Afatinib in advanced pretreated non-small-cell lung cancer— a Canadian experience

Original Article

Afatinib in advanced pretreated non-small-cell lung cancer— a Canadian experience


D.A. Ezeife, MD*, B. Melosky, MDa, R. Tudor, BSc§b, S. Lin, BSc*b, A. Lau*, T. Panzarella, MSc*||, N.B. Leighl, MD MMSc*a


doi: http://dx.doi.org/10.3747/co.25.3914


ABSTRACT

Background

Afatinib, an irreversible epidermal growth factor receptor tyrosine kinase inhibitor (egfr tki), is approved for first-line therapy in advanced EGFR mutation–positive non-small-cell lung cancer (nsclc) and has previously demonstrated activity after failure of chemotherapy and reversible egfr tkis, with improved response and progression-free survival, compared with placebo. Outcomes in pretreated patients with advanced nsclc receiving afatinib through a Canadian special access program (sap) are reported here.

Methods

Patients with nsclc progressing after at least 1 line of chemotherapy and an egfr tki were eligible to enrol in the sap. Characteristics of patients from the two largest accruing Canadian centres were retrospectively reviewed, including demographics, disease and treatment data, and patient outcomes.

Results

The 53 patients who received afatinib (57% women, 51% never-smokers, 26% of East Asian ethnicity, and 66% with adenocarcinoma) had a median age of 59 years. EGFR mutations were documented in 25%, and EGFR wild-type in 8%. All patients had received prior egfr tki treatment, with 42% achieving a response. Patients took afatinib for a median of 2 months (range: 0–26 months); 17% required 1 or more dose reductions. Of 47 evaluable patients receiving afatinib, 10 experienced tumour shrinkage, and 11, stable disease. Median survival from afatinib initiation was 5 months (95% confidence interval: 2 months to 8 months). Grade 3 or greater diarrhea, rash, paronychia, and stomatitis were seen in 9%, 11%, 6%, and 4% of patients respectively.

Conclusions

In an unselected population of pretreated patients with advanced nsclc after tki failure, median survival with afatinib therapy was 5 months. Through a sap, afatinib demonstrated activity in clinical practice, with manageable toxicity.

KEYWORDS: Afatinib, non-small-cell lung cancer

BACKGROUND

Afatinib, an oral irreversible epidermal growth factor receptor tyrosine kinase inhibitor (egfr tki), has demonstrated superiority compared with first-line chemotherapy in advanced EGFR mutation–positive non-small-cell lung cancer (nsclc). The irreversible small-molecule tkis have shown some promise in unselected patients with advanced nsclc who have progressed on platinum-based chemotherapy or on erlotinib or gefitinib (or both)1,2.

The lux-Lung trials studied the efficacy of afatinib in both treatment-naïve and pretreated patients with advanced nsclc3,4. In the treatment-resistant setting, the lux-Lung 1 trial compared afatinib with placebo in unselected patients with advanced nsclc in whom chemotherapy and first-generation egfr tki therapy had previously failed5. The trial showed improved progression- free survival, response rate, quality of life, and symptom control with afatinib treatment, but failed to show a difference between the two groups in its primary endpoint of overall survival (os). However, a clear biologic effect of afatinib was demonstrated in pretreated patients with advanced nsclc, with response rates of up to 50% reported in clinical trials2,5.

The Canadian afatinib special access program (sap) was designed to provide access to afatinib in jurisdictions in which the drug was then not approved or funded for use. There has been a paucity of real-world data reporting outcomes in the subgroup of pretreated patients with advanced nsclc. In the present study, we report the outcomes of Canadian patients with advanced nsclc who were treated with afatinib under the sap after progressing on 1 or more lines of chemotherapy and on first-generation egfr tkis (gefitinib, erlotinib, or both). Patients accessed afatinib through the national sap that was open between 2010 and 2013. We report our experience with afatinib at the 2 largest centres participating in the Canadian sap.

