Advances in oncology research are creating a progressively more competitive treatment landscape, with multiple therapies being appraised by health technology assessment (HTA) organisations for the same type of cancer. For example, programmed-death (ligand)-1, or PD-(L)1 checkpoint inhibitors, which promote the immune system to target tumour cells, are emerging as a promising alternative to chemotherapy, with marketing authorisation for multiple cancers, including melanoma, renal cell carcinoma, urothelial carcinoma, and non-small cell lung cancer (NSCLC).
We used the SIRIUS oncology HTA database to investigate HTA decision making for PD-(L)1 inhibitors in NSCLC, examining how they vary between HTA organisations across several countries. Assessments by the National Institute for Health and Care Excellence (NICE) were compared with the Scottish Medicines Consortium (SMC), the French National Authority for Health (HAS), the German Federal Joint Committee (G-BA), the Australian Pharmaceutical Benefits Advisory Committee (PBAC), and the Canadian Agency for Drugs and Technologies in Health (CADTH).
The PD-(L)1 inhibitors atezolizumab, nivolumab, and pembrolizumab were assessed by the HTA organisations specified above for the treatment of NSCLC. Table 1 summarises the primary clinical evidence used to support the assessments. Docetaxel was the comparator in every trial except for pembrolizumab for first-line PD-(L)1 positive NSCLC, where the main comparator was platinum-based chemotherapy. Each treatment improved overall survival, as demonstrated by hazard ratios favouring the PD-(L)1 inhibitor. Progression-free survival was only significantly improved by nivolumab for squamous NSCLC. This article focuses on the reasons behind HTA decisions. More detailed information regarding quality-adjusted life years (QALYs) and incremental cost-effectiveness ratios (ICERs) is available in the the original HTAs.
Table 1. Clinical efficacy data used to support HTAs for PD-(L)1 inhibitors in NSCLC
CI, confidence interval; HTA, health technology assessment; NSCLC, non-small cell lung cancer; OS, overall survival; PD-(L)1, programmed death ligand-1; PFS, progression-free survival
England and Wales
NICE assessed atezolizumab, nivolumab, and pembrolizumab across five HTAs. All the NICE HTAs reported a positive recommendation. The indications and patient access schemes are displayed in Table 2.
Table 2. NICE HTAs for PD-(L)1 inhibitors for treatment of NSCLC
CDF, cancer drugs fund; MAA, managed access agreement; NICE, National Institute of Health and Care Excellence; NSCLC, non-small cell lung cancer; PAS, patient access scheme; PD-(L)1, programmed death ligand-1.
All three PD-(L)1 inhibitors met NICE end-of-life criteria, meaning that the life expectancy with the current treatment is less than 24 months, and the new treatment extends life by three or more months. The QALYs for medicines that meet these criteria are given a maximum weight of 2.5. In practice, this is interpreted by NICE as increasing the ICER threshold up to £50,000 per QALY gained, as opposed to the usual threshold of £20,000 to £30,000 (6). Nevertheless, atezolizumab and pembrolizumab required confidential price discounts through patient access schemes (PAS) before being recommended. Nivolumab was made available to NHS patients through the Cancer Drugs Fund and a managed access agreement, with future access being conditional on additional data being gathered over an extended period. A clinical stopping rule, allowing a maximum of two years treatment, was in place for all five indications due to limited data regarding prolonged use of immunotherapies. Table 3 compares the NICE decisions with those of the other HTA organisations assessed.
Table 3. Comparison of NICE HTA decisions with Scotland, France, Germany, Australia, and Canada
Recommended (ASMR score included for France); ↑ Added benefit (G-BA); D Deferred (PBAC); û Not recommended; NA No assessment
The SMC assessed atezolizumab, nivolumab, and pembrolizumab for the same five indications as NICE. All five treatment indications were recommended with a confidential discount PAS; however, these were restricted by a two-year clinical stopping rule, except for nivolumab in squamous NSCLC. Although the reason for the stopping rules is unclear, there was a high unmet need for nivolumab as well as improved survival and toxicity profiles. The Patient and Clinical Engagement (PACE) process for end-of-life and/ or very rare conditions was considered by the committee for all five assessments.
HAS conducts a medical benefit assessment (SMR) and then provides an additional medical benefit (ASMR) score of between I-V for the improvement in medical benefit over existing treatments (I being major and V no clinical improvement). A recommendation is made for inclusion on a list of reimbursable products for hospital use based on the SMR, and the ASMR score is used for pricing negotiations.
Nivolumab was recommended for reimbursement for squamous NSCLC with the SMR describing a substantial medical benefit. Nivolumab received an ASMR score of III, which represents moderate added clinical value, based on improved overall survival over docetaxel. The indication for nivolumab was extended for non-squamous NSCLC with the SMR describing an important medical benefit with minor benefit over docetaxel being represented by an ASMR score of IV. The remaining HTAs were also conducted as extensions of indication. Atezolizumab was considered to have an important medical benefit by the SMR report and received an ASMR score of IV compared with docetaxel based on improved overall survival. The SMR assessments for pembrolizumab (first and second-line PD-(L)1 positive) also described an important medical benefit. In the first-line, pembrolizumab received an ASMR score of IV, representing moderate added benefit over platinum-based chemotherapy due to improved overall and progression-free survival. In the second-line, pembrolizumab received an AMSR score of IV based on improved overall survival over docetaxel.
