Targeting KRAS Mutations in Advanced NSCLC - Episode 12

KRAS G12C Inhibitors: Acquired Resistance and Combo Strategies

David R. Gandara, MD: We should talk a little about acquired resistance, and then we can talk about some of the drugs that are even newer that may or can affect acquired resistance. Of the patients who do respond, how long does that response last? Do we have any information to say what changed in the cancer to lead to acquired resistance?

Benjamin P. Levy, MD: I’ll turn my question back to you on acquired resistance because I’d like to learn about clearly identifying mechanisms of resistance that can help sequence therapies or inform us on what therapy is next. A lot of the responses we have seen have been quite durable, and there are many patients who are still having meaningful responses from both the AMG 510 study as well as the MRTX849 study. I can’t recall what the duration of response is from either of these trials or if they’ve been reported. But clearly, many of the patients who have been on drug still remain on drug, at least as of the last presentation that was put out in 2019. I don’t know if you have any other additional insights, David, in terms of the durability. Clearly, these drugs elicit meaningful and durable responses. The question really is, what do you do once these patients progress? Do you have any sense of what the real mechanisms of resistance may be to these drugs?

David R. Gandara, MD: I don’t think we have any definitive answers. I have seen some preclinical data, which were quite intriguing, that say compared with other targeted drugs—such as those for EGFR mutations or ALK translocations that bypass mechanisms may not be predominant here—this may be biochemical resistance with a changing of the binding affinity. The GTP basically outclasses the drug in question. If that’s the case, then the question is going to be, “What can you do to alter that resistance?” In other words, it’s not that the patient came up with a completely new mutation of bypass, for example. We should talk about some of the trials now with combinations. What do you think is rational, and what are you doing?

Benjamin P. Levy, MD: One of the more rational approaches, and 1 we’re using here at Johns Hopkins [Sidney Kimmel Comprehensive Cancer Center], is combining these KRAS G12C–targeted drugs with immunotherapy. There are some preclinical data that suggest these drugs can elicit an immunogenic response and synergize with immunotherapy. At least there have been some data preclinically with the Mirati drug. There are some trial designs ongoing at our institution combining these KRAS G12C–targeted drugs with immunotherapy. There’s some rationale to combine these drugs with potential downstream pathway inhibitors, like MEK inhibitors, so we’re looking at some of these drugs in combination with MEK inhibitors. Combination approaches make sense. Those 2 have been the low-hanging fruit. There are others that have been discussed, and I’m interested to hear what your take is on this. Clearly, other agents that may be important include CHP2 inhibitors, SOS inhibitors, and other types of inhibitors that may synergize with these drugs. But those are the 2 combination approaches we’re looking at.

David R. Gandara, MD: I agree with those. We are participating in the AMG 510 master protocol. Near and dear to my heart is the fact that it is built on and [resembles] Lung-MAP, where they had a series of substudies with combinations. First out of the gate was a combination with the MEK inhibitor trametinib, for the very reasons you mentioned regarding downstream. We know there’s already independent activity of a drug like trametinib, and biochemically this may assist in preserving response in the patients. The second of the trials to come out of the gate is with a checkpoint inhibitor.

Interestingly, there are also preclinical data that suggest our old friend the taxane, docetaxel, may have some magic cure, but I don’t think we know that yet. But I do think, from every oncogene-driven cancer we have in non–small cell lung cancer, we rarely cure stage IV disease.

Benjamin P. Levy, MD: Yes.

David R. Gandara, MD: The treatment is very effective. Patients live better and they can live longer, but eventually they relapse. I think it’s going to be the same with these drugs. Obviously, the companies that are developing them want to get on top of that. They want to see what we can do to make our drug a better drug.

Transcript edited for clarity.