immuno therapy for EGFR pos lung cancers? - 1273470

Hi Kempten,

I'll ask a faculty onc to comment.

Hoping for the best :)
Janine

Personally I don't see it. It's like asking whether baseball coaches will be useful in soccer programs. I see these as two distinctive disease processes with just a common location.

EGFR positive tumors frequently involve non-smokers, younger patients, and appear to be a product of an identifiable mutation setting off a casade of cell reproduction and related activity. The tumors responsive to immunotherapy appear to involve smokers, a variety of cellular disfunctions, and PDL1.

I would think those with EGFR positive cancer would look to a variety of treatments directed at the EGFR, perhaps combining various drugs.

Hi kempten,

From the early data, it appears that immunotherapies are not as effective for patients who have driver mutations such as EGFR. Response rates for first line treatment with immunotherapies for such patients are low, but there are ongoing trials testing the efficacy of a combination of an EGFR inhibitor and an immunotherapy agent. This subject is discussed in a GRACE podcast.

As far as problems with existing autoimmune diseases, each trial would have its own criteria for exclusion, and that may be a disqualifying factor. As discussed previously, the issue of conflict between immunotherapy and autoimmune treatment is discussed in this article: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2764117/

As stated therein:

“The cardinal problem with all approaches that aim to augment the host immune response to cancer is that many tumour antigens that serve as key therapeutic targets are also expressed in normal tissues. Consequently targeting melanoma antigens (which are also melanocyte differentiation antigens) by active vaccination or by adoptive transfer of TILs often results in the development of the autoimmune disease vitiligo.”

Typical treatment for autoimmune disease consists of immunosuppression, which can be at odds with anti-cancer immunotherapies which seek to stimulate the response of the immune system.

The article suggests one possible solution to this problem: “Using a combination of therapeutic agents might allow for a reduction in the dose of each individual drug to levels that are not toxic.”

JimC
Forum moderator

Jim provided a good summary. First, it's important to note that the trials with immunotherapy are still pretty limited, so we don't have an enormous experience with thousands of patients over many years; in particular, with EGFR mutation-positive NSCLC as a small subset of NSCLC, our database of information on immune checkpoint inhibitors in EGFR mutation-positive patients is especially limited.

That said, what we can say is that the patients with an EGFR mutation and/or are never-smokers have tended to have a very low response rate to immune checkpoint inhibitors and have tended to have no improvement in progression-free survival or overall survival relative to chemotherapy. This is the case across the various trials with different (but very similar) immunotherapy agents. This isn't to say that a never-smoker or EGFR mutation-positive patient cannot benefit or won't benefit from an immune checkpoint inhibitor, but the results with second line chemo have been about the same. In particular, I definitely favor platinum doublet chemo as a first "non-EGFR" directed therapy, because a platinum doublet combination is very likely to be superior to either Taxotere or a checkpoint inhibitor in such patients.

As Jim noted, patients with significant auto-immune diseases have been excluded from these trials. They are still being excluded from the vast majority of these trials due to concern about risk of side effects, but I expect that we'll see some reported experiences on how patients in the real world who have autoimmune diseases responded to and tolerated immune checkpoint inhibitors. If that experience is favorable, I expect companies may become emboldened to liberalize their eligibility. But at this time, there is no intervention other than immunosuppressants that could undermine the mechanism of the immune checkpoint inhibitors to minimize the risk of auto-immune complications with these treatments.

Good luck.
-Dr. West

Hopey2000,

It's certainly true that the demographic of patients and biological features of tumors with driver mutations (whether EGFR or ALK or other) tend to be different from those that are most responsive to immune checkpoint inhibitors, this is also a conclusion based on a few dozen patients, not a definitive, well-studied conclusion. Moreover, there are some patients who respond well despite having a driver mutation, just as there are some older longtime smokers who have an EGFR mutation despite not being a "typical" EGFR mutation positive patient.

At the same time, patients with an EGFR mutation can and very often do respond quite well to chemotherapy. There is some evidence that EGFR mutation positive patients can respond to conventional chemo at a much higher rate than patients without an EGFR mutation, even if EGFR inhibitor therapy is often even better. Tumors that have an EGFR mutation or ALK or ROS1 rearrangement are still a subset of NSCLC and can benefit from the same treatments that often help other people with NSCLC. In fact, after the first 1-2 lines of EGFR-directed therapy, the non-EGFR therapies tend to be more effective than trying a 3rd or 4th EGFR inhibitor therapy, even if you can scrounge one up.

As for the soccer vs. baseball analogy, I think that's not quite apt. General oncologists treat all kinds of cancer and are more like a "gym teacher" who teaches kids all sorts of sports, while a subspecialist in lung cancer might be a baseball or football coach exclusively. But even for those who are subspecialized in one cancer type, I don't know of anyone on the planet who is a specialist only in EGFR mutation-positive lung cancer but doesn't have enough expertise in most or all of lung cancer. That would be like being a baseball coach who is only capable of training left-handed right fielders. Every oncologist who has a focus on clinical management of EGFR mutation-positive NSCLC also shares an expertise for lung cancer in general.

Hi kempten,

As far as acquired resistance to EGFR TKIs such as Tarceva and Tagrisso, that resistance is to these targeted therapies only, not to anti-cancer treatment in general. That is why some patients do very well after switching to chemo after TKI resistance.

There is evidence that some P53 mutations may lessen the effect of chemotherapy regimens by preventing cell death after chemotherapy damages their DNA, but there is ongoing research aimed at getting around that problem, for example with the concurrent use of MK-1 inhibitors. It's a relatively new field of research, so the effect of the P53 mutation is not fully understood yet.

JimC
Forum moderator