In Germany, the Institute for Quality and Efficiency in Healthcare (IQWiG) performs an early benefit assessment forming an added benefit rating, provided to the G-BA, who ultimately decide on the magnitude of the added benefit of a new treatment. The added benefit can be non-quantifiable, minor, considerable, or major.
Early benefit assessments were made for the same indications as NICE (Table 2). Atezolizumab was determined by IQWiG to have a considerable added benefit over docetaxel by prolonging overall survival, but this was only in patients whose tumour cells expressed high levels of PD-L1. The G-BA determined that there was considerable added benefit over docetaxel due to improved overall survival and tolerability. Conversely, for patients not eligible to receive docetaxel, pemetrexed, nivolumab, and pembrolizumab, added benefit was not proven due to lack of a direct comparison with standard of care. Nivolumab received positive benefit assessments for squamous and non-squamous NSCLC, with the G-BA reporting a considerable added benefit over the comparators; however, for patients that were ineligible to receive these, benefit over standard of care was not proven. For these HTAs, the treatments for standard of care was not reported. The G-BA described considerable added benefit for pembrolizumab for first and second-line PD-(L)1 positive NSCLC.
All three PD-(L)1 inhibitors were assessed by PBAC for the same indications as NICE, HAS, and the G-BA. However, only atezolizumab and nivolumab, for squamous NSCLC, were recommended. The decisions for nivolumab in non-squamous NSCLC, as well as first-line pembrolizumab, were deferred pending the provision of specific additional information that would be relevant and important for the decision. Nivolumab was deferred due to variation in the effectiveness in patients over 75 years, in addition to high ICERs. The decision for pembrolizumab in the first-line was deferred due as it was not considered to be cost-effective and further information was required concerning a companion diagnostic test. Pembrolizumab was not recommended as a second-line treatment for the PD-L1 positive population because of uncertainty regarding cost-effectiveness.
CADTH assessed all three PD-(L)1 inhibitors for the same indications as the other HTA organisations through the pan-Canadian Oncology Review process; however, nivolumab was assessed for both squamous and non-squamous NSCLC in the same HTA. All the treatments were recommended based on a net clinical benefit and improved toxicity profile over their comparators (docetaxel, except for first-line pembrolizumab in the PD-(L)1 positive population where the comparator was platinum-based chemotherapy). However, these decisions were conditional on the cost-effectiveness being improved to an acceptable level as the drug costs were substantially higher than traditional therapies, such as docetaxel. A maximum of two-years treatment was allowed for atezolizumab and pembrolizumab (first and second line).
Decisions regarding the use of PD-(L)1 inhibitors in NSCLC have varied between HTA organisations, reflecting differences in the processes of technology assessment in different countries. Atezolizumab and pembrolizumab were recommended by NICE after price discounts through a PAS, causing the ICERs to be considered cost-effective. Similarly, a PAS was required for each treatment to be recommended by the SMC. Nivolumab was recommended by NICE for use within the Cancer Drugs Fund, which allows patients to access the treatment for two years while additional information is gathered on the clinical and cost-effectiveness to enable further assessment on whether the treatment is suitable for routine use in the NHS. In contrast, the lack of a provisional system in Australia resulted in deferred PBAC decisions for nivolumab (non-squamous) and pembrolizumab (first-line), delaying patient access. In Canada, all three PD-(L)1 inhibitors were recommended by CADTH, dependent on the cost being reduced to an acceptable level.
HAS and the G-BA assessed all three PD-(L)1 inhibitors for the same indications as NICE and described an added benefit for all HTAs. However, in Germany, atezolizumab and nivolumab were considered to have added benefit over the comparator therapies, but added benefit was not proven over standard of care in patients who were ineligible for those treatments. For both HAS and the G-BA, the extent of added benefit, which is used to negotiate pricing with the manufacturer, varied between assessments.
This article highlights that HTA decisions for PD-(L)1 inhibitors have had varying outcomes in different countries, likely reflecting the different criteria they use when assessing new technologies. Companies must adapt their strategy when submitting new technologies to ensure that patients get access to new treatments in as many countries as possible.
1. NICE [TA520]. Atezolizumab for treating locally advanced or metastatic non-small-cell lung cancer after chemotherapy. 2018.
2. NICE [TA484]. Nivolumab for previously treated non-squamous non-small-cell lung cancer. 2017.
3. NICE [TA483]. Nivolumab for previously treated squamous non-small-cell lung cancer. 2017.
4. NICE [TA531]. Pembrolizumab for untreated PD-L1-positive metastatic non-small-cell lung cancer. 2018.
5. NICE [TA428]. Pembrolizumab for treating PD-L1-positive non-small-cell lung cancer after chemotherapy. 2017.
6. NICE. Guide to the methods of technology appraisal. 2013.