Published on September 17, 2020
Clinical Trials for KRAS Lung Cancer Patients
What clinical trials are available for lung cancer patients with the KRAS mutation? Are there any specifically for G12A patients? Dr. Jyoti Patel from the Robert H. Lurie Comprehensive Cancer Center of Northwestern University and Dr. Jessica Lin from Harvard Medical School explain.
Terri Conneran, patient advocate and founder of the KRAS Kickers Support Group also asks how patients can find out about trials.
This is Part 3 of a 3-part series. Watch all segments in the series below:
Transcript | What KRAS Clinical Trials Are Available?
What KRAS Clinical Trials Are Available?
I would say we are seeing an increasing number of clinical trials become available for our KRAS mutant lung cancer patients. So there are a few categories, right? One category is looking at pills that target specific subtypes of KRAS mutation. So the classic example is the KRAS G12C inhibitor. There are the bucket of trials that fall into exploring combinations, meaning for example, combining a KRAS G12C inhibitor with another drug that may be blocking another protein that's important in the RAS pathway or perhaps another pathway. And the hope there is to maximize the efficacy of the drug, but also perhaps to overcome resistance. And so we know from our experience with other targeted therapies in lung cancer and other cancers that when you use these targeted therapies, cancer cells are smart and they figure out a way to overcome that targeted therapy with resistance. And so one way to overcome that resistance is by combinatorial approach.
And so we are seeing new trials enter the field where KRAS inhibitors are becoming combined with other appeals like SHP2 inhibitors, for example, or MEK inhibitors, which are all important in that RAS signaling pathway. And then I think there will be increasing number of trials, also looking at how to galvanize immune system in treating specifically KRAS mutant lung cancer as well. And so that includes vaccines and looking at T-cell therapies as well.
And I think the most helpful way to think about which trial is right for you is really by talking to your doctors. And there may not be a clinical trial that's right for you at your specific center, but your doctor should be able to then help explore, "Okay, which center close to where you're being treated may have the right trial option for you," looking at different eligibility criteria, different biopsy requirements, what the visit schedule may be like. And I think that that information, even though they have to do more with logistical arrangements are also important to familiarize yourself with, right? In thinking about whether that particular treatment option can fit your lifestyle and your quality of life.
So there are a number of trials that are ongoing. So clearly when the first, particularly for G12D those inhibitors first started hitting and we were so excited about these phase one trials. There were very few sites and we understand that there were often long waiting lists to get onto these studies and the trials were quite restrictive. But now as we have more information over these past two years, the number of trials has opened significantly. And I think are much more widely available during this era of virtual meetings and COVID, there's certainly been this worry about getting to clinical trials. And in particularly for these targeted therapy trials, many of them have been ongoing because they are for distinct patient populations. And so I think the first news hit was sort of what's happening to all of these trials. I would say in lung cancer, in particular for targeted therapies, we've done some survey projects, the vast majority of sites continue to enroll patients on these trials. So it is just finding one that's a good fit.
Are There Any KRAS G12A Trials?
And that seems to be rather hard. There's so much out there right now on G12C and it is very exciting and it is the largest portion. But what about like the G12A? We know people and I know people, you know people in all of those, what about the G12A specifically?
So for patients with G12A there may be one area for trials looking at, for example, SHP2 inhibitors. So there is some preclinical data out of Dr. Trevor Bivona's group, where models with KRAS G12A mutant lung cancer could be sensitive to SHP2 inhibition so that is one option. And there are several actually now SHP2 inhibitor trials that are ongoing, including Novartis SHP2 inhibitor, Relay SHP2 inhibitor and others. And so there are trials that are open, accruing patients. So that is one option. And then you mentioned Terri earlier on the, the SOS1 Boehringer Ingelheim therapy. And so that medication, what it's looking at is blocking the interaction between SOS1, S-O-S-1, and KRAS. And so what SOS1 is, is taking a step back, KRAS exists in this GDP bound form, which is the off form inactive form.
And then it also exists in the GTP bound form, which is the on form, the active form. So GTP bound form is important in driving downstream signaling to drive cancer division and growth and SOS1 is what you can think of as the activator of the KRAS. So it helps keep the KRAS on activated form. And so if you're inhibiting that interaction between SOS1 and KRAS, then the hope is to then block the cancer cell growth. That kind of approach is useful, not just for a specific subtype of KRAS mutation, but for really a variety of KRAS mutations, including G12A, G12D mutations in other residues other than residue 12. And so that is another good option. That trial is also open and enrolling patients as well.
Does the PD-L1 have any sort of implication one way or the other on those?
For these specific trials, PD-L1 marker is not taken into account in enrolling patients. I'm sure there will be correlative, retrospective studies looking at whether that plays a role in likelihood of benefit from these different therapies, but it is not built into the eligibility criteria.
Where Can Patients Find KRAS Trials For Lung Cancer?
Is there a one place that we can go, we can find out about all the KRAS trials for lung cancer?
The best site is clinicaltrials.gov, and there you can sort of search and see what trials are available. It can be a little bit tough to understand if a trial is enrolling immediately or not, but hopefully the nurse navigator at your oncologist office can also help you to find out whether or not a trial's open. There are also a number of trials looking at metabolic inhibitors. And so we know that KRAS probably has a particular sensitivity to hypoxia inducers. And so there are some trials as well, looking at even drugs like metformin that continue to be ongoing. There's glutaminase inhibitors. And so there are a number of studies. Many of these studies are still in early phase, so things open and close and there may be a slot available and then it's not available.
So I say to patients to really think about what their sort of, what the longer journey will look like. Generally, for most patients with KRAS mutations, I think upfront our recommendation remains off of a study chemotherapy with immunotherapy generally or immunotherapy alone, but it really is sort of to start thinking about what would happen, at second line treatment and to sort of acquaint yourself with what studies may or may not be opening.
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