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The Role of Mutated KRAS in NSCLC and Current Challenges With First-Generation KRAS Inhibitors

First, I will start with the role of mutated KRAS in non-small cell lung cancer, as well as challenges with first-generation KRAS inhibitors. We will talk about combination strategies with first-generation KRAS inhibitors. Then my colleague, Dr. Marrone, will move towards investigational next-generation KRAS G12C inhibitors, both as monotherapy and in combination strategies. We will finish with a look to the future of KRAS G12C.

Let us start with where we are today.

KRAS Mutations in Cancer

Approximately 30% of all cancers are associated with a RAS mutation, suggesting that this mutation is one of the leading causes of carcinogenesis. Of the RAS oncogenes, mutations in KRAS are the most frequent, making up about 75% of RAS mutations. You will see that when mutated, KRAS leads to differentiation, proliferation and cell survival.

KRAS Signaling Cascade

Here is another look at the KRAS signaling cascade. When mutated, KRAS stays preferentially in the active form that is GTP bound. This leads to constitutive downstream activation of multiple pathways including PI3K, as well as RAF, MEK and ERK pathway.

These downstream pathways, however, have led to multiple areas of interest of active study and potential combinations. One example is that KRAS and SHP2 co-inhibition may address adaptive resistance by limiting upstream RAS-MAPK pathway reactivation.

KRAS/MEK co-inhibition has early clinical support with disease control reported in lung cancer and colorectal cancer, even after prior KRAS G12C inhibitors.

SOS1 inhibition may suppress KRAS activation across multiple KRAS variants and is being evaluated alone and in combination with KRAS and MEK inhibitors.

KRAS inhibitors plus immunotherapy combinations may enhance anti-tumor immunity, although hepatotoxicity has limited some combinations, particularly sotorasib.

Lastly, RAS(ON) inhibitors are highlighted as next-generation agents targeting active RAS signaling and broader KRAS mutant tumors.

KRAS Mutational Landscape in NSCLC

Looking at the mutational landscape in non-small cell lung cancer, about 30% of non-small cell non-squamous carcinomas harbor a KRAS mutation. Of those, G12C is the most common and occur in about 40% of KRAS mutations. However, the breakdown is different depending on smoking history.

KRAS G12C is the most common mutation among former or current smokers, while G12D is the most prevalent among never smokers who have KRAS mutations. Though it should be noted that very few patients with KRAS mutations are never smokers.

The difference in the mutation predominance also differs between Western populations and Asian populations, with a predominance of KRAS G12C in the Western population.

FDA-Approved Drugs Targeting KRAS G12C Mutation in Advanced NSCLC

Let us start with what is currently available in the clinic. We have sotorasib and adagrasib as the first FDA-approved drugs targeting KRAS G12C. These drugs performed very similar when studied in a randomized controlled trial against docetaxel as second-line therapy. Here we saw a median progression-free survival around 5.5 months, a response rate around 30%, and a duration of response of around eight months for both drugs, very similar clinical outcomes.

There is no question that this has revolutionized how we treat patients with KRAS G12C mutations.

Challenge 1: Patients Continue to Relapse on Sotorasib or Adagrasib Monotherapy in Advanced NSCLC

However, it is worth noting that these still have significant limitations. Patients continue to relapse on sotorasib or adagrasib monotherapy. Here we have the phase I data from the earlier trials, CodeBreak 100 and KYSTAL-1, where we saw response rates around 40% for both drugs. You will see that over time, essentially all patients will progress on this therapy.

Safety Summary for CodeBreaK 200 and KRYSTAL-1

Additionally, there is need for optimization of the side effect profile. On the left, you will see the toxicity profile of sotorasib. Here we see about 36% of patients have a dose interruption, 15% have a dose reduction, and 10% of patients have discontinuation of drug. The predominant toxicities include diarrhea, nausea and elevated LFTs.

On the KRYSTAL-1 study with adagrasib, we saw 60% of patients have a dose interruption, 50% of patients have a dose reduction, and 7% of patients have dose discontinuation with high rates of diarrhea and nausea.

