How to Treat Patients Without an Actionable Mutation [Video Transcript]

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In this segment, I'd like to talk about how I manage, and how there are certain strategies to manage, patients who have advanced adenocarcinoma without an actionable mutation. I think, importantly now, we have been able to identify driver mutations within adenocarcinoma of the lung in which—when we do identify these—that allows us to deliver targeted therapies.

I think we know now that EGFR and ALK mutations can be identified, but that's just the beginning of the story. We now have other actionable, yet rare, mutations in adenocarcinoma, including BRAF, ROS, RET, and MET exon 14 skipping mutations, which, if identified, allow patients to receive targeted therapies.

I think what we know, however, is that for many of our patients, they don't have these targets, and because of that we have to default to chemotherapy. And I think the word “default” is a misnomer, because I think we know now that chemotherapy for this patient population not only improvees survival, but improves quality of life for many of our patients. So, for those patients without an actionable mutation who have advanced adenocarcinoma of the lung, I would make a strong argument that they would need to receive chemothrapy.

So, which chemotherapies do I generally consider? Which ones do the data suggest work better? I think that we've begun to have a nice story woven by pemetrexed with multiple studies. I think what we know now from a very large study comparing cisplatin/pemetrexed to cisplatin/gemcitabine is that patients in that study who had adenocarcinoma did a lot better in terms of survival with cisplatin/pemetrexed, when compared to cisplatin/gemcitabine.

This histology-directed story is still firm and resonates with many of us in the field, and we tend to default to platinum pemetrexed when we're giving our patients without a driver mutation chemotherapy. Whether to use cisplatin or carboplatin I think is up to physician discretion. Certainly there are instances in fit younger patients in which I will consider cisplatin in an advanced age, but more often than not I'm using carboplatin.

I think the next element that needs to be considered is maintenance treatments for these patients. Patients we know, who have advanced adenocarcinoma of the lung, who at least achieve stable disease after 4 to 6 cycles of platinum pemetrexed, should be offered maintenance pemetrexed. I think we have now 2 studies—the JMEN study and the PARAMOUNT data—looking at switch and continuation maintenance, respectively, which have shown survival advantages.

So I think for patients who are receiving a platinum chemotherapy with pemetrexed upfront for advance adenocarcinoma of the lung, we should be considering maintenance treatment. We know that maintenance improves progression free survival and also improves overall survival. I think, importantly, the maintenance discussion should happen at the beginning at diagnosis, not at the time that they're eligible for maintenance, and this is very important. 

When I see patients in the office, and they come to me and we're having that first discussion about chemotherapeutic delivery and strategies, I tell them that they're going to be receiving a platinum pemetrexed-containing regimen, and that if they're tolerating therapy number 1, and at least achieving stable disease after the induction regimen, that I will consider maintenance. And then when we get to that point where we have to consider other maintenance, the patients are already aware of it. So there are no curveballs here; they're clear from the beginning. I will say that maintenance is not for everyone, but for patients that are tolerating platinum pemetrexed regimens, and are doing well in terms of stable disease, I would consider maintenance pemetrexed.

The third and final issue to consider for patients without an actionable mutation in which you are considering chemotherapy is whether you should employ anti-angiogenic strategies like bevacizumab. I think what we know about bevacizumab is that bevacizumab improves response rate, progression free survival, and overall survival when added to carboplatin/paclitaxel, which we learned from the ECOG 4599 study comparing carboplatin/paclitaxel to carboplatin/paclitaxel plus bevacizumab. And again, we saw improved outcomes on all the metrics measured.

I don't think we know whether adding bevacizumab to carboplatin or cisplatin with pemetrexed improves outcomes when compared to carboplatin or cisplatin with pemetrexed alone. And this is an unmet need and an unanswered question. We do have data that there are very good outcomes with cisplatin, pemetrexed, and bevacizumab, followed by maintenance pemetrexed with bevacizumab, and that's the AVAPERL data, certainly showing that patients do quite well with that regimen.

I would say that for patients that are younger and more fit, I would certainly consider using a platinum pemetrexed with bevacizumab, and then considering pemetrexed/bevacizumab as maintenance. But that's not all of our patients. I think, for many of my patients over the age of 65, by the way we have data retrospectively showing that bevacizumab added to platinum doublet doesn't provide a survival advantage in those over the age of 65. In patients who have a performance that may be waning, I would not use bevacizumab, but certainly an individualized approach for these patients.

So in some, I can't state enough how important is to do comprehensive genomic profiling upfront for patients. For those patients without an actual mutation—certainly that have adenocarcinoma—I thing this should receive histology-directed therapy, and then there should be consideration to adding bevacizumab, but that drug, in my opinion, is not for everyone.

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