METHODS

Patients and Treatment

Patients participating in the Health Canada sap from July 2010 to June 2013 at 2 major Canadian cancer centres were retrospectively identified. Ethics approval and data- sharing agreements were obtained at the 2 centres, the BC Cancer Agency (Vancouver) and Princess Margaret Cancer Centre (Toronto). Eligibility criteria for the sap were similar to those for the lux-Lung 1 trial, previously published5. Patients were required to have a diagnosis of stage iiib or iv nsclc with measurable disease, failure of 1 or more lines of chemotherapy (including adjuvant chemotherapy), and disease progression after at least 12 weeks of prior treatment with erlotinib or gefitinib.

EGFR mutation testing methods have previously been described in detail6. Briefly, EGFR mutation testing was performed using fragment analysis for exon 19 deletions and restriction fragment-length polymorphism for exon 21 L858R mutations. EGFR mutation test results were reported as positive for exon 19 deletion, positive for exon 21 L858R mutation, or negative for exon 19 deletion or exon 21 L858R mutation. Testing for T790M was not routinely performed during the period of interest.

To be eligible for the sap, patients were not required to have a tumour with an activating EGFR mutation (similar to the lux-Lung 1 study). Patients were required to have no further treatment options available to them before sap entry. The afatinib starting dose was determined at the discretion of the treating physician (up to 50 mg daily was available). Afatinib was continued until disease progression or development of intolerable adverse events.

Tumour response was assessed by oncologists (BM, NBL) who reviewed computed tomography imaging of chest to pelvis in the patients after 8 weeks of therapy, unless disease progression warranted earlier imaging. “Response” was classified as any tumour shrinkage. Stable disease was documented if tumours were unchanged in size, and progressive disease, if any tumour growth had occurred. Adverse events were assessed using the U.S. National Cancer Institute’s Common Terminology Criteria for Adverse Events (version 3.0).

Retrospective chart review of sap participants was performed at the 2 centres, including extraction of demographics, disease and treatment data, treatment duration, and os. Toxicity, duration, and response data from both the prior egfrtki and afatinib were collected.

Statistical Analysis

The association between afatinib response or toxicity and prior therapy was investigated using chi-square and logistic regression tests, as appropriate. An odds ratio greater than 1 indicates greater odds of response to afatinib. Overall survival was determined from the date of treatment start to the date of death, regardless of cause. Survival analysis was performed using the Kaplan–Meier method. All tests of significance (p values) were 2-sided. Statistical significance was accepted at p < 0.05. The analysis was carried out using the SAS software application (version 9.3: SAS Institute, Cary, NC, U.S.A.).

RESULTS

Patient Characteristics

Between July 2010 and June 2013, 53 patients (57% women, 51% never-smokers, 66% with adenocarcinoma histology, 26% of East Asian ethnicity) were enrolled in the Health Canada sap at the 2 participating centres and received afatinib. Median age in the group was 59 years (Table i). EGFR mutation data were available for only 17 patients, and 13 of those 17 had documented activating mutations.

TABLE I Demographics and treatment history for the study patients

 

Prior Therapy

Patients had received a median of 3 prior therapies, including a prior egfr tki (Table i). Most patients had been exposed to chemotherapy (almost 100%), mainly platinum- based regimens. Most had received prior erlotinib (81%), and some had received both erlotinib and gefitinib. Response to prior egfr tkis was 42%, with approximately one third of the group experiencing grade 2 or greater rash and 8% experiencing grade 2 or greater diarrhea with their first egfrtki.

Afatinib Treatment Outcomes and Adverse Events

The median time from metastatic diagnosis to afatinib start was 23.5 months (range: 3.0–94 months; Table ii). Median duration of therapy was 2.0 months (range: 0–26 months). Most patients started at a dose of 40 mg daily, although 3 patients (5.7%) started at a dose of 50 mg daily. During afatinib therapy, 8 patients (15%) had 1 dose reduction, and 1 patient had 2 dose reductions (2%). Of the evaluable patients, best response to therapy was tumour shrinkage in 19%, stable disease in 21%, and progressive disease in 49%. Of the 10 patients who experienced tumour regression with afatinib, 2 had EGFR wild-type tumours, 3 had EGFR mutation–positive tumours, and the remaining 5 had an unknown genotype. Median survival in afatinib-treated patients was 5.0 months (95% confidence interval: 2.0 months to 8.0 months; Figure 1).