Challenge 2: Intrinsic + Acquired Resistance to KRAS G12C–Selective Inhibitors

Let us turn to resistance. Resistance can be thought of in two main buckets. Primary resistance are those that identify why did the patient not respond in the first place? Here we see about half of patients having a commutation with KEAP1, SMARCA4 or CDKN2A.

Additionally, some percentage of patients will have fusions causing primary resistance or other mutations.

Acquired resistance, on the other hand, are mutations that develop in response to a subsequent progression on this therapy. While over half of patients in the TAN[?] never had a resistance mechanism identified, the other half of patients in orange had an acquired resistance mutation that was identified, and these can include some interesting findings, such as FGFR3 or even RET fusions.

It is also worth noting that two of nine patients were identified to have squamous cell transformation as the primary mechanism of resistance.

Addressing Mechanisms of Resistance to KRAS G12C Inhibitors

How do we address these mechanisms of resistance? Each of these can be targeted in different ways. For those with primary resistance or those who never responded to a KRAS G12C inhibitor, can we potentially overcome this with combination strategies?

This may include, but should not be limited to, chemotherapy, immunotherapy, eGFR inhibitors, SOS1 inhibitors, SHP2 inhibitors, or even potentially MEK inhibitors.

For those who develop acquired resistance, it may depend on whether that resistance is KRAS-based or non-KRAS based. If KRAS-based, potentially next-generation KRAS inhibitors could overcome this acquired resistance.

Potential Roles of KRAS G12C Inhibition in Combination Regimens

With that, let us look now at some potential combinations of KRAS G12C inhibition.

KRAS Mutation Associated With Better Response to PD-1 Inhibition in Absence of STK11/LKB1 or KEAP1 Comutations

We know that patients who have STK11 mutations, which in this particular slide are depicted as labelled KL, or in the orange, have worse outcomes. You see here in the center pictorial the progression-free survival, which is very limited for those with STK11 comutations at only 1.8 months and significantly worse overall survival on the right at 6.4 months.

CodeBreaK 101: Sotorasib + Pembrolizumab in Patients With Pretreated KRAS G12C–Mutated NSCLC

To try to overcome some of these co-mutations or other primary resistance mechanisms, we combined KRAS G12C inhibition with immunotherapy. Here we see sotorasib plus pembrolizumab in patients who had previously treated KRAS G12C-mutated non-small cell lung cancer.

The overall response was about 30%, similar to single-agent therapy. However, the duration of response here was significantly longer than we saw with single-agent at almost 18 months. Unfortunately, the combination was thought not to be tolerable by patients based on level of hepatotoxicity, which you will see in the chart on the right.

Many patients had grade 3 toxicity anywhere from 20% to 60%, depending on the dose of sotorasib.

With this, while this particular combination was limited, it did generate some enthusiasm for combining immunotherapy with KRAS G12C inhibition.

CodeBreaK 101: Sotorasib + Pemetrexed/Carboplatin in Patients With Pretreated KRAS G12C–Mutated NSCLC

As far as how sotorasib is proceeding with combination therapy, we have data for sotorasib plus pemetrexed and carboplatin. Here these are patients who are previously treated, but we saw response rates of 67% overall with the combination of chemo plus sotorasib, and it did demonstrate some durability.

Median progression-free survival here in all comers was 10.8 months in the first-line setting. Based off of this, this combination is being studied in the front-line in CodeBreak 202.

KRYSTAL-7: Efficacy and Safety of Adagrasib + Pembrolizumab as 1L Therapy in KRAS G12C–Mutated NSCLC

Next let us look at adagrasib plus pembrolizumab as first-line therapy for KRAS G12C. On the left you will see the progression-free survival of this combination. This trial did enroll all comers based on PD-L1 status. This graph is broken down by PD-L1 status.

You will see that for patients who are PD-L1 of 50% or greater, which is the lightest orange, the median PFS here was 27 months. That is an incredible median progression-free survival for these PD-L high patients.

KRYSTAL-7: Safety Summary

Additionally, this combination looked better from a side effect profile. Here we saw grade 3 hepatotoxicity rates of 11% to 14%, though it is worth noting that 40% of all patients had some degree of AST or ALT elevation.

