Advanced Lung Cancer Patients’ Use of EGFR Tyrosine Kinase Inhibitors and Overall Survival: Real-World Evidence from Quebec, Canada

Abstract

EGFR tyrosine kinase inhibitors (EGFR-TKIs) are breakthrough palliative treatments for advanced lung cancer patients with tumors harboring mutations in the EGFR gene. Using healthcare administrative data, three cohorts were created to describe the use of three EGFR-TKIs that are publicly funded in Quebec for specific indications (i.e., 1st-line gefitinib, 1st-line afatinib, and post-EGFR-TKI osimertinib). The main objective was to compare overall survival (OS) among patients receiving these treatments to those in previous experimental and real-world studies. The patients who received EGFR-TKIs for indications of interest between 1 April 2001, and 31 March 2019 (or 31 March 2020, for post-EGFR-TKI osimertinib) were included to estimate the Kaplan-Meier-based median OS for each cohort. An extensive literature search was conducted to include comparable studies. For the gefitinib 1st-line (n = 457), the afatinib 1st-line (n = 80), and the post-EGFR-TKI osimertinib (n = 119) cohorts, we found a median OS (in months) of 18.9 (95%CI: 16.3–21.9), 26.6 (95%CI: 13.7-NE) and 19.9 (95%CI: 17.4-NE), respectively. Out of the 20 studies that we retained from the literature review and where comparisons were feasible, 17 (85%) had similar OS results, which further confirms the value of these breakthrough therapies in real-world clinical practice.

1. Introduction

With about half of all cases being diagnosed at stage IV [1], lung cancer is the deadliest cancer in Canada, including Quebec [2]. Patients diagnosed with lung cancer in Canada between 2015 and 2017 had a net survival rate of 22% [2]. Only 24% of all cases in Quebec diagnosed between 2014 to 2016 survived 5 years or more from any cause of death [3].

Patients with advanced cancer (i.e., locally advanced, or metastatic) with limited curative treatment options are typically given palliative treatment with chemotherapy, immunotherapy, or targeted therapy, the latter two being breakthrough therapies introduced in the past decade. Since 2011 in Quebec, oral EGFR tyrosine kinase inhibitors (EGFR-TKI) have been a standard targeted treatment for patients with tumors harboring EGFR-TKI sensitizing mutations, which include resistance mutations [4,5]. In Ontario, up to 20% of advanced patients with non-squamous, non-small-cell lung cancer have the most common EGFR-TKI sensitizing mutations (exon 19 deletions and exon 21-L858R) [6]. About 50–65% of patients progressing on first- and second-generation EGFR-TKIs develop an EGFR-TKI resistance mutation (T790M) that can be treated with third-generation EGFR-TKIs [7,8].

In Quebec, the Institut national d’excellence en santé et en services sociaux (INESSS) evaluates the evidence on new drugs, usually based on at least one randomized controlled trial (RCT), and provides recommendations to the Minister of Health and Social Services who regulates the drug formulary of Quebec’s universal public drug coverage program [9]. EGFR-TKIs are publicly covered in Quebec for specific indications (e.g., line of treatment, EGFR mutation status, etc…) and the clinical guidelines for treatment with these EGFR-TKIs are mainly based on benefits observed in RCTs in surrogate endpoints of overall survival (e.g., progression-free survival [PFS]) [5]. Despite the availability of mature data from these trials, some participants in the control arm received EGFR-TKIs following disease progression, which potentially masked overall survival (OS) benefits.

INESSS is exploring real-world data to assess the value of breakthrough therapies in Quebec’s clinical settings, given its potential for complementing evidence from small prospective studies and assessing the real-world value of interventions after their implementation into practice [10,11,12,13,14]. If results from real-world studies show smaller benefit than RCTs, review of the funding criteria or decision could be justified. This population-based retrospective study provides such evidence to policymakers and other stakeholders by drawing a portrait of advanced lung cancer patients who received EGFR-TKIs that are publicly covered in Quebec for specific indications and comparing estimates of OS in this population to those published in RCTs and real-world studies.

