Novel KRAS G12C Inhibitor Reflects Research Advances in NSCLC and CRC

David S. Hong, MD

The novel, next-generation KRAS G12C inhibitor RMC-6291 may address an area of high unmet need for patients with KRAS G12C–mutant advanced non–small cell lung cancer (NSCLC) and colorectal cancer (CRC), including patients with NSCLC whose disease has progressed on prior treatment with other KRAS G12C(OFF) inhibitors, according to David S. Hong, MD. Additionally, this agent’s favorable safety profile and preliminary efficacy supports its continued investigation as a single agent in these patient populations, according to David Sommerhalder, MD.

“It is currently a crowded space for the KRAS G12C inhibitors, but RMC-6291 may leapfrog some of the other drugs because of its unique nature,” Hong said.

At the 2023 AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics, data from the phase 1 RMC-6291-001 trial (NCT05462717) were presented.¹ This trial investigated RMC-6291 as monotherapy in patients with advanced solid tumors harboring KRAS G12C mutations. In the NSCLC cohort, the agent elicited objective response rates (ORRs) of 50% and 43% in patients who received a prior KRAS G12C inhibitor and those were were naïve to a KRAS G12C inhibitor, respectively, with all patients achieving partial responses (PRs). Additionally, patients with CRC had an ORR of 40%, with all patients achieving PRs.

“We’ve all been impressed [with these findings] and are optimistic for this drug to keep moving forward in colon cancer and seeing what else it can do,” Sommerhalder added.

David Sommerhalder, MD

In interviews with OncLive^®, Hong and Sommerhalder discussed the unmet needs for patients with KRAS G12C–mutant NSCLC and CRC that prompted the initiation of the RMC-6291-001 trial; key efficacy and safety findings with RMC-6291 in NSCLC and CRC; and potential next steps for this agent.

Hong is the deputy chair in the Department of Investigational Cancer Therapeutics in the Division of Cancer Medicine at The University of Texas MD Anderson Cancer Center in Houston. Sommerhalder is a physician at Texas Oncology –– San Antonio Babcock NEXT Oncology.

OncLive: What unmet needs exist for patients with KRAS G12C–mutated solid tumors?

Hong: We don’t yet have a fully approved KRAS G12C inhibitor [for the treatment of any cancer]. We have 2 with accelerated approvals [in KRAS G12C–mutated NSCLC], but [none that are] fully approved. The Oncologic Drugs Advisory Committee [ODAC] meeting that [occurred on October 5, 2023] for sotorasib [(Lumakras) in KRAS G12C–mutant advanced NSCLC] was somewhat unfavorable for sotorasib.² We’ll see what happens, whether we get a full approval or whether the FDA pulls the accelerated approval [for sotorasib]. That leaves Mirati Therapeutics’ adagrasib [Krazati] as the only other [KRAS G12C inhibitor] with accelerated approval that would need to then prove itself in later studies to [gain] full approval.

What the sotorasib ODAC meeting with Amgen showed was that there is a lot of room for improvement with these first-generation KRAS G12C(OFF) inhibitors. It’s such a huge population in NSCLC that you can’t ignore it. There remain many possibilities in the [treatment paradigm]. We’ll see what happens with some of the later studies with sotorasib. I helped develop sotorasib in the phase 1 [CodeBreaK 100] trial [NCT03600883]. My hope is that eventually it will have a place in the standard of care [SOC], but we will see. There remains a lot of room for improvement.

Sommerhalder: There are a few unmet needs. We always want more lines of treatment, more targeted lines of treatment, and treatments that are effective, with as few adverse effects [AEs] as possible. KRAS, as has been said many times over the years, has been thought to be, until the past several years, undruggable. We’ve been testing for it for a long time in colon cancer and a little more often recently in lung cancer.

We see KRAS often mutated in CRC, and this is a cancer with a rising incidence that needs more treatments than just FOLFOX [folinic acid, fluorouracil, and oxaliplatin] and FOLFIRI [folinic acid, fluorouracil, and irinotecan] that we’ve been using. Approximately 3% to 5% of CRCs have KRAS G12C mutations specifically. [These mutations are] more common in lung cancer, at up to 13% in NSCLC. This may be a low percentage, but it amounts to thousands of patients per year who could potentially benefit from [an agent] that targets KRAS, specifically KRAS G12C.

