Impact of Sotorasib and Adagrasib in KRAS G12C–Mutated NSCLC

Sandip P. Patel, MD, Professor in the Department of Medicine at the University of California, San Diego

Regarding the use of sotorasib (Lumakras) and adagrasib (Krazati), for patients with KRAS G12C–mutated non–small cell lung cancer (NSCLC), Sandip P. Patel, MD, emphasized that these treatments for the second-line setting can be impactful after treatment with chemoimmunotherapy in the first line.

Patel, a professor in the Department of Medicine at the University of California, San Diego, also spoke about important trials in the space and where he hopes to see research efforts headed in the future.

Can you give a brief overview of the treatment landscape for KRAS G12C–mutated NSCLC?

Patel: There’s probably no space in oncology that’s had as dramatic an era of drug development as KRAS-mutated [NSCLC, with] targeted therapies and with the development of small molecule inhibitors for KRAS G12C, the 2 FDA-approved agents being sotorasib and adagrasib. Currently, in NSCLC these mutations are also seen in colorectal cancer and pancreatic cancers. One key concept is at the current time, these agents are for second-line use after progression, optimally after chemoimmunotherapy because many patients with KRAS G12C inhibitors will have reasonable and durable responses with immunotherapeutic approaches in the frontline setting. When we think about KRAS G12C, treating [patients] in the second-line setting with the small molecule inhibitors, whether it’s sotorasib or adagrasib, is a very reasonable treatment strategy. Recent data may have tempered some of the enthusiasm around some of the overall survival data compared with docetaxel. The flip side is that in many of those studies, there is differential loss of patients on the control arm, for example. We need to look further in terms of the details.

It’s clear that the tolerability of the small molecule inhibitors is far superior to that of docetaxel, especially when you think about some of the [adverse] effects [AEs] like alopecia and neutropenia. Other AEs that we don’t see with the small molecule inhibitors typically have AEs related to mild liver dysfunction, which we can manage. The first and most important concept is we did test these patients with metastatic NSCLC, with multiplex sequencing, most commonly next-generation sequencing, for all the mutations of which KRAS G12C is a driver that we can target now. However, it’s a driver that we target in the second-line setting optimally, and in my clinic, it still means my preferred choice in the second-line setting with chemotherapy is reasonable. The AE profile and central nervous system [CNS] activity of drugs like sotorasib and adagrasib are reasons I still would favor the oral agent over intravenous [IV], but reasonable [clinicians] can have a discussion on what makes sense for their practice setting.

Is there a specific trial involving this patient population that you think would be pertinent to discuss?

Patel: There have been several studies in the KRAS G12C space that have been illustrative of efficacy; one is the phase 3 CodeBreak 200 trial [NCT04303780] for sotorasib, and we also talk about the phase 1/2 KRYSTAL-1 study [NCT03785249] for adagrasib.^1,2 When we’re talking NSCLC, part of the interest is that historically, KRAS has been thought to be an undruggable target. This is the first generation with multiple novel KRAS inhibitors, including pan-KRAS inhibitors in clinical trials. When we’re thinking about the data, especially because [they are] a subset, it’s reasonable to look at the data and the totality [of them all]. However, the only randomized control comparison we have in the second-line setting of sotorasib vs docetaxel did not show a substantial survival advantage. It’s not unreasonable to give chemotherapy to these patients by any means, especially for patients with brain metastases and whose tolerability for IV infusion may be an issue or who may have concerns about the AEs of chemotherapy. In my clinic, the general preference may be for the oral small molecule inhibitor, though I think reasonable [clinicians] can think about the best opportunity for their patients and a way to sequence them in a way that maximizes their quality and quantity of life.

Are there any AEs clinicians should be aware of when treating patients with sotorasib or adagrasib?

Patel: We know when these agents are given concurrently with or approximately to immunotherapy, [patients] can sometimes get liver toxicity. Typically, that’s aspartate aminotransferase and alanine aminotransferase elevations, less commonly total bilirubin elevations that are clinically meaningful. These generally are managed by holding the drug and then resuming at a lower dose. Some of the other [AEs] are gastrointestinal related that we pay attention to. The main toxicity that I encounter in my clinic utilizing these agents relates to the liver.