 


 

FIGURE 1 Median survival in patients treated with afatinib in a Canadian special access program.

TABLE II Afatinib treatment and outcomes in 53 patients

 

At the time of the analysis, 47 of the 53 patients (89%) had stopped afatinib therapy. The most common reasons for treatment discontinuation were disease progression (34%), deterioration in performance status (30%), and afatinib toxicity (17%). Grade 3 rash was seen in 11% of the patients, diarrhea in 9%, paronychia in 6%, and stomatitis in 4%.

Predictors of Afatinib Response and Toxicity

The association between response to a prior egfr tki and subsequently to afatinib was not statistically significant (chi-square p = 0.12). No association between duration of prior egfr tki therapy and afatinib response was observed (odds ratio: 1.02; 95% confidence interval: 0.96 to 1.09). No significant association between afatinib response and other variables such as rash or diarrhea during prior egfr tki therapy was observed (chi-square p = 0.10).

DISCUSSION

Heavily pretreated patients with advanced nsclc present a challenge because of a lack of effective treatment options. Afatinib was approved by the U.S. Food and Drug Administration, the European Medicines Agency, and Health Canada, among other jurisdictions, for the first-line treatment of patients with advanced EGFR-mutated nsclc3,8,9. Our analysis describes a Canadian experience of afatinib use in pretreated patients with advanced nsclc at 2 large cancer centres.

We found that up to 40% of our patients achieved either tumour regression or stable disease with afatinib therapy and that median survival from the start of afatinib therapy was 5 months. In the pivotal lux-Lung 1 trial and other similar populations, response rates of 10%–20% were reported5,10. The lux-Lung 1 trial reported a median os of 10.8 months in afatinib-treated patients. Additionally, lux-Lung 1 reported rates of grade 3 or greater diarrhea that were higher than were found in our study, although the rash and stomatitis rates were similar. Given that the real-world patient population in our analysis was more heavily pretreated (70% received >2 lines of prior therapy) and more heterogeneous than that in the lux-Lung 1 trial, those differences in outcome are explainable. It should also be noted that these data all precede the advent of immunotherapy. Given that first-line immunotherapy has now become the standard of care in the treatment of advanced nsclc with high PD-L1 expression, the role of afatinib therapy in an unselected heavily pretreated nsclc population remains to be determined.

Our data demonstrate afatinib activity not only in patients with EGFR sensitizing mutations (25%), but also in patients with wild-type EGFR (8%). It is possible that EGFR sensitizing mutations other than the common mutations detected by earlier institutional assays might have been present in the population classified as “wild type” in our analysis. In patients with uncommon EGFR mutations (specifically, subtypes such as G719X, L861Q, and S768I), response rates of 56%–100% have been described with first-line afatinib therapy11. Shen et al.12 reported superior response rates for afatinib compared with erlotinib or gefitinib in patients with uncommon mutations. In heavily pretreated patients, Heigener et al.10 reported clinical activity for afatinib in patients with uncommon mutations, but inferior efficacy for those with the common exon 19 and 21 mutations.

Use of afatinib in a sap for pretreated patients with advanced nsclc in Germany and the United Kingdom achieved response rates similar to those we found (15%–20%)13,14. Those prior data showed that an EGFR mutation was present in up to 80% of the population receiving afatinib therapy. Although most patients in our sap had an unknown EGFR mutation status, the clinical characteristics in most of our cohort raise the possibility of a predominantly EGFR-mutated population. Response rates comparable to those demonstrated by prior data further strengthen that possibility.

Most patients in our cohort had previously received an egfr tki. Unlike the first-generation egfr tkis, afatinib is an irreversible pan-egfr inhibitor, which is theoretically able to overcome acquired first-generation egfr tki resistance. Indeed, afatinib has shown some activity in overcoming such resistance10,15. That action could potentially be augmented if afatinib is combined with other egfr-targeted agents such as egfr-directed monoclonal antibody therapy16.

