Sam Klempner, MD, faculty member, Oncology, Massachusetts General Hospital, Medicine, Harvard Medical School, discusses the incidence of 

 G12C mutations in patients with metastatic colorectal cancer (CRC), the viability of the target in this disease, the efficacy of adagrasib (MRTX849) in combination with cetuximab (Erbitux) in this patient population, and the importance of genetic testing.

 G12C mutations occur with varying prevalence across different types of solid tumors, including gastrointestinal cancers like CRC, Klempner says. Data from retrospective studies have indicated that approximately 3% to 4% of patients with CRC harbor these mutations. These mutations appear to be associated with an inferior prognosis—even compared with other 

 mutations, Klempner adds. Moreover, those with 

 G12C mutations typically derive a shorter duration of benefit from standard frontline chemotherapy options, according to Klempner.

The phase 1b/2 KRYSTAL-1 trial (NCT03785249) evaluated the safety, tolerability, and clinical activity of adagrasib monotherapy and in combination with cetuximab in patients with 

 G12C–mutated tumors, including CRC. Data presented at the 2022 ESMO Congress showed that the activity displayed by adagrasib plus cetuximab confirmed preclinical observations of combining a KRAS G12C inhibitor with an EGFR inhibitor, Klempner says. With a longer follow-up of 17.5 months, the combination elicited a confirmed objective response rate of 46%, with a disease control rate of 100% in 28 evaluable patients with 

Ninety-three percent of patients experienced a decrease in tumor volume, according to Klempner. Moreover, many patients achieved deep responses, with more than a 50% decrease in the tumor volume, Klempner adds. Patients treated with the combination also experienced durable responses, with a median duration of response of 7.6 months. The median time to response with the doublet was rapid, at 1.4 months, Klempner adds. At data cutoff, 5 patients were still receiving treatment with the combination, Klempner says. Treatment-related adverse effects were observed in all 32 patients (100%). 

The most frequent toxicities were nausea (63%), diarrhea (56%), vomiting (53%), dermatitis acneiform (47%), fatigue (47%), and dry skin (41%). The combination was tolerable and had a manageable safety profile.

 G12C mutations represent a viable target in CRC, Klempner adds. The relatively high rates of responses achieved with the doublet, and the durability of those responses, suggest that the regimen may be more beneficial for this subgroup of patients with CRC compared with other options available in the late-line setting, such as regorafenib (Stivarga) and trifluridine/tipiracil (TAS-102; Lonsurf), Klempner says.

 G12C mutations underscores the importance of performing genetic testing in all patients with CRC, Klempner adds. Moreover, if these kinds of mutations are detected, all efforts should be made to identify clinical trials that may be appropriate for this patient subset, Klempner concludes.

Videos

Sam Klempner, MD, discusses the incidence of KRAS G12C mutations in patients with metastatic colorectal cancer, the viability of the target in this disease, the efficacy of adagrasib in combination with cetuximab in this patient population, and the importance of genetic testing.

Dr. Klempner on the Significance of KRYSTAL-1 Data in KRAS G12C–Mutant CRC

Targeted treatment with adagrasib (MRTX849) monotherapy and combination therapy with cetuximab (Erbitux) has shown promise when treating patients with 

 G12C–mutated colorectal cancer (CRC) according to Rona Yaeger, MD.

Investigators of the phase 3 KRYSTAL-10 (NCT04793958) trial seek to build on early efficacy observed with the dual blockade of 

 in patients who have disease progression following standard firstline therapy. Safety data showed that the combination is tolerable with the most frequent treatment-related adverse events including nausea (63%), diarrhea (56%), vomiting (53%), dermatitis acneiform (47%), fatigue (47%), and dry skin (41%).

“The rationale for the combination is that in CRC we have a high level of basal RTK activation, particularly EGFR, [therefore] treatment with adagrasib or any KRAS G12C inhibitor is likely limited by the activation of these receptors. The idea is by [administering] cetuximab you may inhibit with adagrasib 

 G12C signaling and then inhibit the reactivation of EGFR and so any rebound in signaling,” Yaeger said.

, Yaeger, an associate attending physician at Memorial Sloan Kettering Cancer Center in New York, New York, discussed the unmet needs for patients with 

 G12C mutations and the promising combination therapy of adagrasib and cetuximab.

What is important to know about patients with CRC who progress on a first-line chemotherapy regimen?

Patients with metastatic CRC are treated with a combination of chemotherapy and if appropriate targeted therapies. Patients who have a 

 mutation are precluded from receiving targeted therapies right now. In terms of subsequent lines of treatment after progression on chemotherapy, they have fewer options and so the patients with 

 G12C mutations are in need of another treatment.

