Gastro-oesophageal junction (GOJ) and gastric adenocarcinoma treatment recommendations have been made based on evidence for the use of pembrolizumab (Keytruda) in combination with trastuzumab and chemotherapy for untreated locally advanced unresectable or metastatic HER2-positive cases in adults.
The development of the National İnstitute for Health and Care Excellence (NICE) technology appraisal guidance involves a careful consideration of the available evidence. Health professionals are expected to take this guidance into account alongside the individual needs, preferences, and values of their patients. However, the application of these recommendations is at the discretion of health professionals in consultation with their patients and/or their carers or guardians. Any adverse events related to a medicine or medical device used in treatment should be reported to the Medicines and Healthcare products Regulatory Agency using the Yellow Card Scheme.
Commissioners and providers are responsible for providing the necessary funding to implement the guidance when health professionals and their patients wish to use it, in accordance with the NHS Constitution. This responsibility must be balanced with duties to eliminate unlawful discrimination, advance equality of opportunity, and reduce health inequalities.
NICE Recommends Against Pembrolizumab Combination Therapy for GOJ and Gastric Adenocarcinoma
Pembrolizumab with trastuzumab, fluoropyrimidine-, and platinum-containing chemotherapy is not recommended for untreated locally advanced unresectable or metastatic HER2-positive GOJ or gastric adenocarcinoma in adults whose tumors express PD-L1 with a combined positive score (CPS) of 1 or more. This recommendation does not affect treatment started before the publication of this guidance; such treatments may continue without changes to funding arrangements until the patient and their NHS clinician consider it appropriate to stop.
There is a significant unmet need for treatments for untreated locally advanced unresectable or metastatic HER2-positive GOJ or gastric adenocarcinoma. Usual treatment involves trastuzumab plus platinum-containing chemotherapy. Clinical trial evidence suggests that pembrolizumab plus trastuzumab and chemotherapy increases the time before cancer progression and overall survival compared with trastuzumab plus chemotherapy. However, the long-term effect remains uncertain.
The committee found that the cost-effectiveness estimate for pembrolizumab plus trastuzumab and chemotherapy is not within the range that NICE considers an acceptable use of NHS resources. Thus, it is not recommended.
Impact of PBC on Quality of Life and NICE Treatment Recommendations for Gastric Adenocarcinoma
PBC has a substantial impact on quality of life, with symptoms such as lack of appetite, weight loss, fluid in the abdomen, and blood in the stool affecting physical, social, and work life, as well as nutritional status and the ability to eat. Psychological distress due to poor prognosis and demanding treatment pathways also contributes to the burden. The condition is usually diagnosed at an advanced stage due to a lack of screening and vague early symptoms, resulting in limited effective treatment options and a poor survival prognosis.
NICE recommends trastuzumab plus platinum-containing chemotherapy for people with HER2-positive metastatic GOJ or gastric adenocarcinoma. Other options for people with good performance status and no significant comorbidities include doublet or triplet chemotherapy. The EAG agreed that trastuzumab plus chemotherapy is the most relevant comparator for this appraisal.
Evidence for pembrolizumab plus trastuzumab and chemotherapy comes from the phase 3 KEYNOTE-811 trial, which included a global cohort. The company’s submission focused on a subgroup with PD-L1 expression and a CPS of 1 or more, excluding data from the Asia cohort. The committee found the non-Asia cohort data to be generalizable to NHS clinical practice.
NICE Concludes Pembrolizumab and Trastuzumab Combo Not Cost-Effective for GOJ and Gastric Adenocarcinoma
The company used a partitioned survival model to estimate cost-effectiveness. Long-term overall survival predictions were updated using data from interim analysis 3 of KEYNOTE-811. However, both the company’s and EAG’s survival extrapolations were considered uncertain. Utility Values and Treatment Costs The committee preferred a time-to-death approach using linear mixed effect regression modeling for utility values. Trastuzumab treatment was modeled based on the time-to-treatment discontinuation curve from KEYNOTE-811, with no cap applied. Trastuzumab administration costs were aligned with the EAG’s scenario analysis.
Severity and Cost-Effectiveness A severity weight of 1.2 was applied to the QALYs. The cost-effectiveness estimates were above the range normally considered a cost-effective use of NHS resources, leading to the conclusion that pembrolizumab plus trastuzumab and chemotherapy is not recommended.
Conclusion The committee concluded that pembrolizumab plus trastuzumab and chemotherapy is not within the cost-effective range for NHS resources. The evaluation committee, consisting of various stakeholders, reviewed and agreed upon these recommendations, considering the impact on equality and innovation. The final guidance reflects a thorough analysis of clinical and economic evidence, ensuring that the best possible recommendations are made for the treatment of HER2-positive GOJ or gastric adenocarcinoma.
Resource: National İnstitute for Health and Care Excellence, June 12, 2024
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