Recently, acquired resistance to first-generation egfr tkis has been shown to occur by multiple mechanisms, the most common being the development of a T790M mutation in the EGFR gene, which causes resistance of the egfr protein to gefitinib and erlotinib17. That mutation occurs in 50%–60% of patients with acquired resistance to first- generation egfr inhibitors. Osimertinib is a third- generation egfr tki with activity against tumours with the T790M mutation and other somatic tki-sensitizing EGFR mutations. It has been approved for the treatment of patients with metastatic EGFR T790M mutation–positive nsclc whose disease has progressed on or after initial egfr tki therapy8,9,18. Emerging data have demonstrated the safety and efficacy of osimertinib as first-line therapy in EGFR mutation–positive nsclc, with upcoming data comparing third-generation osimertinib with first- generation gefitinib or erlotinib as initial therapy19. In preclinical models, greater activity in EGFR-mutant nsclc brain metastases has been shown for osimertinib than for other tkis (gefitinib, afatinib, rociletinib)20. After development of resistance to osimertinib therapy, some response to gefitinib has been described21. Ultimately, the optimal sequencing of the second- and third-generation egfr inhibitors is not well understood. Future studies should delineate the ideal sequencing of the egfr tkis and should examine whether there remains a role for afatinib after failure of osimertinib or in EGFR T790M–negative disease that is still driven by the egfr signalling pathway.

Some limitations of our study should be noted. The percentage of patients with an unknown EGFR genotype did not allow for optimal characterization of the specific EGFR-mutant population that achieved some tumour shrinkage with prior egfr tkis and with afatinib therapy. Regardless, the population of patients analyzed in this study were pretreated and might represent a heterogeneous group with respect to acquired oncogenic driver mutations, with only limited molecular analysis (mutations in exons 19 and 21) available during the study period.

In the pre-osimertinib era (or the present day T790M-negative setting), patients with progressive nsclc who develop acquired resistance to egfr tkis are often treated with cytotoxic chemotherapy. There are some reports of efficacy with egfr tki rechallenge after development of resistance to first-line tkis2224. Response to egfr tki re-challenge appears to be associated with a sufficient tki-free interval and prior exposure to cytotoxic chemotherapy22. Although the mechanisms for sensitization to egfr tki re-challenge are not fully understood, such sensitization might be attributable to alteration, by cytotoxic chemotherapy, of the initial genetic changes that resulted in tki resistance. An alternative mechanism might be repopulation by the egfr tki–sensitive clones. Future studies elucidating the role of afatinib rechallenge in patients with EGFR-mutated T790M-negative advanced nsclc will be of importance25.

Our data relate to the activity of afatinib in heavily pretreated patients with advanced nsclc. Specifically, afatinib rechallenge might have a role to play in patients with T790M-negative disease.

CONCLUSIONS

The present analysis provides real-world evidence of the activity of afatinib in unselected patients with advanced nsclc who have progressed on chemotherapy and prior egfr tkis. Of 47 evaluable patients, 10 experienced tumour shrinkage with afatinib, and median survival was 5.0 months in this heavily pretreated patient population.

ACKNOWLEDGMENTS

The authors thank Manstein Kan md of BC Cancer, Vancouver, British Columbia. This work was previously presented in part at the 15th World Conference on Lung Cancer; Sydney, Australia; 27–30 October 2013. The divisions of Medical Oncology at the Princess Margaret Cancer Centre and BC Cancer provided funding for this work. NBL is supported by the Princess Margaret Cancer Foundation osi Pharmaceuticals Foundation Chair.

CONFLICT OF INTEREST DISCLOSURES

We have read and understood Current Oncology’s policy on disclosing conflicts of interest, and we declare that we have no relevant conflicts.