2. Materials and Methods

2.1. Study Design and Data

Our study included patients who had public coverage for prescriptions filled at community pharmacies in Quebec and were treated with EGFR-TKIs for indications included in Quebec’s drug formulary (

Table 1. Indications for gefitinib, afatinib, and osimertinib included in the drug formulary of Quebec’s universal public drug coverage program [15].

EGFR-TKI	Line of Palliative Treatment	Indication and Coverage Criteria	Date Added to Formulary
Gefitinib	1st line	1st-line treatment of patients with locally advanced or metastatic NSCLC, with an activating EGFR mutation, and with an ECOG performance status of 0 to 2.	November 2011
Afatinib	1st line	In monotherapy for the 1st-line treatment of patients with metastatic NSCLC, with an activating EGFR mutation, and with an ECOG performance status of 0 or 1.	May 2016
Osimertinib	2nd line or more	Treatment of locally advanced, unresectable, or metastatic NSCLC, with the T790M EGFR mutation in patients: Whose disease progressed during or following treatment with an EGFR-TKI Whose ECOG performance status is 0 or 1.	November 2018
	1st line 1	1st-line treatment of people with locally advanced, unresectable, or metastatic NSCLC, with an activating EGFR mutation, and with an ECOG performance status of 0 to 1.	December 2018

Abbreviations: NSCLC: non-small-cell lung cancer; ECOG: Eastern Cooperative Oncology Group. ¹ EGFR-TKI for this indication was not studied.

): gefitinib or afatinib for 1st-line palliative treatment, or osimertinib as a second EGFR-TKI treatment following 1st-line palliative treatment with an EGFR-TKI. Since the public coverage of EGFR-TKIs requires a treating physician to confirm their patient’s status as advanced cancer with an activating EGFR mutation, payments of these drugs by the public insurer allowed us to infer this status for patients in our study. We did not investigate EGFR-TKIs that were (1) not in Quebec’s drug formulary (e.g., dacomitinib), (2) in Quebec’s drug formulary for indications included after our recruitment period (e.g., osimertinib for 1st-line treatment), and (3) in Quebec’s drug formulary without EGFR mutation status as an indication and reimbursement criterion (e.g., erlotinib for 2nd- or 3rd-line treatments).

Inpatient and outpatient care administrative data (i.e., hospitalization [MED-ECHO], physician billing [SMOD], drugs dispensed in community pharmacies [SMED], health insurance registry [FIPA]) that is managed by the Régie de l’assurance maladie du Québec (RAMQ) and the Ministère de la Santé et des Services sociaux (MSSS) were used to create three EGFR-TKI cohorts: (1) 1st-line gefitinib, (2) 1st-line afatinib, and (3) post-EGFR-TKI osimertinib. For all cohorts, we selected patients who had their first lung cancer diagnostic code in MED-ECHO or SMOD between 1 April 2001, and 31 March 2019, (lung cancer index date) [3] with at least one gefitinib, afatinib, or osimertinib prescription in the same period. We also included in the osimertinib cohort patients with at least one osimertinib prescription before 31 March 2020, after receiving gefitinib, afatinib, or erlotinib between 1 April 2001, and 31 March 2019. International nonproprietary names and drug identification numbers were used to identify EGFR-TKI prescriptions in SMED (Appendix A). All patients were followed until death (captured in FIPA), or 31 March 2020, whichever came first.

We then excluded from each cohort patients that did not receive an EGFR-TKI for the line of treatment of interest. Since we had limited information on the line of palliative treatment and chemotherapy history, we developed an algorithm to identify the line of therapy associated with patients’ 1st EGFR-TKI (Appendix B). From each cohort, we first excluded patients who were covered by a public drug insurance plan in FIPA for less than 90% of the period from 3 months before the 1st EGFR-TKI treatment to the end of follow-up (targeted treatment observation period). From the gefitinib and afatinib cohorts, we also excluded patients whose 1st EGFR-TKI was not gefitinib or afatinib, and for the osimertinib cohort, we excluded those whose 2nd EGFR-TKI was not osimertinib after receiving gefitinib, afatinib, or erlotinib. All patients identified by the algorithm as receiving their 1st EGFR-TKI other than 1st-line palliative treatment were then excluded to form the final cohorts.