Based off of this, KRYSTAL-4, which is a study of adagrasib plus pembrolizumab with platinum doublet chemotherapy compared with pembrolizumab plus platinum doublet chemotherapy is ongoing and now recruiting.

Investigational Next-Generation KRAS G12C Inhibitors as Monotherapy and in Combination

With that, I will turn it to my colleague, Dr. Marrone, to discuss investigational next-generation KRAS G12C inhibitors.

Dr. Kristen Marrone (Sidney Kimmel Comprehensive Cancer Center): Thank you so much, Christine.

Classes of KRAS Inhibitors

This is going to be a fun and whirlwind tour about the drugs that are in development for this space. Just as a reminder, we have a lot of different options that are being developed. It is important to think about, with these agents, if they are mutation-selective inhibitors, where they are going to be hitting specifically one KRAS mutation sparing other KRAS mutations, as you can see here, Pan-KRAS inhibitors, where again, more KRAS mutations will be hit, but it will spare NRAS and HRAS.

Then finally our Pan-RAS inhibitors, where even though it is going to hit all mutations, we always think about what does that mean in terms of tolerability of those agents?

Going back to figure Dr. Bestvina shared earlier was just as a reminder where these agents hit in the KRAS pathway, it is a little different and will ultimately lead, we think to different both mechanisms of outcome as well as resistance and potentially toxicities.

Select Next-Generation KRAS G12C–Selective Inhibitors Currently in Development

When we think about which of these next-generation KRAS G12C inhibitors we are most excited about, you will see here listed on the slide, the four agents that we have the most data currently available to us that I will go through briefly on the next several slides.

Really, the goal here is to see increased durability of responses, as well as decreased toxicity and thinking through, like Dr. Bestvina mentioned, what we can combine and at what line of therapy we should be considering that.

Single-Agent Divarasib in KRAS G12C–Mutated NSCLC

First up is divarasib. This trial, the single-agent study, which was the first open-label dose escalation, phase I study. This is for patients who had been previously treated. You can see this waterfall plot is pretty impressive. The response rate here was about 56% in these 65 patients that were treated. The median duration of response was 18 months, and the median PFS was 13.8 months.

When we think about why we think these agents might have better duration and disease control, you can see here why this initial data was very exciting.

Coupled with, in the bottom table, you can see the high-grade treatment-related adverse events with this agent were lower than what we had seen with our initial G12C inhibitors. Again, when we look through what those are, we are seeing AST, ALT increases and other GI toxicities.

KRAScendo 1: Divarasib vs Sotorasib or Adagrasib in KRAS G12C–Mutated Advanced or Metastatic NSCLC

KRAScendo-1 is divarasib versus our current standard of care, sotorasib or adagrasib in KRAS G12C-mutated advanced or metastatic lung cancer. This is our randomized phase III study, really looking through which of these agents is going to give us the primary endpoint of progression-free survival.

Interestingly, they are stratifying this by KEAP1 mutation status, history of CNS mets. That will actually give us a lot of practical data as well to apply as the results come out from this study. You can see here they are estimated to treat about over 300 patients.

International, Open-Label, Phase I GO42144 Study: Divarasib + Atezolizumab in KRAS G12C–Mutated NSCLC

One of the studies looking at combining divarasib with atezolizumab is seen here. You can see through these patients how well they did in terms of disease response. When we look at all patients dosed on this study, the response rate was about 42%. Then looking at the patients who had not received prior KRAS G12C inhibitors, that raised to about 56%. So certainly encouraging efficacy data here.

Phase I GO42144 Study: Safety Summary

When we look through the safety data from these combinations, again, the rates of high-grade treatment-adverse events about 28%. Again, GI toxicities being the main one.

Again, going back to what Dr. Bestvina had mentioned, really, we want to also check on tolerability and being able to continue these agents. You can see in terms of thinking about resulting in dose modifications or discontinuation, those numbers were pretty tolerable and we are excited about that.

Thinking about the 28% of patients who experience high-grade treatment adverse events, you can see here, these were found to be reversible and there were no grade 4 or 5 treatment-adverse-related events reported.