What is the biggest unmet need in this patient population?

 G12C mutations occur in approximately 3% to 4% of CRC [cases and] [up to] approximately 50% of CRCs have an activating mutation in the 

. The frequency is higher for right-sided colon tumors and is a lower on the left side, but overall, it’s nearly 50% and a small portion of those are the 

 G12C mutations. There’s been a lot of data over the years looking at the prognostic significance of having mutations in the 

 genes and the overall thought is that it’s a modest poor prognostic factor.

 G12C because of potential to target it with new drugs. There have been studies that have looked at whether the presence of this mutation affects prognosis. Investigators have looked retrospectively at patients with metastatic disease and those who have a tumor 

 mutations appear to have shorter overall survival [OS] and shorter [time to] progression. In that sense, there’s clearly a need for new therapies and there’s a need for ideally something matched, which is what we’re trying to develop.

These patients can get standard chemotherapy, but they have no targeted treatment and, in some sense, they’re missing a potential for therapy. Now that there are new drugs which are selective for the 

 G12C mutation, [we] have the potential to give a matched treatment.

What is the mechanism of action of adagrasib?

 is like a switch in that when it is bound to GTP it is active and when it is bound to GDP is inactive. Adagrasib and the other 

 G12C inhibitors that are now moving through clinical trials or being used in the clinic are designed to take advantage of the cysteine to bind to the G12C. Adagrasib binds covalently and traps 

 when it is in the inactive state and by doing that it prevents its activation and the reactivation of 

These drugs take advantage of the natural cycling of KRAS. There is some natural cycling from the active GTP bound state to the GDP bound state and when KRAS G12C is in the GDP bound state if drug is around it, it can trap it in that state. Adagrasib has a longer half-life of approximately 23 hours; it is given twice daily with the idea of [providing] continuous inhibition of 

G12C and to prevent the formation of new, active KRAS molecules. It has central nervous system [CNS] penetration and has been shown to have some activity in tumors with CNS spread such as lung cancer, where we see that more commonly.

What has been observed with adagrasib in combination with cetuximab in this patient population in KRYSTAL-1?

KRYSTAL-1 [NCT03785249] is a phase 1/2 study that has looked at adagrasib alone and in multiple combinations. More mature data were recently reported at the European Society for Medical Oncology [Annual Congress 2022] for the monotherapy cohort as well as the cohort [examining adagrasib in] combination with cetuximab in CRC. In the [phase 2] monotherapy cohort they treated 44 patients and 43 were valuable for a response with an objective response rate of 19% and median PFS [progression-free survival] of 5.6 months.

The combination was tested in a phase 1b cohort [where] 32 patients were treated; 28 of them were evaluable for response with a response rate of 46%, 100% disease control rate, and a median PFS of 6.9 months. The activity of the combination is very encouraging and that sets the stage for the potential to develop this further. If you look at targeted therapy in general and in CRC, I think it stacks quite well [with the progress we’ve seen]. We’ve been through this recently for 

 V600E–mutated CRCs where we see that adding an EGFR antibody improves the activity [of targeted agents] rather than just inhibiting the activated oncogene. When we look at the activity that we’re seeing with 

 G12C inhibitors, the combination of these drugs with EGFR inhibitors is very encouraging in the context of what we see with targeted therapies for CRC.

Can you expand on the design of the KRYSTAL-10 study and the overall trial objectives?

KRYSTAL-10 is a [phase 3] study looking at [adagrasib and cetuximab] in the secondline setting for patients who have metastatic 

Patients [must] have received first-line treatment with a fluoropyrimidine containing doublet. They are then randomly assigned 1:1 to receive either cetuximab and adagrasib or the fluoropyrimidine containing doublet [they did not previously receive]—mFOLFOX6 or FOLFIRI or vice versa—with an anti-VEGF agent per investigator discretion. The primary end points are PFS and OS; this is really looking to compare adagrasib and cetuximab to standard treatment, but it’s taking place in the second line.

Thinking about recruitment, first, patients need to know their 

 G12C mutation. It would take many patients to find a large portion of 

 testing done. Being aware of this [is important] prior to the secondline setting. [Clinicians should] not wait until after patients have progressed through all therapies and then look for trials.

Second, patients will have to have had received a fluoropyrimidine containing doublet [in the first-line setting], but some patients may have received triplet therapy, such as FOLFOXIRI. Those patients are not eligible because the goal is to compare standard fluoropyrimidine containing doublet to the targeted therapy.

Patients need to have tissue sequencing results available, but they can do central testing for screening or for confirmation if screening is done locally. The study is open and enrolling internationally.

