Borghaei Breaks Down the Impact of Sotorasib in KRAS G12C–Mutant NSCLC and Future Research Directions

The May 2021 FDA approval of sotorasib (Lumakras) as a treatment for patients with non– small cell lung cancer (NSCLC) whose tumors harbor KRAS G12C mutations has opened the door for more research into therapies that target KRAS subtypes and laid the foundation to further examine the agent in the frontline setting and as a part of novel combinations with immunotherapy or chemotherapy, according to Hossein Borghaei, DO, MS.

The regulatory decision to approve the agent was based on results from the phase 2 CodeBreak100 trial (NCT03600883), which demonstrated that the KRAS G12C inhibitor induced an objective response rate of 36% (95% CI, 28%-45%) in patients with KRAS G12C–mutated NSCLC who had progressed after treatment with an immunotherapy and/or chemotherapy. Moreover, the median DOR was 10 months, with 58% of patients experiencing a DOR that persisted for 6 months or longer. Sotorasib resulted in a disease control rate of 81% (95% CI, 73%-87%).

“The role of co-mutations that can occur with KRAS should be explored, and they are being explored; this is important,” Borghaei said. “We should be able to identify subpopulations that either absolutely do not benefit, or conversely, derive more benefit from this agent. This must also be explored.”

In an interview with OncLive^®, Borghaei, Chief, Division of Thoracic Medical Oncology, Professor, Department of Hematology/Oncology, Co-Director, Immune Monitoring Facility, Gloria and Edmund M. Dunn Chair in Thoracic Oncology, Fox Chase Cancer Center at Temple Health, further discussed the clinical implications of the FDA approval of sotorasib in patients with KRAS G12C–mutant NSCLC.

OncLive^®: What is the impact of the FDA approval of sotorasib on the treatment of patients with KRAS G12C-mutated NSCLC?

Borghaei: The impact [of this approval] is significant because this is the first time we have a drug specifically for any KRAS subtype. G12C is the more common subtype of KRAS alterations that we see, so having a first-in-class drug that is now approved [for use] is quite meaningful. The impact [of this] cannot be underestimated. However, it must be realized that this is the first time we have been able to have a drug for [this disease], as such, we are [likely] going to see further improvements coming down the road.

Historically, what are some of the challenges that have been faced with regard to targeting KRAS in lung cancer? What efforts are underway to target subtypes beyond KRAS G12C?

KRAS is one of the more common mutations that we find in NSCLC, [particularly in] non-squamous histology. G12C is one of the more common subtypes of KRAS. Collectively, [the approval of sotorasib] is going to have an impact on a large patient population, given the unfortunate fact that many people worldwide are still diagnosed with NSCLC.

As far [historically], [we were not] able to [develop] an inhibitor for KRAS because it appears [to be] a heterogeneous mutation, meaning that different subtypes can appear in different patient populations and they seem to have different responses to standard chemotherapy. As such, it has been difficult to come up with very specific drugs.

Previously, we used to have studies where 2 drugs were combined to have an impact upstream and downstream [with regard to] KRAS, just to see whether it was possible to [achieve] pathway inhibition. However, with the advent of these newer-generation drugs, which will hopefully be coming to the market soon, the chemistry [questions we had been facing] have been solved [for].

The challenge now is [determining] how to move forward with the rest of the KRAS subtypes. This [agent] is good for [patients with KRAS] G12C for now, but what about the other subtypes? The short answer is that other drugs for other KRAS subtypes are now entering into clinical trials. Moving forward, we are going to see further improvements, and we are going to see more drugs [emerge] for these other subtypes.

Data from the CodeBreak100 trial supported the approval of sotorasib for this patient population. What were some of the key takeaways from this research?

There was a larger study that included patients with both lung cancer and colorectal cancer, and there was a publication in the New England Journal of Medicine that detailed the phase 1 experience. More recently, another publication described the experience of about 120 patients with lung cancer, the majority of whom had prior treatment with chemotherapy and immunotherapy, who had G12C and were able to receive sotorasib at the standard dose.

