Oncogene-Positive Lung Cancer: What Therapy to Start?

Mark G. Kris, MD


April 20, 2022

This transcript has been edited for clarity.

I am Mark Kris from Memorial Sloan Kettering, speaking today on a recurring group of commentaries I've titled, "Reading Between the Studies."

There are many issues that we have to face in the day-to-day care of patients with lung cancers for which we do not have clinical trial data to guide us, and therefore, we have to make the best judgments we can based on the available data we have and the consensus among experts.

The topic I'd like to tackle today is: What is the optimal initial therapy for a patient with an oncogenic driver? Let's say you have identified a driver at the start of therapy. Do you start with a targeted therapy, or do you start with a more traditional or standard combination chemotherapy with or without a checkpoint inhibitor?

In terms of data, there are randomized trials for patients with EGFR-mutant disease and for ALK fusion–positive patients demonstrating that chemotherapy is not quite as good in terms of response and disease-free survival as targeted therapy. I think there is consensus — at least there is among the 21-member oncology group that that I work with — that for EGFR, ALK, RET, ROS1, NTRK, and MET, we generally start with targeted therapy.

Today, I will not get into which targeted therapy to use. We do have good choices for some of these targets. And for those, there is consensus, at least among our 21-physician thoracic oncology group, to start with a targeted therapy.

Where there isn't consensus is for the four other drivers: BRAF, HER2, EGFR exon 20, and KRAS.

The majority in my group — about three quarters — would start with the targeted therapy for BRAF. Usually, the combination of a BRAF inhibitor and a MEK inhibitor.

For the other targets — HER2, EGFR exon 20, and KRAS G12C — the majority of people in my practice group would still start with combination chemotherapy, with or without a checkpoint inhibitor.

I think KRAS is a special case. I personally tend to recommend a targeted therapy. Part of this is because results with checkpoint inhibitors, and particularly in the HER2 space where we have done some investigations, are checkered. In looking at the data, it's probably not quite as good as in patients who don't have a HER2 amplification or mutation.

I will say that my opinion is in the minority here. Most of my partners would start with combination chemotherapy with or without a checkpoint inhibitor.

For KRAS G12C, there is near unanimity that we would start chemotherapy with a checkpoint inhibitor as well. Only about 15% of my group said that they would start with sotorasib if they had the opportunity to do so.

Looking at the results in patients with KRAS G12C, particularly in the absence of the STK11 co-mutation, there is a degree of benefit from the combination that is at least equivalent to that in other adenocarcinomas that don't have KRAS.

A couple of other thoughts about using chemotherapy in these patients. The first is that when you've started somebody on chemotherapy and you later discover that they have a driver oncogene, in the absence of severe toxicity, the consensus is that you keep the patient on the chemotherapy or combination until you can assess response.

Then, based on the response seen and the tolerability of therapy, you decide whether to switch to the targeted therapy or continue chemotherapy until progression or unacceptable toxicity.

The second thing to remember is that even though we're talking about targeted therapy over chemotherapies, chemotherapy clearly helps patients with oncogenic drivers. The data are probably strongest with EGFR. We know that patients with EGFR mutations have double the rate of response to carboplatin and paclitaxel than patients who don't have EGFR mutations. It's pretty potent information. Also, we know that adding chemotherapy to first-generation EGFR tyrosine kinase inhibitors (TKIs) improves disease-free and overall survival.

Clearly, chemotherapy helps these patients. It's not an issue that it doesn't help, it's an issue of priority and what's the best choice for these patients.

It's an evolving field and it's going to change as we get more data, particularly in the KRAS space, so hang in there.

In general, I think targeted therapy should be used for patients with targets, with a little extra thought required for those patients with KRAS G12C.

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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