Transcript:
Martin J. Edelman: My name is Martin Edelman. I'm Chair of the Department of Hematology and Oncology at Fox Chase Cancer Center in Philadelphia, Pennsylvania.
For the treatment of advance non-small cell lung cancer, we are in a very remarkable era. As recently as 20 years ago, our approach was the use of various combinations of platinum-based chemotherapy.
We then had evolved into an era where a fraction of patients -- 10 to 15 percent -- were identified with driver mutations and could then be treated with what's been termed "targeted therapy," a population that continually expands as we identify more targetable mutations.
Our major recent advance has been the use of immunotherapy. Immunotherapy, specifically the anti-PD-1 and anti-PD-L1 inhibitors has been conclusively demonstrated to be superior to chemotherapy in many subsets of patients, particularly those that expressed PD-L1 at greater than 50 percent, and the combination of immunotherapy with chemotherapy is also superior to chemotherapy across a broad range of patients.
Our current question is, how do we best employ this? In what situation should immunotherapy be used by itself? Where would the combination of chemotherapy and immunotherapy be optimal?
An essential breakdown is there are probably three groups of patients that we can look at based on PD-L1 status -- those with less than 1 percent PD-L1 expression, those with 1 to 49 percent, and those with 50 percent or greater PD-L1 expression. This is an expression of PD-L1 that's determined by the 22C3 assay, or an equivalent.
In the situation of those with over 50 percent expression, immunotherapy by itself is clearly superior to chemotherapy, and it's not clear that the addition of chemotherapy in this situation is advantageous.
Though there is some hint, as one evaluates the studies, that there's an early drop off of patients who are treated with immunotherapy alone who may be rescued by the concurrent use of chemotherapy. There is an impression that perhaps the response rate may be somewhat higher, and that this may be a better approach for those with bulkier disease.
However, I would caution that this is all somewhat hypothetical, and that we don't have a completely good understanding of who would benefit from chemoimmunotherapy versus immunotherapy alone.
However, in any situation, I would point out that the use of chemotherapy in all of these situations, it is only for a brief period of time. For example, for a patient with squamous carcinoma, it would be a combination of carboplatin and paclitaxel, nan-paclitaxel, with an immunotherapeutic agent, with the chemotherapy drugs dropping off after four courses, and then only immunotherapy in somewhat similar situations in non-squamous with platinum/pemetrexed, and at least the platinum agent dropping off after four courses of therapy.
That pretty much summarizes it for the over 50 percent group. 1 to 49 percent, it appears that the use of concurrent chemoimmunotherapy is superior, with clear advantages in terms of both progression and overall survival. The regimen should be -- that has been development -- on the basis of histology.
For those with less than one percent, again, chemoimmunotherapy has been demonstrated to be better than chemotherapy. However, when one looks at the progression-free survival curves in some of these situations -- for example, the KEYNOTE-189 study that was published by Dr. Gandhi -- the PFS results are, well, positive do cross one, and are not as impressive as we would like.
However, in other studies, such as I believe it was KEYNOTE-407, there's a clear separation. It's not nearly as impressive as the results at the higher PD-L1 levels. Nevertheless, in the less than one percent group, the combination of chemotherapy and immunotherapy is beneficial.
Entering into this mix is the combination of two immunotherapy agents -- the anti-PD-1 agent nivolumab, and the anti-CTLA-4 agent ipilimumab -- and studies that were published by Dr. Hellmann, these do appear to have substantial activity in all groups, and most curiously in those less than one percent.
Entering into this also is the role of tumor mutational burden. However, this is not a standardized assay, and still needs to be validated.
The combination immunotherapy approach has not been approved yet, but it's intriguing, given its long-term survival in this population.
The other group, in addition to the various PD-L1 groups that's important to recognize, are those with activating mutations, specifically EGFR mutations. The IMpower150 trial, that evaluated platinum-based chemotherapy with atezolizumab as well as with bevacizumab, demonstrating an advantage for this population which was, for the most part, excluded from other studies.
Whether or not that will be sufficient evidence to use this in his population remains unclear. The FDA did not approve it in that subset, which was somewhat surprising. Though there is subset analysis that bevacizumab seem to provide a unique advantage in this population when added to chemotherapy, and atezolizumab, I think that remains to be fully validated.
The role of immunotherapy in these populations -- EGFR mutant, ALK translocated, as well as all the other less frequent activating mutations in translocations, such as ROS, RET, TRAT, etc., remains to be seen.