This study was carried out at INESSS as part of a Health System Impact Fellowship (SQ) of the Canadian Institutes of Health Research. It was part of an initiative to promote the use of real-world data for health technology assessment in line with INESSS’s work on real-world evidence in its 2019–2022 Three-Year Business Plan which aims to “Assess the value of interventions in real care settings using medico-administrative data” [16]. INESSS is not responsible for the content of this publication, however, the results reported here were part of a larger INESSS project to study EGFR-TKIs in Quebec [17]. Access to de-identified data for this study was made possible through a tripartite agreement between the MSSS, the RAMQ, and INESSS [18]. Clinical experts were consulted to select relevant intervention codes and develop the algorithm used to identify line of treatment. A scientific advisory committee and INESSS’ Comité de l’évolution des pratiques en oncologie (CEPO), a panel of experts in cancer (hemato- and radio-oncologists, surgeons and pharmacists), were consulted throughout the study [17].

2.2. Outcomes

For each cohort, we reported the annual number of new users and other estimates from the distributions of patient characteristics, total days of the EGFR-TKI supplied, and OS.

The date of the 1st EGFR-TKI prescription fill was used to count the number of new users by fiscal year (April to March) and calculate patients’ age. The age and sex distributions in each cohort were compared to distributions of a previous population-level lung cancer cohort created by INESSS with Quebec’s health administrative databases [3]. For the post-EGFR-TKI osimertinib cohort, we reported the EGFR-TKI that was also received as 1st-line treatment. The total number of days’ supply of EGFR-TKI per patient was obtained by adding the treatment duration (in days) of each EGFR-TKI prescription reimbursed by the RAMQ.

Patients’ overall survival time was calculated as months elapsed between patients’ first EGFR-TKI prescription of interest and the date of death from any cause. Administrative censoring occurred on 31 March 2020. Patients’ follow-up in the 1st-line gefitinib and afatinib cohorts was also censored at the time of receiving osimertinib, if applicable; osimertinib increases OS relative to standard chemotherapy when given as a subsequent line after another EGFR-TKI [19,20]. Censoring at the time of receiving osimertinib was applied to compare our survival results to studies in which patients did not receive osimertinib as a subsequent therapy, including studies submitted to INESSS for evaluation of gefitinib and afatinib.

2.3. Statistical Analyses

Frequencies and proportions, means and standard deviations, or medians and ranges (minimum to maximum), were reported for distributions of age, sex, the 1st-line EGFR-TKI drug, and new users. Boxplots were used to display the distribution of total days’ supply. Median follow-up time was estimated with the reverse Kaplan-Meier method in the prodlim package in R [21], and the survival package was used to plot Kaplan-Meier survival curves and estimate median overall survival times [22].

2.4. Comparison of Overall Survival

Our study could not include a comparator group of patients with EGFR mutated tumors who were not treated with EGFR-TKIs since we did not have information on mutation status, and more importantly, in the real-world clinical setting, it would be unethical to withhold EGFR-TKI treatment in the presence of an activating EGFR mutation. Therefore, we relied on the indirect comparison of the median OS in our cohorts to that of cohorts with similar EGFR-TKI use in previous studies. In May 2021, we conducted an extensive literature review to include all published experimental trials and real-world studies that reported OS estimates related to the three EGFR-TKIs for the indications of interest (Appendix C). The studies submitted to INESSS for evaluation of these treatments that reported estimates of median OS were automatically included in our review [20,23,24,25,26,27,28].

The similarity between our results and those of other studies (point estimates and 95% confidence intervals) was assessed with the degree of overlap that took into consideration the absolute difference between point estimates and the width of the confidence intervals, but without any formal statistical tests.

