Difficulties on the access to innovative targeted therapies for lung cancer in Spain

Purpose Spanish Lung Cancer Group (SLCG) conducted a review to analyze the barriers to access to innovative targeted therapies for non-small cell lung cancer (NSCLC) in clinical practice in Spain. Methods Review all relevant content published on websites of European Commission, European Medicines Agency, and Spanish Agency of Medicines and Medical Products regarding the authorization and access to oncology treatments. Results More than 20 targeted therapies are available to treat different molecular alterations in patients with NSCLC. European Commission has approved treatments for genomic alterations involving the following genes: ALK, RET, ROS1, EGFR, BRAF, NTRK, KRAS, MET. However, the availability of these therapies in Spain is not complete, as innovative treatments are not reimbursed or funded late, with only five of these alterations currently covered by National Health System. Conclusion SLCG considers imperative to improve the access in Spain to innovative treatments for NSCLC to reduce inequity across European countries.


Introduction
Lung cancer is the second leading cancer diagnosis in the United States for men (12%) or women (13%).It is the most common cause of death, accounting for 21% of estimated deaths in both sexes [1].According to the Spanish Network of Cancer Registries (REDECAN), it is estimated that more than 30,000 new cases of lung cancer will be detected in Spain in 2023, 22,266 in men and 9016 in women, making it the third most common cancer in Spain [2].
In general, there has been a marked decrease in cancer mortality in Spain in recent decades.In the case of lung cancer, it remains the main cause of cancer death.In 2021, more than 22,000 people died of lung cancer.Mortality will increase in women, mainly due to the later incorporation into smoking [2].
Historically, NSCLC patients were treated with cytotoxic therapies.With the introduction of targeted and immune therapies in the last decade, there has been a dramatic improvement in survival outcomes in advanced NSCLC.Numerous oncogenic alterations have been identified in NSCLC which are considered actionable [4].Currently, more than 20 targeted therapies are available to treat different molecular alterations across 8 genes in patients with NSCLC.The European Medical Agency (EMA) approved treatments for these molecular alterations: anaplastic lymphoma kinase (ALK) gene arrangements, rearranged during transfection (RET), ROS proto-oncogene 1 receptor tyrosine kinase (ROS1) rearrangements, epidermal growth factor receptor (EGFR) mutations, EGFR exon 20 insertions, B-RAF proto-oncogene serine/threonine kinase (BRAF) V600E, neurotrophic tyrosine receptor kinase rearrangements (NTRK), Kirsten rat sarcoma viral oncogene (KRAS), mesenchymal-epithelial transition (MET) [4,5].
However, the availability of these treatments in Spain is not complete due to the lack of reimbursement for innovative treatments or delayed funding, only five of these driver alterations are currently covered from a therapeutic point of view (Fig. 1) [6].
In this paper, we analyzed the barriers delaying the incorporation of these innovative treatments into the Spanish National Health System (SNS).

Materials and methods
A literature review was conducted of all relevant content published on the websites of the European Commission (EC), the European Medicines Agency (EMA), and the Spanish Agency of Medicines and Medical Products (AEMPS) regarding the authorization of and access to oncology treatments.

