Thread by @Garth_Nicholas1

7 November: IPASS and cross-over

This year for Lung Cancer Awareness Month #LCAM I’m going to summarize 30 important lung cancer trials over 30 days. These posts are directed at non-medical professionals, with descriptions of the results and of what makes a good trial.#lcsm 1/13

Lung cancer with an EGFR mutation is in some ways similar to the ALK mutations we discussed two days ago. It’s a type of lung cancer that tends to affect non-smokers, and accounts for around 4-5% of all lung cancers. Today’s trial was a pivotal advance in its treatment, from 2009

Early in the EGFR story we had drugs that inhibited the action of EGFR, but were not sure what test would best determine who would respond to those drugs. Expression of EGFR protein? Extra copies of EGFR gene? Changes (mutation) in EGFR gene? 3/13

This trial enrolled patients with advanced lung cancer and characteristics known to be associated with EGFR mutation: former or non-smokers of east Asian ancestry. They were randomized to receive either standard chemotherapy or the EGFR inhibitor Gefitinib (Iressa). 4/13

The primary outcome was time to the cancer worsening (progression-free survival, PFS). There was a planned subgroup analysis to look at those with and without an EGFR mutation. The trial design was for non-inferiority, a topic that we’ll cover at a later date. 5/13

PFS was slightly better with gefitinib in the whole study population (Panel A below).
But in the EFGR mutation subgroup median PFS was about 4 months longer with gefitinib (p<0.001 Panel B).
In the group with no mutation PFS was about 4 months longer with chemo (p<0.001 Panel C)

People with mutation who got gefitinib had greater improvement in quality of life and fewer side effects from treatment than people on chemo.
This trial established that presence of EGFR mutation is the correct test to identify those who will benefit from EGFR blocking drugs.

Given all the advantages of gefitinib, it may come as a surprise to hear that for patients with EGFR mutation the overall survival was the same in the two arms (21.6 vs 21.9 months, p=0.99). This is probably related to an important factor: cross-over 8/13

Cross-over is when study participants who were randomized to one treatment get the other treatment after study completion. For instance, in this study, 66% of patients with EGFR mutation on the chemo arm got gefitinib after their tumours progressed on chemo. 9/13

This suggests that people with EGFR mutation will get the survival benefit of gefitinib whether it's given as their 1st or 2nd treatment, as long as they get it at some point. Crossover is a reason why highly beneficial drugs may not seem to demonstrate a survival advantage.10/13

Trials like this one, and the crizotinib trial described 5 November, had an unexpected effect on lung cancer research: a population of long-living, reasonably well people with lung cancer is probably a prerequisite to the development of patient advocacy groups. 11/13

These groups, like @EGFRResisters, @ros1cancer, and @ALKCancer among others, have become powerful sources of community and advocacy for people living with cancer and their families, as well as increasingly influential research partners. 12/13

@TonyMok9 led this trial and is active on Twitter. We'd love to hear any comment or recollections.
I hope you’ll be back tomorrow when we’ll take our first look at a mesothelioma trial. See you then! 13/13