A New Standard of Care

Osimertinib has largely superseded first-generation agents in the United States. Rare exceptions might arise when patients with NSCLC initiate immunotherapy prior to receiving their genetic testing results, which could indicate the presence of an EGFR exon 19 or 21 mutation, thereby necessitating the transition to targeted therapy, Dr Ramalingam added. Switching from immunotherapies with long half-lives to targeted therapy can carry the potential for additional side effects due to the interaction between the drugs.

“There have been some reports that osimertinib may have more side effects compared [with] erlotinib in the post-immunotherapy setting,” making an earlier-generation EGFR inhibitor possibly more preferable in that setting, he explained.


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So far, there is no prospective phase 3 data that directly compare first-line osimertinib with second-generation agents such as afatinib or dacomitinib, Dr Santos noted. Although dacomitinib has shown activity, it was studied in patients without brain metastases and likely has higher toxicity compared with osimertinib, based on the fact that 67% of patients in the ARCHER 1050 trial (NCT01774721) required dose reduction due to toxicity, Dr Ramalingam said, adding “There is no specific setting where one would prefer dacomitinib over osimertinib.”

However, others see a use for second-generation agents. Some providers simply prefer sequential treatment—for instance, first observing how a patient’s disease responds to afatinib or dacomitinib, and then introducing osimertinib only if the patient develops a T790M mutation, Dr Santos added.

For others, toxicity management is a key factor when deciding between second- and third-generation agents for use in patients with advanced-disease. For instance, “younger patients may be able to handle some of the leukocytosis and skin toxicities better compared with older patients . . . and then they may be considered for a second-generation drug,” said Tony Mok, BMSc, MD, FRCPC, FASCO, who chairs the department of clinical oncology at the Chinese University of Hong Kong.

Another consideration is cost, added Dr Mok, who is distinguished as the Li Shu Fan Medical Foundation Professor of Clinical Oncology. “In many parts of the world, patients have to self-pay. If you had to pay out of pocket, a third-generation drug is a lot more expensive, and so that is a realistic factor that determines the choice of the drug.”

Adding to this growing treatment portfolio and putting first-generation agents back into the spotlight, the FDA recently approved erlotinib in combination with the anti-angiogenic VEGFR2-targeting antibody ramucirumab (Cyramza) for the first-line treatment of patients with metastatic NSCLC with EGFR exon 19 or exon 21 L858R mutations.13 The May 29, 2020 indication was based on results from the phase 3 RELAY study (NCT02411448), in which 449 patients without brain metastases were randomly assigned to receive erlotinib with either intravenous ramucirumab or placebo. The dual blockade of the EGFR and VEGF pathways showed significantly longer PFS (19.4 months) compared with placebo (12.4 months).14

A remarkable finding of that study, Dr Santos said, is that similar PFS was obtained in patients irrespective of whether they had the exon 21 anomaly or the exon 19 mutation.

By contrast, data from previous studies have suggested that the exon 19 deletion is much more sensitive to TKI therapy—including osimertinib—than the exon 21 mutation, and PFS was much lower with the latter.

“[The RELAY] study opened [up] the possibility that if you have someone with an exon 21 [mutation] and the patient does not have any brain metastases . . . and there is no contraindication to use [ramucirumab], then the patient has 2 options: To use either osimertinib as a single agent or the combination of erlotinib plus [ramucirumab],” Dr Santos said. When he sees such patients, he discusses the data available to make a decision with them, he added.

A major disadvantage with the doublet therapy, however, is that patients have to visit the clinic regularly to receive intravenous (IV) ramucirumab; patients and doctors usually prefer an oral medication, Dr Mok said.

In addition, the trial has yet to report OS results, and the IV administration of ramucirumab comes with additional toxicities that warrant consideration such as proteinuria and hypertension, Dr Ramalingam added. Given that osimertinib has now become the standard therapy, “the utility of this combination in practice is limited,” he said. “I [use] osimertinib in the clinic.”