AUTHOR AFFILIATIONS

*Princess Margaret Cancer Centre, University Health Network, Toronto, ON,
BC Cancer–Vancouver Centre, Vancouver, BC,
University of Calgary, Calgary, AB,
§London Health Sciences Centre, London, ON,
||Division of Biostatistics, Dalla Lana School of Public Health, University of Toronto, Toronto, ON.

REFERENCES

1 Ramalingam SS, O’Byrne K, Boyer M, et al. Dacomitinib versus erlotinib in patients with EGFR-mutated advanced nonsmall-cell lung cancer (nsclc): pooled subset analyses from two randomized trials. Ann Oncol 2016;27:423–9. [Erratum in: Ann Oncol 2016;27:1363]
cross-ref  pubmed  

2 Yang JC, Shih JY, Su WC, et al. Afatinib for patients with lung adenocarcinoma and epidermal growth factor receptor mutations (lux-Lung 2): a phase 2 trial. Lancet Oncol 2012;13:539–48.
cross-ref  pubmed  

3 Sequist LV, Yang JC, Yamamoto N, et al. Phase iii study of afatinib or cisplatin plus pemetrexed in patients with metastatic lung adenocarcinoma with EGFR mutations. J Clin Oncol 2013;31:3327–34.
cross-ref  pubmed  

4 Wu YL, Zhou C, Hu CP, et al. Afatinib versus cisplatin plus gemcitabine for first-line treatment of Asian patients with advanced non-small-cell lung cancer harbouring EGFR mutations (lux-Lung 6): an open-label, randomised phase 3 trial. Lancet Oncol 2014;15:213–22.
cross-ref  pubmed  

5 Miller VA, Hirsh V, Cadranel J, et al. Afatinib versus placebo for patients with advanced, metastatic non-small-cell lung cancer after failure of erlotinib, gefitinib, or both, and one or two lines of chemotherapy (lux-Lung 1): a phase 2b/3 randomised trial. Lancet Oncol 2012;13:528–38. [Erratum in: Lancet Oncol 2012;13:e186]
cross-ref  pubmed  

6 Martin P, Shiau CJ, Pasic M, et al. Clinical impact of mutation fraction in epidermal growth factor receptor mutation positive nsclc patients. Br J Cancer 2016;114:616–22.
cross-ref  pubmed  pmc  

7 Yang JC, Hirsh V, Schuler M, et al. Symptom control and quality of life in lux-Lung 3: a phase iii study of afatinib or cisplatin/pemetrexed in patients with advanced lung adenocarcinoma with EGFR mutations. J Clin Oncol 2013;31:3342–50.
cross-ref  pubmed  

8 United States, Department of Health and Human Services, Food and Drug Administration. NDA Approval [letter, for afatinib] Silver Spring, MD: fda; 2013. [Available online at: https://www.accessdata.fda.gov/drugsatfda_docs/appletter/2013/201292Orig1s000ltr.pdf; cited 27 August 2018]

9 European Medicines Agency (ema). EPAR Summary for the Public: Giotrif [afatinib]. London, U.K.: ema; 2013. [Available online at: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Summary_for_the_public/human/002280/WC500152395.pdf; cited 27 August 2018]

10 Heigener DF, Schumann C, Sebastian M, et al. Afatinib in non-small cell lung cancer harboring uncommon EGFR mutations pretreated with reversible egfr inhibitors. Oncologist 2015;20:1167–74.
cross-ref  pubmed  pmc  

11 Yang JC, Sequist LV, Geater SL, et al. Clinical activity of afatinib in patients with advanced non-small-cell lung cancer harbouring uncommon egfr mutations: a combined post-hoc analysis of lux-Lung 2, lux-Lung 3, and lux-Lung 6. Lancet Oncol 2015;16:830–8.
cross-ref  pubmed  

12 Shen YC, Tseng GC, Tu CY, et al. Comparing the effects of afatinib with gefitinib or erlotinib in patients with advanced-stage lung adenocarcinoma harboring non-classical epidermal growth factor receptor mutations. Lung Cancer 2017;110:56–62.
cross-ref  pubmed  

