Treatment Options for EGFR+ NSCLC

John Heymach, MD: Now what are the treatment options for this patient? Well, first of all, I’ll note that the patient has a typical EGFR mutation. The typical EGFR mutations are the exon 19 deletion or L858R which is in exon 21. And if you have those 2 different alterations, you have got several treatment options. You have first- and second-generation drugs that are still FDA approved. That’s gefitinib or erlotinib as first-generation drugs, or afatinib as a second-generation drug.

Recently, based on the results of the FLAURA study, which was a first-line study that compared osimertinib versus first-line drugs, erlotinib and gefitinib, osimertinib has become a first-line option as well. And given that it was superior in that study to the other drugs, I think many people, including myself, will often use osimertinib in the study.

Now the RELAY results actually offer another potential option for patients as well, assuming this is FDA approved and recently the RELAY results have led to a favorable ruling from ODAC which often precedes an FDA approval for a regimen.

Now the RELAY results were as follows. It was a study comparing erlotinib and ramucirumab versus erlotinib alone, or erlotinib with a placebo. And that showed a significantly improved progression-free survival, which was the primary endpoint of the study. The PFS in that study was 19.4 months as compared to 12.4 months for erlotinib alone. That’s a 7-month improvement in PFS. Now, it’s worth nothing that in the FLAURA study, osimertinib as monotherapy had an 18.9-month PFS. That’s slightly shorter than was seen in the RELAY study. If you look head-to-head with erlotinib and ramucirumab versus osimertinib, that frontline PFS results are really comparable between the 2.

Now, this brings up the question, why would one take an IV drug, ramucirumab in combination with erlotinib when you could just start with osimertinib? Well, starting with osimertinib is unquestionably still a reasonable treatment option. But I think a lot of people would consider erlotinib and ramucirumab, including myself, in good performance status patients who do not have CNS metastases because you still have the ability to use osimertinib later. So, in other words, if you start with erlotinib and ramucirumab, just about half of the patients then subsequently develop at the time of resistance, a T790M secondary mutation. And T790M mutations can be successfully treated with osimertinib. That was the original FDA label for osimertinib.

So if you start with erlotinib and ramucirumab one can then move on to osimertinib later, whereas if you start with osimertinib at the time of resistance, currently there are no FDA approved targeted regimens for resistance mechanisms that might emerge for osimertinib. Those resistance mechanisms are diverse, one from our group and a number of other groups, have shown that patients with osimertinib, who are receiving osimertinib, can develop resistance by a host of different mechanisms that include MET amplification, it includes additional EGFR mutation like a C797S mutation or L792H mutations, includes PIK3CA mutations. Other fusions like RET fusions have been observed as well; BRAF mutations and so forth. In fact, there is a whole variety of different resistance mechanisms, and in a lot of cases the resistance mechanisms can’t be seen by a genetic profiling. The reason why we may start with erlotinib and ramucirumab is at least open the option of osimertinib later if T790M alterations develop, whereas if you start with osimertinib, you don’t have the option of erlotinib and ramucirumab later.

How does PD-L1 status factor into the decision making here? Well I noted that the PD-L1 level, the TPS score was 20%. And for a patient who doesn’t have a driver alteration, with a TPS of 20%, you certainly may think about immunotherapy as an option.

But I think it’s important to note that patients with EGFR mutations do not typically have good responses to immunotherapy. In fact, in retrospective studies, the response rates for EGFR-mutant patients to single-agent immunotherapy is typically on the order of 5% to 10%, as compared to a targeted agent, if you’ve got a typical EGFR mutation where the response rates are in the range of 60% to 70% typically.

If you have the choice in the EGFR mutation between a PD-1 or a PD-L1 inhibitor or a targeted agent, the targeted agent is always the way you want to go to start with. And we typically reserve the immunotherapy further down the line after chemotherapy for patients with EGFR mutation.

So, if you put those factors together, in fact there was a typical EGFR mutation, and brain metastases were not present, I think the choice of erlotinib and ramucirumab would be a very reasonable treatment option here.

Other reasonable treatment options would include osimertinib and the other older EGFR inhibitors is afatinib, gefitinib, and erlotinib are still FDA approved. But given the recent results of the RELAY study, as well as the FLAURA study, I would usually think of adding osimertinib first or erlotinib with ramucirumab if that regimen is approved.

Transcript edited for clarity.

Case:A 68-Year-Old Man With Metastatic EGFR+ NSCLC

Initial presentation

• A 68-year-old man presented with recent onset shortness of breath and unintentional weight loss; he denies nausea, vomiting or headaches
• PMH: Hyperlipidemia controlled on a statin; former smoker, quit 10 years ago with a 30 pack-year history
• PE: Decreased breath sounds in left lower lung field on auscultation
  
  

Clinical workup

• Labs: WNL
• PFT: FEV1/FVC 55%; DLCO 65%
• Chest X-ray showed a left lower lobe soft tissue mass
• Chest/abdominal/pelvic CT showed a 3.3-cm solid pulmonary mass involving the left main bronchus and ipsilateral subcarinal lymph nodes, and adrenal metastases
• CT-guided core needle biopsy lung lesion and lymph nodes revealed grade 2 lung adenocarcinoma
• Contrast‐enhanced MRI of the brain was negative
• Molecular testing: EGFR exon 19 deletion, ALK-, ROS1-, BRAF-, PD-L1 TPS 20%
• Stage IVA – T2N2M1a; ECOG PS 1
  
  

Treatment

• Patient was started on erlotinib 150 mg PO qDay + ramucirumab 10 mg/kg IV q2weeks
  • Imaging at 3-month showed partial response with decrease size of lung and adrenal lesions
  • Imaging at 6-, 12- and 18-month follow-up showed stable disease