Keytruda (pembrolizumab) combined with trastuzumab, fluoropyrimidine, and platinum-based chemotherapy is not recommended for initial treatment of locally advanced unresectable or metastatic HER2-positive gastric or gastro-oesophageal junction (GOJ) adenocarcinoma in adults with PD-L1 expressing tumors (CPS of 1 or more), according to its marketing authorization.
This recommendation does not affect ongoing NHS treatments involving pembrolizumab with trastuzumab, fluoropyrimidine, and platinum-based chemotherapy started before this guidance was issued. Patients currently receiving this treatment may continue under existing funding arrangements until they and their NHS clinician decide to stop.
Clinical Effectiveness
The company presented interim analysis 2 results (data cut-off May 2022) with median follow-ups of 17 months for the pembrolizumab plus trastuzumab and chemotherapy group and 13.9 months for the trastuzumab plus chemotherapy group. At the initial appraisal meeting, the committee noted interim analysis 3 of the KEYNOTE-811 trial, which had a longer follow-up.
During consultation, the company provided results from interim analysis 3 (data cut-off March 2023) with median follow-ups of 20 months for the pembrolizumab group and 18.2 months for the trastuzumab group. For the non-Asia cohort with PD-L1 and a CPS of 1 or more, pembrolizumab plus trastuzumab and chemotherapy significantly improved progression-free survival and overall survival compared to trastuzumab plus chemotherapy. The committee concluded that interim analysis 3 of KEYNOTE-811 was suitable for decision-making.
The company utilized EQ-5D-5L data from the non-Asia cohort with PD-L1 and a CPS of 1 or more from KEYNOTE-811 to estimate utility values, mapping them to the EQ-5D-3L value set via the Decision Support Unit's mapping function. The base case included utility values based on a time-to-death approach with four categories: less than 30 days, 30 to 179 days, 180 to 359 days, and 360 days or more from death.
A progression-based approach was also modeled. The EAG used the time-to-death approach but highlighted significant uncertainty in this method for applying utility values, noting that both approaches have limitations due to heavily censored data at progression or treatment discontinuation points. The progression-based approach is more common, with clinical advice suggesting progression and adverse events are key utility drivers in this disease area.
NICE acknowledged the lack of utility data in gastric or GOJ cancer and accepted the time-to-death approach's appropriateness despite the uncertainty. The company used descriptive statistics without adjusting for repeated measures to estimate utility values, while the EAG preferred a linear mixed effects regression model to account for repeated measures and covariates. The committee found the linear mixed effects regression model more appropriate.
NICE's health technology evaluation manual states that for ICERs above £20,000 per QALY gained, the acceptability of a technology will consider the degree of certainty around the ICER. The committee will be more cautious if less certain about the ICERs but will consider other aspects, including uncaptured health benefits. Due to high uncertainty in long-term survival estimates for both treatment regimens, the committee concluded that an acceptable ICER would be around the middle of NICE's cost-effectiveness range (£20,000 to £30,000 per QALY gained).
Cost-Effectiveness Estimates
The committee considered confidential cost-effectiveness estimates, including discounts for comparators and follow-up treatments. The company and EAG's base case results for pembrolizumab plus trastuzumab and chemotherapy were above the range normally deemed cost-effective for NHS resources.
Committee Preferences The committee's preferred assumptions included data from the non-Asia cohort, long-term survival extrapolations using specific spline models for each treatment arm, utility values from the time-to-death approach using linear mixed effect regression modeling, PD-L1 testing costs for the pembrolizumab arm only, trastuzumab treatment modeled based on the time-to-treatment discontinuation curve from KEYNOTE-811, trastuzumab administration costs per EAG's scenario analysis, and a severity weighting of 1.2 applied to QALYs. These assumptions led to cost-effectiveness estimates outside the range NICE usually considers acceptable.
Recommendation
Clinical evidence indicates that pembrolizumab plus trastuzumab and chemotherapy improves overall survival in untreated locally advanced unresectable or metastatic HER2-positive gastric or GOJ cancer in adults with PD-L1 expressing tumors (CPS of 1 or more). However, long-term survival extrapolations for both treatment regimens are very uncertain. The committee concluded that the ICER with preferred assumptions is not within NICE's acceptable range for NHS resources, thus pembrolizumab plus trastuzumab and chemotherapy is not recommended.
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