Jack West, MD: Use of TKI Therapy in Patients with EGRF Exon 21 Substitutions (L858R)

What efficacy data support the use of this TKI therapy in a patient such as Sarah with EGFR exon 21 substitutions (L858R)?

Over the last several years several different trials with various EGFR TKIs have  demonstrated a  profound improvement in PFS. Much higher response rates in  patients withEGFRmutation specifically and activating mutation such as an exon 19 deletion or L858R substitution in exon 21. Patients who receive the oral therapy do remarkably better than those on standard chemotherapy and because of that, it has become a clear standard of care for us to give one of these oral therapies as a first-line treatment for patients who are prospectively identified as having an activatingEGFRmutation.

In patients with an exon 19 deletion there is actually evidence that afatinib, in particular, is associated with a survival benefit compared with chemotherapy that hasn’t been seen with other agents. In patients with an exon 21 L858R substitution there is not that survival difference demonstrated, but you do have the same remarkable improvement in PFS and response rate, and it is one of the handful of agents that we would reach for first, such as afatinib, gefitinib, or possibly, erlotinib.

It is certainly a compelling option to pursue in  any patient with a knownEGFRmutation.

CASE 2: mNSCLC

Sarah W. is a 58-year old physical therapist from Brooklyn, New York who is also active in a community theater group; her prior medical history is notable for mild GERD controlled with diet and proton pump inhibitor, and hyperlipidemia, controlled with atorvastatin.

She has a 12-pack-year smoking history but quit about 20 years ago after developing a severe respiratory infection. After showing chest x-ray abnormalities on a routine visit to her PCP, she is referred for further evaluation.

Her initial CT scan shows multiple bilateral lung nodules, a large 8-cm mass in the left upper lobe (LUL), suspicious for malignant pleural effusion, and several hepatic nodules

Transbronchial biopsy of the LUL mass shows adenocarcinoma T3 (based on size); biopsy of the hepatic nodules was consistent with metastatic disease, and she was deemed unresectable on surgical consult

Mutational status was reported asEGFRexon 21 (L858R) substitution; no other actionable mutations detected

At the time of diagnosis the patients performance status is 0

Sarah wishes to continue with her normal work schedule and rehearsals for an upcoming community theater production. Her oncologist initiates her on afatinib 40 mg/day.

At her 2-week follow-up, she shows symptoms of increasing diarrhea (≥6 stools/day), which has not improved with antidiarrheals, and a papular rash on her upper arms

Rash is not very itchy or bothersome, however, diarrhea interferes with both her work schedule and rehearsals

Diet modifications and loperamide are recommended for diarrhea, and topical corticosteroids for her rash; she continues therapy at 40 mg/day

At 3 months, while other symptoms have begun to improve, she shows symptoms of gingival stomatitis, and the nursing team recommends diet modifications and a mouth rinse as needed; she continues therapy at 40 mg/day

At her next follow-up, CT scan shows stable disease, with shrinkage in the primary mass and no new hepatic nodules.

Her diarrhea has improved to grade 1 with loperamide and diet; stomatitis and rash have been effectively managed with prior recommendations