What differentiates RMC-6291 from other KRAS G12C inhibitors?

Hong: RMC-6291 is a unique molecule relative to what we see with sotorasib, adagrasib, the Lilly’s KRAS G12C inhibitor [LY3537982], the Novartis [KRAS G12C inhibitor (JDQ443)], and the drug from Genentech, divarasib [GDC-6036]. These are all off inhibitors. That means they lock KRAS G12C in an off state, because KRAS exists in off and on states.

What’s unique about the Revolution Medicines platform is that [RMC-6291] is a molecular glue. It binds to another molecule, cyclophilin A. That forms a tertiary compound with the [ON form] KRAS, and that prevents it from binding to downstream regulating molecules, such as RAF, MEK, etc. It’s unique in that context from the other OFF inhibitors.

Sommerhalder: [RMC-6291] is not the first [KRAS G12C inhibitor]. [Two] KRAS G12C inhibitors already have [accelerated] approval for patients with NSCLC. Revolution Medicines has designed RMC-6291 and some of their other KRAS inhibitors to target KRAS in the ON state, which is when it is bound to GTP, rather than in its OFF state, which is [the target of] currently available and approved [KRAS G12C inhibitors] for patients with NSCLC. Preclinical data show that when you do that, you might to get more targeting within the tumor and less in the normal cells, [leading to fewer] off-target or undesirable AEs and potentially a deeper suppression with less resistance. That’s the theory.

The way RMC-6291 works is unique. It is not an inhibitor in and of itself; it needs to form a binary complex with the chaperone protein cyclophilin A, which is already found inside all our cells. Once it binds to the chaperone protein, it can then bind to the KRAS [in the on state] and form that tri complex. [It is] a small molecule that can become a much larger molecule and form this complex that then covalently inhibits KRAS G12C in the ON state only.

What are the some of the key eligibility criteria in the RMC-6291-001 trial?

Hong: Usually, phase 1 trials [enroll] patients with advanced cancer, patients who have had lots of chemotherapy in the past. What’s unique about RMC-6291-001 is that many of these patients had prior [treatment with] KRAS G12C inhibitors. Most other trials [investigating KRAS G12C inhibitors] did not allow for that.

RMC-6291-001 included patients with known KRAS G12C mutations, but these KRAS G12C mutations are found in approximately 13% of all patients with NSCLC and approximately 3% to 5% of all patients with CRC, and less than 1% of all patients with pancreatic cancer. There is also a smattering of other diseases where we see these [mutations]. [This trial used] standard eligibility criteria that you would see in a phase 1 trial.

Sommerhalder: This study of RMC-6291 is currently still in dose [optimization]. The data that were presented at AACR-NCI-EORTC focused on the patients with CRC and NSCLC. The study includes and allows [patients with] any solid tumor with KRAS G12C [mutations] to enroll. However, the highest number of patients were [those with CRC and NSCLC], so that’s what was presented, where there were more mature data.

The study was typical for a phase 1 dose-escalation study. It allowed patients with an ECOG performance score of 0 or 1. Early on, it also allowed patients who had been on prior KRAS G12C inhibitors, which is important and a factor to look at in the responses. Like many [trials], it did not allow any [patients with] active or untreated brain metastases. Patients needed to have prior SOC therapy and have progressed on or been intolerant to those therapies.

What preliminary efficacy data were observed in the trial thus far?

Hong: One of the challenges with phase 1 trials is that the numbers remain small. You can get fooled by the numbers because things can change with 1 response. [The data] were still impressive. In the NSCLC cohort, the patients who were naïve to KRAS G12C inhibitors had an ORR of 43%. What was more unique and interesting was 50% of patients [with NSCLC] who had prior KRAS G12C inhibitors responded. The Lilly trial protocol allowed [patients with prior KRAS G12C inhibitors], but their [responses] were small. Even in some of the [trials investigating] combinations that allowed for [prior KRAS G12C inhibitors], such as sotorasib plus afatinib [Gilotrif] and sotorasib plus the MEK inhibitor trametinib [Mekinist], we have not seen that high response rate.