3. Results

Among 552 patients who received gefitinib, 457 (82.8%) were included in the 1st-line gefitinib cohort. Out of 117 patients receiving afatinib, 80 (68.4%) were included in the 1st-line afatinib cohort. Similarly, of 178 patients who received osimertinib, 119 (66.9%) were included in the post-EGFR-TKI osimertinib cohort (Figure 1). New users of 1st-line palliative treatments with gefitinib or afatinib started to accrue in the same year as their listing in Quebec’s drug formulary in November 2011 and May 2016, respectively. In contrast, 32 patients in the osimertinib cohort received the drug in the 2 years before it was listed on the formulary in November 2018, when the highest numbers of users were observed (Figure 2 and Table 1).

Compared to lung cancer patients in Quebec, there was a larger proportion of women in all three cohorts (60–71% vs. 49%) (

Table 2. Characteristics of patients in EGR-TKI cohorts.

Characteristics	1st-Line Gefitinib Cohort 1		1st-Line Afatinib Cohort 1		Post-EGFR-TKI Osimertinib Cohort 1		Lung Cancer Cohort 2016 2
	n	(%)	n	(%)	n	(%)	n	(%)
Sex
Female	313	(68.5)	48	(60.0)	84	(70.6)	4803	(49.3)
Male	144	(31.5)	32	(40.0)	35	(29.4)	4936	(50.6)
Age in years
Median (range) 3	70.6	(34; 93)	68.4	(22; 93)	72.3	(24; 92)	70.7	(NR)
<50 years	15	(3.3)	4	(5.0)	5	(4.2)	249	(2.6)
50–64 years	91	(19.9)	24	(30.0)	26	(21.8)	2716	(27.9)
65–79 years	271	(59.3)	46	(57.5)	64	(53.8)	4762	(48.8)
≥80	80	(17.5)	6	(7.5)	24	(20.2)	2012	(20.6)
1st-line EGFR-TKI
Gefitinib	457	(100)	-		92	(77.5)	-
Afatinib	-		80	(100)	25	(21.0)	-
Erlotinib	-		-		2	(1.7)	-
Total	457		80		119		9752

Abbreviations: NR: not reported. ¹ Age measured at the start of the EGFR-TKI of interest. ² Quebec lung cancer cohort developed by INESSS, in which age was measured at the diagnosis date [3]. ³ Range: minimum; maximum.

and Appendix D). The median age for the gefitinib cohort was the same as the overall cohort (71 years), whereas the median age for the afatinib cohort was lower (68 years) and that for the osimertinib cohort was higher (72 years). There was a much smaller portion of patients that were 80 years and over in the afatinib cohort in comparison to the overall cohort (7.5% vs 20.6%).

The median total days’ supply was 300 days (9.9 months) for gefitinib and osimertinib, and 274.5 days (9.0 months) for afatinib (Figure 3). Approximately 5% of patients had a total days’ supply of gefitinib that was greater than 3 years. Only 1 patient received a supply of afatinib for more than 3 years, while no one received a supply of osimertinib for this length of time.

With a median follow-up of 29.6 months in the gefitinib cohort, we observed 295 (65%) deaths and a median OS of 18.9 months (95%CI: 16.3–21.9) (Figure 4). The afatinib cohort had a median follow-up of 17.6 months, 36 (45%) deaths and a median OS of 26.6 months (95%CI: 13.7-NE). With a median of 17.3 months of follow-up after receiving osimertinib in the post-EGFR-TKI osimertinib cohort, we observed 44 (38%) deaths and median OS was 19.9 months (95%CI: 17.4-NE). The upper bounds of the 95%CI for median OS in the afatinib and osimertinib groups were non-evaluable (NE) due to the immaturity of the data (i.e., less than 50% of patients in the cohort had the outcome).