KRAScendo 170 (Cohorts A1 and A2): 1L Divarasib + Pembrolizumab in Adv or Metastatic KRAS G12C–Positive NSCLC

Looking at other data of divarasib, so KRAScendo 170. They have reported out initial data for cohorts A1 and A2. This would be first-line divarasib plus pembrolizumab. The data shown here is specifically looking at cohort A1, which would be PD-L1 positive. Then cohort A2, which I actually think is super interesting as well, so that is in PD-L1 negative disease. You can see those waterfall plots are still pretty impressive.

Then looking through the efficacy data on the right. Again, PD-L1 positive tumors had a response rate of about 73%. Cohort A2 in the PD-L1 negative was still almost 70%.

When you look at the toxicity data along the bottom there, high-grade treatment-related adverse events were significant. You can see here in terms of where you saw dose reductions and dose interruptions, we are interested to see more about that data to think about what it means for the patients combining divarasib and pembrolizumab.

KRAScendo 2: 1L Divarasib + Pembrolizumab vs Pembrolizumab + Pemetrexed + Carboplatin or Cisplatin in NSCLC

They are going to continue to look at this in another study. KRAScendo 2 is first-line divarasib plus pembrolizumab versus pembrolizumab plus chemotherapy. Again, this is their phase III study looking at outcomes. Specifically the primary endpoint here is PFS as well as overall survival.

This study is being stratified by PD-L1 expression and CNS met history. Again, that gives us a lot of really important data to talk through once it finally gets to us with our patients, in terms of what these agents and combinations can offer them. This is an exciting trial as well.

NAUTIKA1: Neoadjuvant Divarasib Before Surgery in KRAS G12C Resectable Stage IB-III or Selected IIIB NSCLC

They are also moving this agent into the early-stage lung cancer space, which you are going to see is a trend as we talk about these agents.

NAUTIKA1 one is looking at neoadjuvant divarasib before surgery. This is part of a centralized study. They will give divarasib before surgery. Then following surgery and major pathologic response assessment, their adjuvant strategy will be determined based off of PD-L1 and response status.

This is an interesting trial. As we see perioperative approaches in this space evolve, figuring out where this will fit in is going to be something that will be the topic of further conversation for sure.

Single-Agent Olomorasib in KRAS G12C–Mutated Tumors

Switching gears into olomorasib. The initial study in KRAS G12C-mutated tumors. The original first-in-human phase I study. You can see the waterfall plot here. When we look through our patients with lung cancer are the orange patients on this waterfall plot. You can see how well they did.

When we look at the treatment-related adverse events here, high-grade treatment-related adverse events, we are seeing very few. Again, thinking through the diarrhea, fatigue is something that we see with this class of agents, but fewer quantitatively than maybe with some of our others.

LOXO-RAS-20001: Olomorasib + Pembrolizumab in KRAS G12C–Mutated Advanced/Metastatic NSCLC

Looking at LOXO-RAS-2001. This is a study looking at olomorasib plus pembrolizumab. This is very interestingly designed study which gives us data both in the first-line space as well as in patients who are previously treated.

If you look on the right of that waterfall plot, those are the first 45 patients treated in the first-line setting. That response rate was about 74%. When you look on the left there, you will see of the 46 patients who had been previously treated, they actually included patients who had been previously treated with chemotherapy and/or immunotherapy. That response rate was 48%.

Other patients, which is super important when we think through sequencing and how we are going to use these agents, or where this agent may help us in patients who received already therapies FDA approved. For those patients who had gotten chemotherapy and/or IO as well as a G12C inhibitor, the response rate there was 28%.

LOXO-RAS-20001: Olomorasib + Pembrolizumab + Chemotherapy in KRAS G12C–Mutated Metastatic NSCLC

Looking at the data about safety, that larger table on the right there, you can see the high-grade treatment-related adverse events you can see listed there. Again, in this study, cytopenias were seen, which we think is mostly related to the chemotherapy, but again, some diarrhea and then ALT increase as well.