One of the challenges that emerges from KRAS G12C off inhibition is that there are multiple ways to develop resistance. However, perhaps because of this different mechanism of this KRAS G12C(ON) inhibition, [RMC-6291] overcame some of that resistance in a fair number of patients. We’ll need to see what those numbers are when we have larger sets of patients, but it is encouraging. The ORR of 43% in the KRAS G12C inhibitor–naïve patients is respectable, if not better than some of the existing [KRAS G12C(OFF) inhibitors].

Sommerhalder: The waterfall plots that were presented at AACR-NCI-EORTC were impressive, with most patients having some reduction in tumor size. [Patients with] NSCLC could have been previously treated or not with KRAS G12C inhibitors. There, the ORR was 50% in the patients treated with prior KRAS G12C inhibitors, and 43% in the patients who were naïve [to KRAS G12C inhibitors], interestingly, even those with stable disease [SD], if you look at the waterfall plot, [these patients] often had some reduction in tumor size or are still ongoing and might later have some response.

Separately, the patients with CRC with KRAS G12C mutations were also presented and had a similar waterfall plot, where many of the responses were below the X axis, which is nice to see. These patients were a little different [than the NSCLC]. [Only data from] those naïve to KRAS G12C inhibitors were presented, because [no KRAS G12C inhibitors are] currently approved for patients with CRC. There, the ORR was 40%. The disease control rate, which is also important [in a disease such as] CRC, was 80%. Many of those patients are still ongoing and might have further, deeper responses as we go through the data.

One part of the study that they looked at as a secondary end point was a reduction in the circulating tumor DNA [ctDNA]. That correlated well with the responses. Even patients with SD had some reduction in KRAS G12C. It’s nice that it correlated well. Everyone wants to use more ctDNA. The more correlation we see, the more we will trust it and be able to use ctDNA. I’m happy to see they incorporated that in the study and that it matched with what the patients [experienced].

What is the potential for RMC-6291 as a single agent for patients with CRC based on the responses that have been seen with this drug thus far?

Sommerhalder: [The data] we’ve seen in [KRAS G12C inhibitor–naïve patients with] CRC is promising for [the use of the drug as a] single agent because [responses are] seen across various dose levels, some much lower than others. Many of the patients are still ongoing. [RMC-6291] is still an agent worth exploring in combination to get deeper or even longer responses. However, even with what we’ve seen so far by itself, this agent looks promising, which is unique to KRAS inhibitors, which often have had lower success, especially in colon cancer, when used as single agents.

What is the safety profile of RMC-6291 as monotherapy?

Hong: RMC-6291 was a relatively well-tolerated drug. Most of the AEs were gastrointestinal related. [The investigators did not see many] dose-limiting toxicities. One aspect that was unique about this molecule that some people were concerned about was QTc prolongation, [which occurred in] 25% of patients. Most of those patients had grade 1 or 2 QTc prolongation.

As physicians, it’s not that we don’t care about QTc prolongation, but it’s not too concerning. I’ve rarely seen QTc prolongation that ultimately leads to [issues such as] arrythmia or torsades de pointes. From a clinical standpoint, the FDA requires most protocols with small molecules to assess for [QTc prolongation], but I’m not too concerned. The other toxicities were typical small molecule toxicities. One patient had grade 3 QTc prolongation [of greater than 500 msec]. I’m less concerned about that. Overall, it was a well-tolerated drug.

Sommerhalder: RMC-6291, when it comes to safety, has been wonderful. You want to see both the efficacy and the safety. The holy grail of cancer treatment is [an agent] that works well and has no or few AEs. There were few grade 3 toxicities. Most were related to QTc prolongation only at the highest doses tested. That came out to 11% of the patients. The CTCAE toxicity grading includes both the absolute QT value and the increase from baseline. Many of those patients had an increase from baseline [of over 60 msec] that made them have grade 3 [QTc prolongation]. However, these patients were within what would be considered normal [range for QTc], and most were below 500 milliseconds [except for] 1 patient [who had QTc prolongation] over 500 msec.