From 2565 articles identified, we selected 10 RCTs (9 articles) and 17 real-world studies (18 articles) for indirect comparison with our OS results (Appendix C). We retained 7 RCTs [26,27,29,30,31,32,33] and 10 real-world studies [34,35,36,37,38,39,40,41,42,43] on gefitinib as 1st-line treatment (Figure 5). Among these studies, 5 RCTs and 6 real-world studies had median OS estimates similar to ours, 1 RCT [30] and 1 real-world study [40] had results superior to ours. We were limited in making comparisons with the estimates from other studies, which did not overlap our results and lacked confidence intervals. For afatinib as 1st-line treatment we retained 2 RCTs [28], and 1 study combining these RCTs [28], and 3 real-word studies [34,44,45]. All studies had similar results to ours, except for 1 real-world study for which we were limited in making a comparison due to a lack of overlap of results and the non-evaluable upper bound for our estimate’s 95%CI. We retained only 1 RCT [20] and 5 real-world studies [46,47,48,49,50] on osimertinib as a post-EGFR-TKI treatment. One real-world study [49] had a median inferior to ours and two others [47,50] had results similar to ours. Due to a lack of overlap of results and the non-evaluable upper bound of our estimate’s 95%CI, our comparisons with the other 2 real-world studies [46,48] were limited. Similarly, we were limited in the comparison with the single RCT, which had a longer median OS.

4. Discussion

In our study, the annual number of new users of gefitinib always exceeded the number of new patients using the second-generation EGFR-TKI afatinib as a 1st-line treatment. However, a decline in the use of gefitinib relative to afatinib was noted in the years following the introduction of afatinib in 2016. In contrast with other EGFR-TKIs, the use of osimertinib began before it was listed in Quebec’s drug formulary, which most likely occurred through the “exceptional patient program” that provides coverage for drugs that are not listed in Quebec’s drug formulary under exceptional circumstances. These trends indicate physicians’ proactiveness in integrating newer generations of EGFR-TKIs into clinical practice.

The high proportion of women (60–71%) we observed in all three of our cohorts is concordant with a previous study reporting that 57% of EGFR mutations in lung cancer tumours are found in women in Canada [6]. Our results are also concordant with the studies we selected from our literature review and one recent single-center study in Quebec that reported 71% of its 1st-line EGFR-TKI users being women [51]. Knowledge of a higher EGFR mutation rate in women could also drive a higher testing rate in women, as seen previously in Canada [52], and further contribute to the higher rates of EGFR-TKI use in women.

In general, all our cohorts included patients above the age of 80 years. Older patients may be less likely to receive cytotoxic chemotherapy due to a lack of clinical data on tolerability, but also due to clinical experience with the elderly who show more complications. In contrast, EGFR-TKIs have better tolerability than chemotherapy [19,32,33,53,54,55]. Furthermore, in RCTs on EGFR-TKIs, patients older than 80 years (maximum of 89 years) have been included [19,29,31,56,57], and studies on patients of 75 years or older, have reported median OS estimates similar to those of the overall population (19–35.2 months) [58,59,60,61,62,63]. However, we noted that patients in the afatinib cohort, compared to the gefitinib cohort, had a lower proportion of patients of 80 years and older (7.5% vs. 17.5%). Physicians may be hesitant in prescribing afatinib for the elderly due to its higher toxicity profile in comparison to gefitinib [56]. The trend of fewer older patients using afatinib in comparison to gefitinib has also been observed in other real-world studies [34,44,64].

When daily treatment is continuous until disease progression, estimates of total days’ supply should resemble time to treatment discontinuation, which is a proxy for PFS [65]. Indeed, the total days’ supply of EGFR-TKI in our cohorts were close to the PFS reported in the RCTs we selected from our literature review, and in one recent single-center study in Quebec. The studies reported a PFS of 8.4–11.9 months (median 10.4) for gefitinib as 1st-line treatment [27,29,31,32,33,51,53,54], and a PFS of 10.1 months for osimertinib as a post-EGFR-TKI treatment [20], while we found medians of total days’ supply of 9.9 months for both treatments. Two RCTs reported a PFS of 11.0–11.1 months for afatinib as a 1st-line treatment [28], while we found a total days’ supply of 9 months. Total days’ supply and PFS may not be equivalent when daily treatment is paused or discontinued for reasons other than progression, such as adverse events. Therefore, the small difference between both parameters that we observed for afatinib as a 1st-line treatment may have been led by its higher toxicity profile.

