF) before this guidance was published. In the CDF, pembrolizumab will continue to be funded by Merck, the developer of the PD-1 inhibitor, until patients and their National Health Service (NHS) clinician choose to discontinue therapy.

The current indication in the NHS for pembrolizumab is for the treatment of patients with locally advanced or metastatic urothelial carcinoma who have received platinum-based chemotherapy. The PD-1 inhibitor is currently indicated at a 200 mg every-3-week dose intravenously (IV), or 400 mg IV every 6 weeks until disease progression or unacceptable toxicity.

Merck currently has a commercial agreement in which pembrolizumab is made available to the NHS at a discount, and would have been applied to its current indication if it had been recommended by NICE.

Clinical evidence for the decision came from the open-label, randomized, phase III KEYNOTE-045 trial, in which patients with urothelial cancer who progressed on a platinum-containing regimen were randomized to receive pembrolizumab or investigator’s choice of paclitaxel or docetaxel.

Moreover, in May 2017, the FDA approved pembrolizumab for the treatment of patients with locally advanced or metastatic urothelial carcinoma who have disease progression during or following platinum-containing chemotherapy, or within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy.

Simultaneously, the FDA granted an accelerated approval to frontline pembrolizumab for patients with locally advanced or metastatic urothelial carcinoma who are ineligible for cisplatin-containing chemotherapy.

The second-line approval is based on earlier findings from the phase II KEYNOTE-045 study, in which pembrolizumab monotherapy led to a 27% reduction in the risk of death compared with chemotherapy in patients with advanced urothelial carcinoma whose disease progressed after prior treatment.²

In the KEYNOTE-045 trial, investigators enrolled patients with locally advanced or metastatic, unresectable urothelial carcinoma of the renal pelvis, ureter, bladder, or urethra who had progressed after 1 to 2 lines of platinum-based chemotherapy or who had experienced recurrence after 1 year of chemotherapy.

A total 542 patients were randomized to receive pembrolizumab at 200 mg IV every 3 weeks for 2 years versus chemotherapy consisting of either paclitaxel at 175 mg/m², docetaxel at 75 mg/m², or vinflunine at 320 mg/m² every 3 weeks for 2 years. The median age of patients was 67 years in the pembrolizumab arm and 65 years in the chemotherapy cohort.

The treatment groups were well balanced for 4 key prognostic factors: hemoglobin level (>10 g/dL vs ≥10 g/dL); ECOG performance status (0/1 vs 2); liver metastases (yes vs no); and time from last chemotherapy dose (<3 vs ≥3 months).

The primary end points were OS and progression-free survival (PFS) in the total population, as well as among participants with a combined positive score (CPS) ≥10% for PD-L1 expression.

Results showed that the median OS for patients receiving pembrolizumab was 10.3 months (95% CI, 8.0-11.8 months) versus 7.4 months (95% CI, 6.1-8.3 months) for those who received chemotherapy (HR, 0.73; 95% CI, 0.59-0.91; P = .004). The survival benefit was observed regardless of PD-L1 expression status.

However, the median PFS was not superior with pembrolizumab by the time of data cutoff. The median PFS was 2.1 months (95% CI, 2.0-2.2 months) with the PD-1 inhibitor versus 3.3 months (95% CI, 2.3-3.5 months) with chemotherapy (P = .42).

In patients with CPS ≥10%, the OS analysis showed that there was a 43% reduction in the risk of death with pembrolizumab versus chemotherapy (HR, 0.57; 95% CI, 0.37-0.88; P = .0048). The median OS was 8.0 months (95% CI, 5.0-12.3 months) with pembrolizumab versus 5.2 months (95% CI, 4.0-7.4 months) with chemotherapy.

Moreover, the objective response rate (ORR) was 21% with pembrolizumab versus 11% with chemotherapy (P = .002); the complete response (CR) rate was also much higher with pembrolizumab at 7.0% compared with a 3.3% CR with chemotherapy.

The median duration of response (DOR) with pembrolizumab was not reached (range, 1.6+ to 15+ months); an estimated 68% of responders were considered likely to maintain a response for ≥12 months. In the chemotherapy arm, the median DOR was 4.3 months (range, 1.4+ to 15.4+ months) with an estimated 35% likely to maintain a response for ≥12 months.

Regarding safety, patients who received pembrolizumab had fewer toxicities than those treated with chemotherapy. The incidence of treatment-related adverse events (AEs) was lower with pembrolizumab compared with chemotherapy, respectively, for any grade (60.9% vs 90.2%) and for AEs of grade 3 to 5 severity (15.0% vs 49.4%).

Treatment-related AEs (TRAEs) occurring in ≥10% of participants were generally lower with pembrolizumab as opposed to chemotherapy, respectively, including for fatigue (13.9% vs 27.8%), nausea (10.9% vs 24.3%), diarrhea (9.0% vs 12.9%), asthenia (5.6% vs 14.1%), and anemia (3.4% vs 24.7% with chemotherapy).

The incidence of pruritus was higher in the pembrolizumab arm at 19.5% versus the chemotherapy group at 2.7%. Immune-related AEs that were higher with pembrolizumab compared with chemotherapy, respectively, included thyroid abnormalities (9.4% vs 1.6%), pneumonitis (4.1% vs 0.4%), and colitis (2.3% vs 0.4%).

Fifteen patients in the pembrolizumab arm and 28 patients in the chemotherapy group discontinued treatment due to a treatment-related AE. Each arm had 4 treatment-related deaths.

Two-year follow-up findings demonstrated that, at a median follow-up of 27.7 months as of October 2017, the median 1- and 2-year OS rates were 44.2% and 26.9 with pembrolizumab and 29.8% and 14.3% with chemotherapy.³ While the 1- and 2-year PFS rates were higher with pembrolizumab, the rates did not differ between arms.

The longer follow-up also showed that the ORR was also higher with pembrolizumab (21.1% versus 11.0%), and the median DOR with pembrolizumab was not reached (range 1.6+ to 30.0+ months) versus chemotherapy (4.4&thinsp;months; range 1.4+ to 29.9+ months).

Regarding safety, the all-grade TRAEs were 62.0% and 90.6% with pembrolizumab and chemotherapy; grade ≥3 TRAEs were 16.5% versus 50.2%, respectively.

References

1. Appraisal consultation document: Pembrolizumab for treating locally advanced or metastatic urothelial carcinoma after platinum-containing chemotherapy. National Institute for Health and Care Excellence. Published March 2020. https://bit.ly/2vQxuel. Accessed March 12, 2020.
2. Bellmunt J, de Wit R, Vaughn DJ, et al. Keynote-045: open-label, phase III study of pembrolizumab versus investigator’s choice of paclitaxel, docetaxel, or vinflunine for previously treated advanced urothelial cancer. Presented at: 2016 SITC Annual Meeting; November 9-13, 2016; National Harbor, MD. Abstract 470.
3. Fradet Y, Bellmunt J, Vaughn DJ, et al. Randomized phase III KEYNOTE-045 trial of pembrolizumab versus paclitaxel, docetaxel, or vinflunine in recurrent advanced urothelial cancer: results of >2 years of follow-up. Ann Oncol. 2019;30(6):970-976. doi: 10.1093/annonc/mdz127.