Living Longer: Stage 4 Lung Adenocarcinoma EGFR Mutation positive

Introduction

Firstly, with optimal palliative chemotherapy treatment for stage 4 lung cancer, the average survival is slightly under a year; 7.4 months – 8.1 months (Schiller JH, 2002), which doubled the average survival with just best supportive care, 3.9 months.

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Outcome according to different platinum-doublet treatment groups. The plateau of chemotherapy efficacy – all almost similar duration of survival. Schiller JH (2002)
Screen Shot 2018-07-03 at 11.55.48 AM.png
Overall Survival (Panel A) and the Time to Progression of Disease (Panel B) in the Study Patients, According to the Assigned Treatment – All almost similar!. Schiller JH (2002)

Although improvement in survival was achieved with chemotherapy, it seemed like chemotherapy alone had reached it’s maximal possible/ plateau results for advanced lung cancer.

Newer therapy was finally available in 2004, when EGFR tyrosine kinase inhibitor (TKI) was first made available.

In healthy and normal cells, EGFR allows cells to grow and divide. When there are mutation in EGFR receptors, cells begin to change and grow uncontrollably, forming a mass of cancer cells called a tumor.

EGFR tyrosine kinase inhibitors (EGFR TKIs), is a type of targeted therapy that can ONLY treat lung cancer with EGFR mutation.

For wild type (non-mutated) EGFR, this treatment is not effective at all.

EGFR TKIs block EGFR mutant from working, which help to stop or slow tumor growth.

EGFR mutation is much higher in Asian populations compared with Western population.

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Advanced lung adenocarcinoma mutation frequency in Asian and Caucasion populations. K Li (2017)

The Advancement

Screen Shot 2018-11-06 at 10.51.36 PM.png
Types of EGFR TKIs – 1st, 2nd and 3rd generation and their landmark papers. More details below about each of the EGFR TKI and its efficacy (median overall survival, progression free survival) 

1st generation EGFR TKIs (gefitinib, erlotinib)

Gefitinib (IPASS, WJTOG-3405, NEJ002)

  • Duration of progression free survival (PFS) ranges from 5.7 months – 10.8 months.
  • Average/ median overall survival (OS) ranges from 18.6 months – 34.8 months.
  • Patient assistance programme 2+1 (free) and free for life after 4 cycles – purchase 8x in total.

Erlotinib (OPTIMAL, EURTAC)

  • Duration of progression free survival (PFS) ranges from 9.7 months – 13.1 months.
  • Average/ median overall survival (OS) ranges from 22.8 months – 22.9 months.
  • Free for life after 10 months purchase.

2nd generation EGFR TKIs (afatinib, dacomitinib)

Afatinib (LUX-Lung 3, LUX-Lung 6, LUX-Lung 7)

  • Duration of progression free survival (PFS) ranges from 11 months – 11.1 months.
  • Average/ median overall survival (OS) ranges from 19.3 months – 27.9 months.
  • There is new patient assistance program; 1, FOC, 1, 1, 1, FOC, 1, 1, 1, FOC, 1, 1, 1, Free until progression disease – purchase 10x in total.

Dacomitinib (ARCHER 1050) – Not available in Malaysia yet

  • Duration of progression free survival (PFS) is 16.6 months.
  • Average/ median overall survival (OS) is 34.1 months.
  • Not available in Malaysia yet.

3rd generation EGFR TKIs (osimertinib)

Osimertinib (AURA 3, FLAURA)

  • Duration of progression free survival (PFS) ranges from 10.1 months (second line treatment) – 18.9 months (first line treatment).
  • Survival rate at 18 months was 83%.
  • Patient assistance programme 1+1 (free) and free for life after purchasing 8 times.

Progression free survival (PFS) is the duration of disease control with the treatment before it’s not effective anymore.

So, the cost of treatment can be roughly calculated by multiplying the PFS (number of months) with the monthly cost of the medication.

Achieving More For Less

The Combinations

By optimally using 1st generation EGFR TKI (by combining chemotherapy platinum doublet), duration of survival could be improved around 50%.

Average/ median overall survival was more than 4 years or 52.2 months to be exact (A Inoue, 2014).

As the cost of 1st generation EGFR TKI treatment is minimal and not as high as 3rd generation EGFR TKI treatment, a lot of cost saving can be achieved.

Screen Shot 2018-07-04 at 1.29.08 PM.png
NEJ 009; Presented By Atsushi Nakamura at 2018 ASCO Annual Meeting

However, combination with biologic therapy doesn’t’ seem to offer much benefit compared to 1st generation EGFR TKI alone (see below) for the time being.

Further combination trials using 2nd generation EGFR TKI with biologic therapy is being conducted.

Screen Shot 2018-07-04 at 1.28.33 PM.png
JO 25567; Presented By Noboru Yamamoto at 2018 ASCO Annual Meeting

The Sequencing

The dilemma faced by clinicians these days is whether to use 3rd generation EGFR TKI immediately as first line or second line because of the encouraging results from both AURA3 and FLAURA clinical trials.

Secondly, it is because of the high cost of treatment with 3rd generation EGFR TKI in country like Malaysia, where most of the latest/ newest medications are not reimbursable (patients pay for the medication themselves).

Clinicians are also left pondering what treatment to use after failure of 3rd generation EGFR TKI because 4th generation EGFR TKI or other newer treatments are still not available yet.

There is study of second line treatment with osimertinib (AURA 3) after failure of first line treatment but there is no study of any second line treatment after failure of osimertinib (FLAURA). Confused? (see diagram below, no recommended treatment available after osimertinib).

Finally, there is a study that showed that those who are on 3rd generation EGFR treatment for mutation exon 20 T790M, and then end up with loss of T790M during treatment (and progression disease) will end up having poorer prognosis.

Screen Shot 2018-07-04 at 1.31.44 PM.png
Progress in the Management of Advanced Thoracic Malignancies in 2017 (R Ferrara, 2018)

Finally

In summary, as can be seen from above, average/ median overall survival (OS) and progression free survival (PFS) can be prolonged with the correct combination and sequencing of treatment based on the latest clinical trials (a lot to read up and update these days!).

Emphasis here is on how to achieve longer duration of survival, with least and tolerable side effects and at lower/ lowest cost to the patients.

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