Along the left there and to the bottom, which we should just point out that there was actually updated first-line efficacy data from this study, as well as another study I will talk about called SUNRAY-01, which showed that in the first-line space, the response rate was 61% with a disease control rate of 90%, which again, certainly is encouraging, and we look forward to seeing more of this data play out.

SUNRAY-01: Olomorasib + Pembrolizumab vs Placebo + Pembrolizumab in Locally Advanced, Unresectable, and/or Metastatic NSCLC

That study I just mentioned, SUNRAY-01. This is their global randomized phase III study of olomorasib plus pembrolizumab versus placebo, plus pembrolizumab alone in locally advanced unresectable or metastatic lung cancer. This is almost two sub-studies within.

For patients whose tumors are PD-L1 high 50% or greater, who would be considered suitable for pembrolizumab monotherapy, they are randomized to olomorasib plus pembrolizumab or placebo plus pembrolizumab.

For tumors that are 0% to 100% PD-L1 expression, those patients are randomized olomorasib plus pembrolizumab plus chemo versus placebo plus pembrolizumab plus chemo.

The primary endpoint, you can see here is PFS.

SUNRAY-01: Olomorasib + Pembrolizumab as 1L in KRAS G12C–Mutant Advanced NSCLC and PD-L1 0-49%

Initial data coming out of this study, which is looking at the combination of olomorasib plus pembrolizumab. You can see here along the left in that waterfall plot. This is for patients PD-L1 zero to 49 and where they lined up in terms of their response and what is ongoing.

Again, this is a very early look looking at the treatment-related adverse events. You can see along the right there, primarily low-grade toxicity with the higher grade, the blue boxes being diarrhea, ALT, AST increase.

Looking at the patients that they were able to present the efficacy data for, so that table right along the bottom left there. For tumors that were PD-L1 less than 50%, the response rate was 63%, PD-L1 of less than one, so zero would be 58 and then PD-L1 zero to 49 grouping together was about 66%.

Median time to response, which is an outcome we have not necessarily talked about in some of these other studies, so just to point out, is about 1.5 months across all three, which is encouraging when we think about trying to improve time to response for some of these patients’ tumors who, historically, we have sometimes had to wait a little bit longer when we are using immunotherapy alone. The duration of response, you can see along the bottom there as well.

LOXO-RAS-20001 and SUNRAY-01: Olomorasib + Pembro ± Chemotherapy in KRAS G12C+ NSCLC ± Prior Cycle of SoC

When we look at the combination, so the pooled data of the LOXO-RAS-2001 and SUNRAY-01 of olomorasib plus pembrolizumab with or without chemotherapy. This study did allow actually prior cycles of standard of care therapy.

This data was interesting, and I will be interested to see the final presentation of this. What you can see along the left there is the efficacy data. For patients who got one cycle of standard of care prior to enrolment. That was about a third of patients. Their response rate was 72%. When you look at the patients who did not get that, so 52 of the patients, their response rate was a little lower at 55%.

I do not have a great rationale for that. Also the other thing when you look down there, the other efficacy metrics were very similar. This study allows us to think about the fact that these patients really need to be on therapy quickly and that adding in this G12C inhibitor, even if it is a little bit delayed, perhaps while in the real-world, we are waiting for NGS to come back is actually totally feasible and in fact helps our patients and their tumor control.

Looking at the TRAEs, which is always important when we add stuff to what we are already giving patients. You can see, again, for some reason, patients who did not get that first cycle of standard of care, they had a higher rate of treatment-related AEs. We will see why that might have been.

Importantly, when you look at that one box, the discontinuation of the treatment regimen across all of those patients, six patients in total had to discontinue their therapy due to toxicity. So something to learn more about as this data comes out.

I should clarify that data is hot off the press from ASCO 2026, so I do think we will be hearing about it relatively soon.

SUNRAY-02: Immunotherapy ± Olomorasib in Resected Stage II-IIIB or Unresectable Stage III KRAS G12C–Mutant NSCLC

The other study to talk about with olomorasib is SUNRAY-02. This looks at olomorasib with or without immunotherapy in early-stage KRAS G12C-mutated lung cancer. Their part A is for tumors that have been resected and those patients are randomized to olomorasib plus pembrolizumab or placebo plus pembrolizumab, pembrolizumab for a year, olomorasib for three years.

