COMMENTARY

Gefitinib Plus Chemo for NSCLC With EGFR Mutations

Mark G. Kris, MD

Disclosures

July 27, 2020

This transcript has been edited for clarity.

Hello. This is Mark Kris from Memorial Sloan Kettering Cancer Center.

A series of articles recently appeared about the use of chemotherapy with osimertinib and other EGFR tyrosine kinase inhibitors (TKIs) as initial therapy. Together they make a strong statement that we need to do more for patients with EGFR-positive disease, in addition to the TKIs we recommend, and that chemotherapy is probably an effective and immediately available way to extend their lives.

We know that osimertinib and the earlier generations of agents are effective. They are beneficial with relatively few adverse effects compared with other agents. However, no one is cured by these agents and eventually they fail. Yes, it's much better with osimertinib, but sadly, they fail nonetheless.

There has been a long history of using chemotherapy with these drugs. Much of the older literature with chemotherapy was in patients without EGFR mutations. Really, you can't count that other than for toxicity, and maybe even that isn't legitimate because those patients have a different disease.

When you look at the literature about giving chemotherapy to patients with EGFR mutations, you find that there is good preclinical evidence that it works and may work better. When you look at the clinical trial data, like in the IPASS trial, patients with EGFR mutations had twice the response rate with chemotherapy than those who did not. Chemotherapy works in these patients.

The three articles that have come out in the past few months — the article by Noronha and the article by Hosomi in the Journal of Clinical Oncology, and the article by Yang in the Journal of Thoracic Oncology — also demonstrate impressive improvements in progression-free survival (PFS).

To me, PFS is the standard we need to meet. PFS means a life approximating the normal life of our patients before they had cancer. Any kind of a relapse is a health crisis and an emotional crisis. Relapse is associated with much more dire outcomes, so preventing relapse is important.

In the articles, there was a strong improvement in PFS over the single-agent comparator: 8 months and 10 months in the two Journal of Clinical Oncology articles and 5 months in the Journal of Thoracic Oncology article, giving pemetrexed as a single agent. That degree of improvement over an established active standard is the highest that has been reported in these kinds of trials. If we can say that we're going to have 8 and 10 months' improvement in PFS when adding chemotherapy upfront with TKIs, what can we do when we add it to osimertinib? That is where we're going; to me, that is the future.

From the two articles in Journal of Clinical Oncology and the accompanying editorial by Rotow and Jänne, the conclusion is that for patients without access to first-line osimertinib, the overall survival benefit demonstrated in these two studies establishes a new standard of care: upfront gefitinib with carboplatin plus pemetrexed chemotherapy for first-line treatment of non–small cell lung cancer with EGFR-activating mutations. I agree with the editorialists here. It makes sense, and we need to do more for these patients.

There are other ways to do more.

Remember the role of local therapies in treating oligometastases, oligo–residual disease, or oligoprogression.

There is clearly a role for antiangiogenesis drugs, both bevacizumab and ramucirumab. But the effects of combining them with these agents have not been studied and will be a source of debate. These antiangiogenesis drugs have been around for quite a while, yet the oncology and thoracic oncology communities have not embraced them. It's my understanding that less than 20% of patients with lung cancers who were eligible to receive bevacizumab back in the day, before the checkpoint inhibitor era, still didn't receive it. Oncologists have walked away from these drugs.

Chemotherapy is the future. As Rotow and Jänne said in their editorial, it's a new standard of care. I urge you to think about adding chemotherapy to every patient with newly diagnosed EGFR-mutant lung cancer. My own bias would be to add it to osimertinib.

Mark G. Kris, MD, is chief of the thoracic oncology service and the William and Joy Ruane Chair in Thoracic Oncology at Memorial Sloan Kettering Cancer Center in New York City. His research interests include targeted therapies for lung cancer, multimodality therapy, the development of new anticancer drugs, and symptom management with a focus on preventing emesis.

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