Evidence on barriers to access to innovative treatments
Access to cancer care innovations will be an important metric to measure whether cancer patients have access to clinical advances.
Fig. 1 Adapted from [4].Timeline of EMA-approved targeted therapies for non-small cell lung cancer with actionable alterations.Drug availability in Spain is represented by the flag icon Several reports have been published to demonstrate the level of uptake of innovation in oncology.One of the most relevant reports in terms of its history (more than 15 years) is the "EFPIA Patients W.A.I.T. Indicator Survey" [7], published bi-annually since 2004 by the European Federation of Pharmaceutical Industries and Associations (EFPIA).This document analyzes the funding situation in several European countries, allowing a comparative analysis.The access indicators analyzed are the percentage of treatment availability and the time to funding.Regarding the percentage of availability of oncology drugs, it can be observed that, compared to other European countries such as Germany, Italy, United Kingdom, and France, Spain is the country with the lowest level of access to cancer drugs approved by the EMA.Only 28% of the drugs approved by the EMA between 2018 and 2021 are fully available to patients, while 28% are available with restrictions and 41% are unavailable (Fig. 2).
In terms of the time taken to adopt a pharmaceutical innovation, the average in Spain is 629 days for all medicines and 611 days for a cancer drug, making it the country with the longest time from EMA approval to adoption of the innovation among the countries mentioned above (Fig. 3).This time has worsened over the years and is now more than 100 days longer than in the previous report (629 vs 517 days).
Societies and scientific groups, such as the Spanish Lung Cancer Group (SLCG) or the ECO Foundation, have expressed their concern about access to oncological innovation in our country by publishing reports analyzing information from the W.A.I.T. published in 2022.The SLCG, in 2021, published the report "Delays and restrictions in access to innovative treatments for lung cancer in Spain" with the aim of "estimating the potential loss of clinical benefit implied by delays in the incorporation of innovation" [8].In both reports, the experts concluded that the situation in Spain regarding the availability of innovation has worsens in recent years.This has a direct impact on patients, who are deprived of the potential clinical benefits of medicines.The ECO Foundation recently launched the ECO Observatory, an initiative designed to highlight the importance of patient access to oncology innovation.The results are included in a report recently published in collaboration with IQVIA.This report analyzes the current situation in Spain and identifies possible ways to improve patient access to oncological innovation [9].The findings from the ECO Observatory are consistent with those of the recent W.A.I.T. report: between 01/01/2018 and 06/30/2021, only 38% EMA-approved drugs and 36% of new indications were included in supply on 01/12/2022.Furthermore, in terms of the time to complete the pricing and financing process, it took on average 16.2 months to include new medicines and 17.8 months to finance new oncological indications [10].
The Ministry of Health has also produced a report on the 'Evolution of the financing and pricing of oncological drugs in the SNS (2016-2021)' which shows similar results to those previously described by both EFPIA and the ECO Observatory in terms of the time taken to finance cancer drugs, which is always more than 1 year (416 days).
The Spanish Society of Medical Oncology (SEOM) and the Spanish Society of Hematology and Hemotherapy (SEHH) have submitted a document to the AEMPS containing 12 aims to improve 4 aspects of the process: registration procedures, positioning reports, assessment nodes, and pricing and funding.These included ensuring the transparency and traceability of the registration process for new drug or indication, specifying the duration of the pilot phase of the consolidation plan for Therapeutic  Positioning Reports (IPTs) and publishing the criteria for funding medicines or indications.
It is important to remember that Spain has a decentralized health system.This means that for a medicine to be used in the health centers of the SNS, it must not only be included in the portfolio of common services of the SNS, but it must also be available regionally in each of the Autonomous Communities (AACC), which cover the cost of the medicine (Fig. 4).
To all these reports, we need to add the perspective of patients, who also express their concern about the lack of access to oncological innovation in Spain, as they are the most affected by this situation.In the specific case of lung cancer, the Spanish Association of People Affected by Lung Cancer (AEACaP) has drawn up a document in which it asks the health authorities for "rapid and equitable access to medicines for lung cancer" given the rejection and lack of funding for various medicines by the Ministry of Health [11].

Analysis of the situation of access to innovative treatments for lung cancer in Spain
We reviewed the status of new treatments/indications approved by the EMA since 2018 (Table 1, Fig. 5).

I. Brigatinib (Alunbrig®) [12-21]
1.1.Brigatinib indications funded by SNS in Spain, according to EMA Data Sheet: • SNS indication #1: Brigatinib monotherapy is indicated for the treatment of adult patients with advanced ALK-positive NSCLC who have not been previously treated with an ALK tyrosine kinase inhibitor (TKI) [12]: -Clinical evidence approval SNS indication #1: Phase III randomized study ALTA-1L (NCT02737501) evaluating efficacy and safety of brigatinib in patients with ALK-positive NSCLC who had not received prior treatment with an ALK TKI.Progression-free survival (PFS) was significantly higher in those patients who received brigatinib versus those who were treated with crizotinib [13,14].-EC indication approval date: April 2020 [15].
-Delay between EC approval and funding in Spain:

Discussion
In the last decade, more than 15 drugs covering more than 20 indications have been approved by the EC to treat patients with lung cancer harboring oncogenic driver molecular alterations.Fifteen drugs were approved between 2018 and 2023.We observed a common denominator when reviewing the latest EMA approvals: 1. Except for capmatinib, which was reimbursed in 8 months after EC approval, all EMA-approved indications or innovative medicines took more than a year to be funded, with an average of approximately 14 months from EC approval to reimbursement.