Part B is for those patients with unresectable stage III disease who have completed chemo RT, again randomized to the same treatment options and duration of therapy. Their primary endpoint here being DFS for part A and PFS for part B.

Posttest 1

Let us do a quick vote for post-test one. Which clinical trial approach would be most reasonable to discuss for a patient with newly diagnosed advanced metastatic non-squamous KRAS G12C mutated non-small cell lung cancer in the frontline setting?

1. Sotorasib plus immunotherapy;
2. Olomorasib plus pembrolizumab plus/minus chemotherapy;
3. Adagrasib plus pembrolizumab plus/minus chemotherapy;
4. Divarasib plus immunotherapy.

Question two is, how confident are you in your answer? Choices would be, I am guessing; I am probably right, and I am sure.

The majority of the group picked olomorasib plus pembrolizumab plus/minus chemotherapy, which we just talked through. It is a great answer. I will point out that there are definitely studies related to option C and D in terms of looking through the available trials, perhaps on clinicaltrials.gov.

Posttest 1: Rationale

The reason why we wanted to really highlight olomorasib plus pembrolizumab is because that is the immune checkpoint inhibitor that is specifically been used and has been shown the most safety efficacy data with KRAS G12C inhibitors. I would definitely encourage you to consider trials like these for your patients in the metastatic first-line KRAS G12C space.

Posttest 2

Moving on to post-test question two. Which clinical trial strategy is most appropriate to discuss with this patient after R0 resection reveals residual KRAS G12C-mutated adenocarcinoma?

1. Observation alone, because negative margins exclude the need for systemic therapy;
2. Adjuvant olomorasib plus pembrolizumab versus pembrolizumab plus placebo;
3. First-line calderasib plus pembrolizumab for KRAS G12C-mutated lung cancer;
4. Sotorasib or adagrasib monotherapy as standard adjuvant therapy.

Question two. How confident are you in your answer? If you are guessing, probably right or sure.

Posttest 2: Rationale

The answer was adjuvant olomorasib plus pembrolizumab versus pembrolizumab plus placebo. This was the study, SUNRAY-02, which looks at this as an option for patients. Again, hopefully you all are able to obtain NGS data for our patients with early-stage non-metastatic disease just because some of these trials more and more are going to be available for patients outside of what is already FDA approved in this space. So this would definitely be a great option.

KANDLELIT-001: Calderasib as Monotherapy in KRAS G12C–Mutated Advanced Solid Tumors

Moving on to KANDLEIT-001. This is calderasib as monotherapy. Initial data across all solid tumors. You can see here in the lung cancer cohort, 21 patients, the response rate was about 38%, median PFS of eight months. Again, looking at high-grade treatment-related adverse events, we see ALT and AST increases.

In terms of thinking about did they lead to discontinuation of the therapy, we did not see that, which is again encouraging thinking about keeping people on these drugs to control their disease.

KANDLELIT-004: 1L Calderasib + Pembrolizumab inPD-L1-High KRAS G12C–Mutated Advanced NSCLC

KANDLELIT-004. This is a first-line calderasib plus pembrolizumab in PD-L1 high, KRAS G12C-mutated lung cancer. This is their large randomized, double blind, phase III study. This is again just specifically looking at PD-L1 high tumors. They are hoping to treat 600 patients on this study. We are looking forward to hearing more about that.

KANDLELIT-007: 1L Calderasib + SC Pembrolizumab in KRAS G12C–Mutated Nonsquamous Advanced/Metastatic NSCLC

KANDLELIT-007 is first-line calderasib plus subcutaneous pembrolizumab in non-squamous KRAS G12C-mutated lung cancer. This is also a phase III study. They are going to compare calderasib plus subcutaneous pembrolizumab to subcutaneous pembrolizumab plus chemotherapy.

Primary endpoint interestingly is PFS in PD-L1 TPS at least 1%. It will be interesting to see how that data is presented by PD-L1 status as we see it read out.