Data from the KRYSTAL-1b cohort showed the use of adagrasib in this population with untreated CNS metastases.³ What are your thoughts on these results?

Patel: Anytime we have a small molecule inhibitor, we’re particularly keen to understand its ability to affect the CNS and hopefully help patients with CNS metastasis, which is unfortunately a major burden for our patients with refractory NSCLC. In this analysis from the investigators, we saw that in about 33 patients there was a response rate of about 33%, so 1 in 3 patients had shrinkage of tumor that had previously not been radiated with adagrasib. The reason that data are provocative is given the preponderance of brain metastases in the patient, adagrasib represents a niche as chemotherapy, especially docetaxel, doesn’t have a high level of CNS penetration. [The data do] represent the type of patient population where it may make more sense to leave them with a small molecule inhibitor as opposed to going with chemotherapy, above and beyond any AE and tolerability angles to treatment selection.

Where do you hope to see this field headed?

Patel: Broadly, KRAS is probably the most exciting area in clinical trials right now, not only in thoracic oncology but also pancreatic and colorectal cancer, where we’ve seen a lot of combination therapies. My view is the small molecule inhibitors are the base, not the ceiling. The idea is that we would get monotherapy efficacy; frankly, with these agents, any efficacy at all is quite surprising because of how tough KRAS is to target. The idea that we were going to combination approaches, eventually, made it make a lot of sense. We’re starting to see in some of these biomarker design combinations some interesting therapeutic activity. On the one hand, [we have] combinations featuring agents such as sotorasib and adagrasib, and then on the other hand there is a whole class of pan-KRAS inhibitors, and these come in multiple [options], like small molecule [inhibitors], protein degraders, or antisense molecules. There are cell therapy approaches and vaccine approaches, really a myriad of approaches. Understanding the biomarker development and understanding which patient populations may benefit is key so that we can ensure that we deliver the right drug to the right patient at the right time.

Is there anything else you’d like to add?

Patel: We only know if we can use these agents in a broad sense. If we do proper molecular testing, and in patients with metastatic nonsquamous NSCLC, every guideline recommends molecular testing. When [patients] say that molecular testing has a cost, well, immunologic agents also have a cost. If you give those without molecular testing, not only will they not work, but they’ll not work at a very expensive price point. Unfortunately, if you get certain mutations like EGFR and try to introduce drugs like osimertinib [Tagrisso] afterward, you’ll have pneumonitis. It’s the wrong thing to do. It’s important for us to “measure twice and cut once.” You could do that in a blood draw with cell-free DNA, if you don’t have the tissue. The timespan for cell-free DNA is usually 7 to 10 days, and tissue is about 14 to 20 weeks.

I tell my patients who are often very eager to get started on therapy that even though I’m as eager as they are, if we don’t wait for the results of the test, we will inevitably regret it because there may have been a small molecule inhibitor instead of chemotherapy, there may have been another opportunity for them, and we’re not going to pick their best therapy. We can’t deliver precision medicine without precision diagnostics. We can’t find the patients who will benefit from KRAS G12C inhibitors unless we do the molecular testing and secondarily,…the current use of these agents in the second-line setting documenting that mutation somewhere is readily available so that you don’t forget that the patient has a KRAS [mutation].

References

1. de Langen AJ, Johnson ML, Mazieres J, et al; CodeBreak 200 Investigators. Sotorasib versus docetaxel for previously treated non-small-cell lung cancer with KRASG12C mutation: a randomised, open-label, phase 3 trial. Lancet. 2023;401(10378):733-746. doi:10.1016/S0140-6736(23)00221-0
2. Pant S, Yaeger R, Spira AI, et al. KRYSTAL-1: activity and safety of adagrasib (MRTX849) in patients with advanced solid tumors harboring a KRASG12C mutation. J Clin Oncol. 2023;41(suppl 36):425082. doi:10.1200/JCO.2023.41.36_suppl.425082
3. Mirati presents two-year follow-up data from KRYSTAL-1 study demonstrating durable response and long-term overall survival at 2023 World Conference on Lung Cancer. News release. Mirati Therapeutics, Inc. September 9, 2023. Accessed November 17, 2023. https://shorturl.at/mpBFR