Conclusion
There is, therefore, a significant inequity in terms of access to cancer treatments across distinct European countries.
Unfortunately, Spain is one of the countries with the longest average time from EMA approval to drug reimbursement.In this article, we focused on treatments indicated on patients with NSCLC with a driver alteration in which it was shown that the barriers to precision medicine have major impact on their life expectancy and quality of life.
The SLCG undertakes to report this inequity and to strive to improve the situation of access to oncological medicines in our country.
Funding This work was funding by Spanish Lung Cancer Group.

Fig. 2
Fig. 2 Adapted from the report "EFPIA Patients W.A.I.T. Indicator 2022 Survey".Comparison of the state of funding of oncology drugs approved by the European Medicines Agency between Germany, Italy, the United Kingdom, France, and Spain between 2018 and 2021

Fig. 3
Fig. 3 Adapted from the report "EFPIA Patients W.A.I.T. Indicator 2022 Survey".Comparison of the average time to financing of drugs since their approval by the EMA (2018-2021) between Spain, France, Italy, the United Kingdom, and Germany

Fig. 4
Fig. 4 Time to access innovative cancer treatments in the different Autonomous Communities.Source: National Cancer Profiles 2023 Report (Spain), published by the Organization for Economic Cooperation and Development (OECD).Note: the data refer to the 17 Autonomous Communities and the Autonomous City of Ceuta.They were collected from 58% of the centers contacted in the first quarter of 2019 and include relevant drugs with pricing and reimbursement conditions established between January 2016 and April 2018 for lung, breast, melanoma, and uterine cancer

Table 1
New treatments approved by the EMA since 2018

Table 1 (
• EMA indication #1: Larotrectinib monotherapy is indicated for treatment of adult and pediatric patients with solid tumors that harbor a NTRK gene fusion, whose disease is locally advanced, metastatic, or where surgical resection is likely to result in severe • EMA indication #2: Entrectinib monotherapy is indicated for treatment of adult patients with ROS1-

VIII. Amivantamab (Rybrevant®) [60-65]
ORR in the first line population was 61.1% and in the previously treated population was 66.7%.-EC indication approval date: February 2017 [79].-Delay between EC approval and funding in Spain: Non-financing proposal in CIPM 179 (≥ 330 days) [80].-Number of times in CIPM: 1, CIPM 179.Reason for proposal not to finance (CIMP 179): "taking into account the criteria for rationalizing public expenditure and the budgetary impact of the SNS" [81].
2. The average number of times that a drug/indication is presented to the CIPM is more than once.Apart from lorlatinib, no other drug received a funding agreement at the first CIPM.3. Before 2023, only lorlatinib achieved funding with a single-arm phase I/II study in its second-line indication.A review of the reasons for non-inclusion in the SNS pathway shows that clinical uncertainty is the most cited reason.Randomized clinical trials to demonstrate the superiority over standard of care is not feasible and probably not strictly needed in the context of highly selected population based on a driver alteration that is very uncommon in the general population.4. Advances in precision oncology are not yet reality in Spain.For patients with EGFR exon 20 insertion, NTRK fusion, KRAS G12C, and BRAF V600E mutations, no specific treatments are available due to lack of funding.These mutations are low frequency, but collectively they account for about 20% of patients diagnosed with a lung adenocarcinoma, which represent a large population denied access to innovation. 5. Lack of availability of effective targeted therapy for lung cancer patients with actionable genomic alterations is concerning, because it denies patients potential clinical benefit, both in terms of overall survival and quality of life.