The ORR in this group was about 36%, which is fairly good. Additionally, some patients achieved complete responses [CRs]. What was even more interesting was that the DOR was durable, at approximately 11 months. Again, the progression-free survival [PFS] was just under 7 months.

We have a simple targeted therapy that has good clinical activity, a good safety profile, and again, [addresses an unmet need] in a space where we have many patients who could use it, and [where we have lacked] viable options before. [We] have come to expect a lot from targeted therapies based on our prior experiences with drugs in the EGFR space, or drugs in the ALK translocation space.

Clearly, in this setting, a 36% ORR in a pretreated patient population might not sound that exciting when you have [seen an ORR of] 60%, for instance, with some of the others. However, we must keep in mind that this is a different target. It has been very challenging to make drugs [for this mutation], and this was a group of patients who were heavily pretreated. As such, if you put it into [this] context, and [factor in] the rest of the clinical activity [seen with sotorasib], you see that this a very reasonable drug for this population. I hope we will continue to build on this [to further improve outcomes for these patients].

Were any notable toxicities observed with the agent? What did the safety profile look like?

In general, the drug appeared to be well tolerated. We have come to assess the safety and efficacy of these drugs by standard criteria, and for safety, we look at severe toxicities, so grade 3 to 4 toxicities. Some [were reported], but they were not very common. Under 20% of patients had grade 3 adverse effects [AEs].

Overall, 30% of patients had some form of diarrhea. The majority [of effects] were grades 1 and 2, but approximately 4% or so had grade 3 diarrhea, which requires attention. Additionally, 19% of patients experienced nausea, but those [effects] were also mostly grades 1 and 2. The [rate of] gastrointestinal AEs was low, but they did occur.

What we do have to be aware of is that the drug can cause an elevation in liver function tests. That was [seen in] approximately 15% of all the patients; of those [cases], 6% were grade 3. This tells us that continued monitoring of these patients is absolutely needed, and not just with office visits, but also with lab monitoring. Very little vomiting or rash [was observed with the agent]. The safety profile is in line with other targeted therapies. All of these [agents[ can have AEs, and we all must be aware of them.

What are some potential future directions to take with sotorasib?

The ORR and PFS is reasonable, but we want to make it better. For a drug to move into the frontline [setting], it should have more activity and durability. We have to come up with ways to improve response rates. Maybe we can generate some data in the first-line setting, meaning [we can offer] the drug in the context of a clinical trial to treatment-naïve patients to have a better assessment of what the clinical activity is with it.

We tend to combine drugs that are well tolerated with chemotherapy in the frontline space. The standard of care right now is chemotherapy and immunotherapy, so the question remains whether this drug can be combined with these other therapies safely. If it is safe, can it improve outcomes? This must be investigated in the context of a well-controlled clinical trial.

Many of these efforts are already underway by many different groups, and for different drugs in this category. However, we must be cautious. We should not just take this drug and offer it to someone who is treatment naïve on our own, because we really do not know what the safety or efficacy is in the treatment-naïve patient population. That is why we have these clinical trials, so the right patients can be identified. They should be referred to centers that have these trials, so we can get more information and build on [our knowledge base so that] everyone can benefit.

What other KRAS G12C inhibitors are emerging? Where will future efforts focus with regard to targeting this specific mutation?

At least 1 or 2 other G12C specific drugs, and they have generated some good data. I look forward to those findings to see when we might be able to have some way of comparing these drugs to each other, to see if one is superior.

In our phase 1 program, we have drugs that are considered to more pan-KRAS inhibitors. There is a tremendous amount of activity in the space, which is expected. Once we learn how to address a particular issue, improvements and other drugs usually follow, and that is where we are right now. I am looking forward to all the other data that are going to be generated in the future.

Reference

1. FDA approves first targeted therapy for lung cancer mutation previously considered resistant to drug therapy. News release. FDA. May 28, 2021. Accessed July 27, 2021. https://bit.ly/2UPjv4P