In a review of the evolution of tyrosine kinase inhibitors (TKIs) for the treatment of epidermal growth factor receptor (EGFR) mutated lung cancer, PhD candidate, Dr Pei Ding, a Medical Oncologist from the Nepean Cancer Care Centre painted a compelling picture to use the best treatments up front to her colleagues at the Roche Lung Day 2019. “I think the important thing to keep in mind is to use the best we’ve got earlier, as not every patient is going to make it through every generation of TKI we have. The iterations in molecule development mean we’ve got the ability to be more personalised in our approach,” explained Dr Ding.

First-line, first-generation TKIs changed the game for EGFR+ lung cancer

“The IPASS study showed the value of a TKI versus chemotherapy in the frontline setting.¹ It’s been well-demonstrated now across a number of trials that progression-free survival (PFS) is prolonged versus chemotherapy with the first-generation molecules, but overall survival (OS) was not.² They are useful in patients with a poor Eastern Cooperative Oncology Group (ECOG) performance, such as the elderly, where they produced good responses,”³ said Dr Ding.

Second-generation TKIs was the battle between efficacy and toxicity

“In an attempt to produce more potent, less toxic treatments, we learnt more about the role of the irreversible covalent bonds. When applied to TKIs we saw the rise of afatanib, dacomitinib and the demonstration of its superiority to gefitinib in terms of PFS,”^4,5 explained Dr Ding. She presented data on the utility of second-generation TKIs in uncommon mutations of LUX-Lung 2,3 and 6.⁶ “Even today,” she continued, “it’s a balance between toxicity vs efficacy. As we evolve the treatments it’s not that we decrease toxicity altogether, we’re dealing with different types of toxicity. For example, one treatment might have a higher incidence of diarrhoea, but lower incidence of rash. That means we need to stay across the nuances so we can monitor and manage them.”

Third-generation TKIs – should the winner win it all?

Dr Ding explained the search for lead molecules began in 2009 with a library search against resistant NSCLC isolates.⁷ “This is where they discovered osimertinib,” said Dr Ding, “which led to where we are today with the results of the FLAURA study showing improved survival versus first-generation TKIs.⁸ But for me, one of the important findings of FLAURA was that one third of patients didn’t receive any subsequent anticancer treatments. This is a strong reason to use the best treatment we have first as we know OS is still not where we want it to be.”

Sequence or combine non-small cell lung cancer therapies?

Finally, Dr Ding discussed the combination treatment approaches and the complexity of trial comparison that makes treatment guidance a challenge. “We’ve got first-line combinations of TKIs with chemotherapy and with immune-oncology(I-O) therapies – with studies done in different populations and a range of PFS improvements versus first-generation TKI monotherapy. There’s also the IMPOWER 150 study that now shows four-drug combination therapy improves PFS and OS in patients with EGFR and ALK mutations after failure of appropriate targeted therapies.⁹ On the flip side, data from IMPRESS suggests you don’t want to be using a TKI at progression as this had a detrimental effect on OS.”¹⁰

Here’s Dr Ding’s summary of TKI options in NSCLC:

First line

• Osimertinib* or afatinib rather than first-generation TKI

At progression with first-line TKI

• Osimertinib for T790M positive
• 4-drug combination for T790M negative

*Osimertinib not listed on the PBS for first line therapy

This article was sponsored by Roche, which has no control over editorial content. The content is entirely independent and based on published studies and experts’ opinions, the views expressed are not necessarily those of Roche.

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