KANDLELIT-013: Adjuvant Calderasib + SC Pembrolizumab After Complete Resection of KRAS G12C–Mutated NSCLC

We are getting through KANDLELIT-013. This is looking at adjuvant calderasib plus subcutaneous pembrolizumab following resection of KRAS G12C-mutated lung cancer. This is a phase III study looking at stage IIA to IIIB, including N2 disease non-squamous lung cancer. You can see here in terms of route one. This is before adjuvant randomization, neoadjuvant subcutaneous pembrolizumab plus platinum chemotherapy.

Route two would be if people had upfront resection and adjuvant platinum doublet. Then thinking through these options and then they will follow disease-free survival rates.

Ongoing Phase II Trial of Neoadjuvant Opnurasib in KRAS G12C–Mutated, Surgically Resectable NSCLC

Then finally going through opnurasib. This is an ongoing phase II trial of neoadjuvant therapy. This is looking at patients who are previously untreated, they will receive a targeted therapy and surgery, and then go from there in terms of their standard of care adjuvant therapy with the possibility of adjuvant opnurasib if they had major pathologic response or pathologic complete response. They are looking at the primary endpoint of MPR.

Other Next-Generation KRAS G12C Inhibitors Currently in Development in China

Always important to point out what other G12C inhibitors are currently being studied internationally. You can see here in terms of the five different trials that have data available out of China.

Fulzerasib is approved in China. Elisrasib has clinical trial locations in the United States. So something you are going to continually hear about in the coming months and years, as we see these agents play out and think about where they fit in and if they will be available for our patients.

A Look to the Future of KRAS G12C Inhibition in NSCLC

We are going to move quickly. Just to highlight a few things about the future of KRAS G12C inhibition in lung cancer. This could be its own talk. We can think about where you all think the unmet need is for these patients.

Elironrasib Efficacy/Safety in Patients With KRAS G12C NSCLC Following Treatment With a KRAS(OFF) G12C Inhibitor

This data is really exciting. This is elironrasib looking at patients who have KRAS G12C non-small cell lung cancer, who had previously received KRAS(OFF) G12C inhibitors. So switching on over to the KRAS(ON) inhibitor mechanism.

You can see here, they release very preliminary data of their first 24 patients. The patients had a median of three prior lines of therapy. 92% of patients disease had progressed on their prior G12C inhibitor. Response rate of 42%. Median duration of response of 11 months. Median PFS of six months. Median overall survival, not evaluable. 12-month OS of 62%.

Again, always important to think about toxicity. High-grade treatment-related adverse events, again diarrhea, nausea, abdominal pain.

The peripheral edema is new, so we will have to watch that and see what comes of that. Other grade 3 events included QTc prolongation, hypokalemia. They did not have any TRAE-related discontinuations, which is great and less than 10% of patients required dose reductions.

This is really the future, thinking about how we are going to sequence these agents, what they mean in terms of lines of therapy combinations. Something for us to talk about if of interest moving into the discussion at the end.

Phase II TRITON Study of Tremelimumab + Durvalumab + Chemotherapy vs Pembrolizumab + Chemotherapy

Another important piece of data that was presented at ASCO a few weeks ago for our patients, when they have KRAS mutations are at higher risk of having STK11 and KEAP1 alteration. This is the idea that PD-1/PD-L1 immune checkpoint inhibitors are not enough in terms of controlling tumors with poor molecular profile.

This data was presented and you can see here what the patient population was. Treatment-naive non-squamous non-small cell lung cancer with STK11, KEAP1, KRAS-mutated tumors. The patients who were stratified by their mutation status and the PD-L1 status of their tumors, they received either what we would consider standard of care pembrolizumab plus platinum pemetrexed or tremelimumab/durvalumab/platinum/pemetrexed.

You can see here looking at the response rate, they were relatively similar. When you look at the median duration of response though, you can see pretty significant, or I should not say significant. Clinically important point, which is the median duration of response with our pembrolizumab/chemotherapy being 6.4 months and then not reached for the patients who received dual checkpoint inhibition.