From a safety standpoint, [QTc prolongation is an AE] to watch for and one we’re paying close attention to, but not a major issue so far. Additionally, there was efficacy seen at much lower doses than where we began seeing the QTc prolongation. Beyond that, there was mild nausea, vomiting, and diarrhea, but it was not common that those led to dose reductions or dose holds. [RMC-6291 is] tolerable. Patients I’ve treated on this study have felt great and have enjoyed this compared with the chemotherapy they’ve often been on.

What additional ongoing research in KRAS G12C–mutant cancer would you like to highlight?

Hong: The most interesting data have come from the Genentech/Roche molecule, divarasib. Adrian Sacher, MD, [of Princess Margaret Cancer Centre in Toronto, Ontario, Canada] et al published [findings with this drug] in the New England Journal of Medicine.³ The response rates were impressive at 53.4% in NSCLC. However, more clinically relevant is the progression-free survival [PFS]. The median PFS was 13.1 months, which is almost double that of adagrasib and sotorasib. Sotorasib got into trouble [with PFS data] at the ODAC meeting.

Many other new KRAS G12C inhibitors are emerging. There’s a KRAS G12C inhibitor from Frontier Medicines. Others look incredibly potent preclinically. This KRAS G12C [inhibitor] story, or the RAS [inhibitor] story in general, is in many ways like the EGFR [inhibitor] story. This is the first generation of [KRASG12C inhibitors]. There’s a fourth generation of EGFR inhibitors that preclinically look even better than the generation before.

Over time, we will continue to make incremental improvements in all these molecules, which is great because there’s a huge number of unmet patients with KRAS G12C mutations who may be helped by this. For example, I’m currently working on [RMC-6236], which is a pan-RAS inhibitor. There are some initial signals that that drug will work across different KRAS-mutant alleles. It’s an exciting time. KRAS, which has been the Mount Everest of oncogene addiction, is starting to be whittled down. In the next several years, we may have several KRAS G12C inhibitors and other KRAS inhibitors approved as SOC for patients.

Sommerhalder: Revolution Medicines has started to open studies investigating RMC-6291, a covalent KRAS G12C inhibitor, in combination with their KRAS[MULTI] inhibitor RMC-6236. That study has just started to get underway, and we’re excited to see what that can bring to these patients.

What is your main message for colleagues regarding the investigation of RMC-6291?

Hong: RMC-6291 appears to be a relatively safe drug. Its initial efficacy, at least in the KRASG12C [inhibitor]–naïve NSCLC patient population, looks as good as or better than that of the off-state inhibitors. What’s unique [about RMC-6291] is that we’re seeing some activity in patients who have had prior KRAS G12C inhibitor [therapy].

Sommerhalder: So far from what we’ve seen on the study, this drug has been a pleasure to use and to put patients on. If we can get more treatments that have fewer AEs and better on-target effects that lead to good responses, we’d all be excited. It’s important, though, if oncologists are seeing these patients, to refer them for trials. They’re out there, they’re working, but we need more patients to get these [agents] out to all patients as soon as possible.

References

1. Jänne PA, Bigot F, Papadopoulos K, et al. Preliminary safety and anti-tumor activity of RMC-6291, a first-in-class, tri-complex KRAS G12C(ON) inhibitor in patients with or without prior KRAS G12C(OFF) inhibitor treatment. Presented at: AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; October 11-15, 2023.
2. Oncologic Drugs Advisory Committee Meeting. FDA. October 5, 2023. Accessed October 18, 2023. https://www.youtube.com/watch?v=yH0mGVt1fP4
3. Sacher A, LoRusso P, Patel MR, et al. Single-agent divarasib (GDC-6036) in solid tumors with a KRAS G12C mutation. N Engl J Med. 2023;389(8):710-721. doi:10.1056/NEJMoa2303810