13 Schuler M, Fischer JR, Grohé C, et al. on behalf of the Afatinib Compassionate Use Consortium. Experience with afatinib in patients with non–small cell lung cancer progressing after clinical benefit from gefitinib and erlotinib. Oncologist 2014;19:1100–9.
cross-ref  pubmed  pmc  

14 Khan F, Ottensmeier C, Popat S, et al. Afatinib use in non–small cell lung cancer previously sensitive to epidermal growth factor receptor inhibitors: the United Kingdom Named Patient Programme. Eur J Cancer 2014;50:1717–21.
cross-ref  pubmed  

15 Heigener DF, Reck M. Mutations in the epidermal growth factor receptor gene in non–small cell lung cancer: impact on treatment beyond gefitinib and erlotinib. Adv Ther 2011;28:126–33.
cross-ref  

16 Janjigian YY, Smit EF, Groen HJ, et al. Dual inhibition of egfr with afatinib and cetuximab in kinase inhibitor–resistant EGFR-mutant lung cancer with and without T790M mutations. Cancer Discov 2014;4:1036–45.
cross-ref  pubmed  pmc  

17 Nguyen KS, Kobayashi S, Costa DB. Acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors in non-small-cell lung cancers dependent on the epidermal growth factor receptor pathway. Clin Lung Cancer 2009;10:281–9.
cross-ref  pubmed  pmc  

18 Mok TS, Wu YL, Ahn MJ, et al. Osimertinib or platinum- pemetrexed in EGFR T790M–positive lung cancer. N Engl J Med 2017;376:629–40.
cross-ref  

19 Soria JC, Ohe Y, Vansteenkiste J, et al. on behalf of the flaura investigators. Osimertinib in untreated EGFR-mutated advanced non-small-cell lung cancer. N Engl J Med 2018;378:113–25.
cross-ref  

20 Ballard P, Yates JW, Yang Z, et al. Preclinical comparison of osimertinib with other egfr-tkis in EGFR-mutant nsclc brain metastases models, and early evidence of clinical brain metastases activity. Clin Cancer Res 2016;22:5130–40.
cross-ref  pubmed  

21 Chic N, Mayo-de-Las-Casas C, Reguart N. Successful treatment with gefitinib in advanced non–small cell lung cancer after acquired resistance to osimertinib. J Thorac Oncol 2017;12:e78–80.
cross-ref  

22 Tomizawa Y, Fujita Y, Tamura A, et al. Effect of gefitinib re- challenge to initial gefitinib responder with non–small cell lung cancer followed by chemotherapy. Lung Cancer 2010;68:269–72.
cross-ref  

23 Oh IJ, Ban HJ, Kim KS, Kim YC. Retreatment of gefitinib in patients with non-small-cell lung cancer who previously controlled to gefitinib: a single-arm, open-label, phase ii study. Lung Cancer 2012;77:121–7.
cross-ref  pubmed  

24 Kuiper JL, Heideman DA, Würdinger T, Grünberg K, Groen HJ, Smit EF. Rationale and study design of the irene-Trial (nvalt-16): a phase ii trial to evaluate Iressa rechallenge in advanced nsclc patients with an activating EGFR mutation who responded to an egfr-tki used as first-line or previous treatment. Clin Lung Cancer 2015;16:60–6.
cross-ref  

25 Oda N, Ichihara E, Hotta K, et al. Phaseii study of the egfr-tki rechallenge with afatinib in patients with advanced nsclc harboring sensitive EGFR mutation without T790M: Okayama Lung Cancer Study Group Trial olcsg1403. Clin Lung Cancer 2017;18:241–4.
cross-ref  


Correspondence to: Natasha B. Leighl, Princess Margaret Cancer Centre, 7-913 700 University Avenue, Toronto, Ontario M5G 1Z5. E-mail: Natasha.Leighl@uhn.ca

aSenior responsible co-authors. ( Return to Text )

bThese authors contributed equally to the present work. ( Return to Text )


Current Oncology, VOLUME 25, NUMBER 5, October 2018








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