Certainly treatment-related adverse events important to watch. In this particular subset not an increased rate of IRAEs or high-grade IRAEs with the addition of CTLA-4 inhibition, but certainly something we want to think about as we wait for this data to mature.

Posttest 3

With that, we are going to move to post-test three. During a multidisciplinary team discussion, a colleague asks how next-generation KRAS G12C inhibitors compare with first-generation agents such as sotorasib and adagrasib. What would you tell them based on current clinical trial data?

1. They show limited activity after prior sotorasib or adagrasib;
2. They bind both active and inactive KRAS states at the same time to prevent resistance;
3. They produce deeper and more durable anti-tumor responses;
4. They show similar levels of hepatotoxicity to sotorasib and adagrasib;

Question two. How confident are you in your answer: guessing, probably right, or unsure.

Posttest 3: Rationale

Great. The correct answer is C. They produce deeper and more durable anti-tumor responses. When we look at how these next-generation G12C inhibitors have been performing across all of this initial data that we shared, we see deeper and more durable anti-tumor responses when we think about the duration of response.

This is including activity after prior G12C(OFF) inhibitors. There are both KRAS(ON) and KRAS(OFF) inhibitors under investigation. These agents do not target both states at the same time.

Hepatotoxicity is definitely something that we will continually to watch, but appears to be less frequent and more manageable compared to our FDA-approved agents.

Practice Change Polls

We will move into the practice change polls.

Poll 3

Do you plan to make any changes in your clinical practice based on what you learned in today's program?

1. Yes;
2. No;
3. Uncertain.

Poll 4

Great. Our next question for you all is, if you could please take a moment to text in one key change that you plan to make in your clinical practice based on this education? We would love to hear your responses. We are going to keep these behind the curtain, so they will not be shared right now.

Q&A

There was a question that came up in the chat about how to understand the relationship between surrogate endpoints like DFS or PFS with OS in non-small cell lung cancer. It is an excellent question. We are always very cautious to do that, although you could probably hear from my tone that we are excited about what we have so far.

Maybe the clinical excitement versus the regulatory approval process probably has a little bit of a different answer. We have seen both really exciting first looks at data that have ultimately panned out. We have seen things where ultimately overall survival has not panned out, which we still believe is the gold standard and what we should push for, for any new agent in therapy.

I guess my answer would be, we are seeing this data play out in real time to try to give our patients more access and options, but the way we have our process set up in the United States, we are waiting on overall survival data to really see FDA approvals with these agents.

Christine, I do not know if there is anything else you would add.

Dr. Bestvina: Yes, it is a great question, and it may be alluding to the second-line data for sotorasib and adagrasib, where we did see an improvement in PFS that did not translate into an improvement in overall survival, although knowing we still have not seen the adagrasib final OS data yet.

The only thing I will add to what Dr. Marrone already said is that I do think PFS is important in and of itself. PFS is reflective of when patients do not have symptoms related to their cancer progressing. Mentally and emotionally, it is important to patients that they know that their cancer is not progressing.

I do not think of PFS necessarily only as a surrogate endpoint for overall survival. It really can be its own endpoint as well.

Jerfiz Constanzo: Wonderful. I have another question for you guys. Based on the data that is currently available, do you foresee the next-generation KRAS inhibitors somehow replacing or stepping in for the standard first-generation agents in non-small cell lung cancer?

Dr. Bestvina: I think lots of companies are betting on that being the case. I do think that the data for a next-generation KRAS G12C inhibitors does look more impressive than what we saw with the first-generation agents, and in particular, seeing activity post first generation agents really does make me think that this will overcome.

That being said, it is going to take some time for that to happen since the frontline trials were a bit delayed after what we saw with the first-generation combination first-line strategies. I do think it will win, but it is also going to take some time.

Dr. Marrone: Yes. When you look at the data we have so far, a lot of them are going in similar places at the same time. So the next question is going to be, which one do you pick over the other one? That is going to be really tough too.

I do applaud that some of the trial constructs in terms of thinking about specific questions like comutational status, CNS disease at baseline to try to further elucidate that. But like Dr. Bestvina mentioned, all the data so far is pretty encouraging. I would envision we are going to be having this conversation. Yes, for sure.