When indirect comparisons with our OS estimates were possible, we found 3 RCTs submitted to INESSS for evaluation of gefitinib and afatinib (IPASS, LUX-Lung 3, and LUX-Lung 6) to have results similar to ours. Among the 12 other RCT and real-world studies on gefitinib that we were able to indirectly compare with the current study, 10 studies had similar results. The 2 real-world studies on afatinib that we were able to compare with our study also had similar results. Similarly, among the 3 real-world studies on osimertinib that we were able to compare with, 2 had similar results. There were 7 out of 27 studies that reported longer median OS estimates than those in the current study, but these comparisons were limited because of a lack of overlap of results due to unreported or non-evaluable confidence intervals. Despite the uncertainty in these comparisons, it is likely that the OS gap between the RCT of osimertinib (AURA3) and the current study is real. Contrary to AURA3, patients in our post-EGFR-TKI osimertinib cohort may have received chemotherapy in between their 1st-line treatment with an EGFR-TKI and osimertinib as a second EGFR-TKI, which may have reduced the length of survival at the time of receiving osimertinib.

Based on the indirect comparisons, we conclude that the real-world estimates of OS in Quebec related to the use of the three EGFR-TKIs for specific indications are not different from most published studies that we selected from our literature review. This is further supported by one recent population-level study in Ontario that reported results similar to ours: a median OS of 21.6 months (95%CI: 19.3–23.3) for 1st-line gefitinib, and a median OS of 31.0 months (95%CI: 23.4–42.1) for 1st-line afatinib [64].

The limitations of this study include that we could not directly verify whether patients had a non-small cell type histology and an activating EGFR mutation. However, public coverage of EGFR-TKIs is conditional on these characteristics, making it unlikely for patients receiving public coverage of these medicines not to have them. The indirect comparisons in this study are subject to confounding by multiple factors such as age, smoking status, the type of EGFR mutation, and palliative treatments following EGFR-TKIs. For example, we did not include patients that had received EGFR-TKIs through private drug insurance, which likely rendered our cohorts slightly older than the ones in the RCTs submitted to INESSS for evaluations. However, we estimate the proportion of patients with private drug insurance among all EGFR-TKI users to be low since about 70% of lung cancer patients in Quebec are diagnosed at age 65 or older, when 90% of Quebec residents are registered for public drug coverage [3,66,67]. Finally, the survival estimates for the afatinib and osimertinib cohorts are less precise due to data immaturity, and the indirect comparisons of results from these cohorts with other studies imply a greater level of uncertainty.

Our study also has strengths. To our knowledge, this is the first population-level study on the use of EGFR-TKIs for specific indications in a Canadian province where public drug insurance offers full coverage of oral cancer drugs [66]. The involvement of clinical experts and a scientific committee helped us generate real-world evidence on these breakthrough therapies with analyses of Quebec’s health administrative data that are grounded in clinical and scientific expertise. Our holistic analytical approach through an extensive literature review also produced more meaningful results.

5. Conclusions

RCTs have shown that EGFR-TKIs are breakthrough therapies for advanced lung cancer patients. EGFR-TKIs have been included in Quebec’s drug formulary for specific indications, mainly based on the efficacy observed in surrogate endpoints of OS. Our study further confirms the value of these treatments in real-world clinical care, with OS rates in Quebec similar to those reported in most real-world studies and RCTs, including most RCTs used in the evaluation of these treatments for public drug coverage. Future studies should re-evaluate EGFR-TKIs with mature and richer data and, given their potential real-world value, further investigate inequities in access to these treatments.