G12C mutations in CRC would you like to impart to colleagues?

 being targetable is a whole paradigm shift. It’s a huge deal and in the data we have now, we can see that many patients can benefit from these drugs. Hopefully they will be developed further, and we’ll see [more positive] results in the KRYSTAL-10 study.

What I would like clinicians to take from this is to be alert, to look at the sequencing results for patients, [and] if patients do have a 

 G12C mutation to consider them for clinical trials and be able to connect them with clinical trials so they have the potential to receive targeted therapies.

Klempner SJ, Weiss J, Pelster M, et al. KRYSTAL-1: updated efficacy and safety of adagrasib (MRTX849) with or without cetuximab in patients with advanced colorectal cancer (CRC) harboring a KRASG12C mutation. 

. 2022;33(suppl 7):S1391. doi:10.1016/ j.annonc.2022.08.020

Articles

Rona Yaeger, MD, discusses the unmet needs for patients with KRAS G12C–mutated colorectal cancer and the promising combination therapy of adagrasib and cetuximab.

Adagrasib With Cetuximab Moves Into Phase 3 for KRAS G12C–Mutated CRC

Shirish M. Gadgeel, MD, head, the Division of Hematology/Oncology, associate director, Patient Experience and Clinical Care, the Henry Ford Cancer Institute, discusses the efficacy of adagrasib in patients with 

 G12C–mutated non–small cell lung cancer (NSCLC) and central nervous system (CNS) metastases. 

The phase 1/2 KRYSTAL-1 trial (NCT03785249) examined the use of adagrasib in patients with advanced solid tumors, including NSCLC, whose tumors harbored 

The phase 1b cohort included 19 patients who had 

 G12C–mutant NSCLC and CNS metastases that had not been previously treated with local approaches such as radiation or surgery, Gadgeel says. Data presented during the 2022 ASCO Annual Meeting showed that in this patient population, adagrasib produced an intracranial overall response rate (ORR) of 32%; the median intracranial duration of response (DOR) was not yet reached, Gadgeel adds.

Cohort A of the phase 2 portion of the trial included 33 patients with treated, stable CNS metastases. In this population, the intracranial ORR achieved with adagrasib was 33%, and the median intracranial DOR was 11.2 months. In the full cohort of patients with previously treated 

 G12C–mutated disease (n = 112), the ORR with adagrasib was 43%.

Because adagrasib demonstrated activity both inside and outside of the CNS, the drug has a clear advantage, Gadgeel concludes.

Shirish M. Gadgeel, MD, discusses the efficacy of adagrasib in patients with KRAS G12C–mutated non–small cell lung cancer and central nervous system metastases. 

Dr. Gadgeel on CNS Activity Achieved With Adagrasib in KRAS G12C+ NSCLC

Adagrasib, a KRAS G12C inhibitor, showed early responses in the phase 1b portion of the phase 1/2 KRYSTAL-1 multi-cohort trial (NCT03785249), which studied patients with 

 G12C–mutated non–small cell lung cancer (NSCLC) who harbored active and untreated brain metastases, according to Joshua K. Sabari, MD.

In the phase 1b cohort of KRYSTAL-1, the overall response rate (ORR) of 19 evaluable patients with active, untreated central nervous system (CNS) metastases was 32% (n = 6; 95% CI, 12.6%-56.6%), with objective intracranial responses observed in patients with target and non-target lesions. Sabari presented these data at the 2022 ASCO Annual Meeting.1

 has been undruggable for many years, and we’ve had many failed trials in this disease,” Sabari said. “[Adagrasib and sotorasib (Lumakras)] are the first generation of KRAS G12C inhibitors. It’s an exciting time.” Adagrasib has a long half-life, 23 hours, which differentiates it from other KRAS G12C inhibitors, Sabari added.

, Sabari, an assistant professor in the Department of Medicine at NYU Grossman School of Medicine and the medical director of Kimmel Pavilion 12 at NYU Langone Health, discussed the significance of adagrasib as an agent with favorable CNS penetration. He also emphasized the importance of performing next-generation sequencing (NGS) in all patients with NSCLC to detect 

: Could you provide some background on adagrasib and explain what makes this agent unique from others available in this patient population?

: Adagrasib, formerly known as MRTX849, is a KRAS G12C inhibitor. It has dose-dependent pharmacokinetics. It also has a long half-life, 23 hours, which differentiates it from other KRAS G12C inhibitors.

What has been previously observed with this agent regarding CNS penetration in treated, stable CNS metastases?

 G12C mutations are quite common, occurring in 10%−12% of patients with NSCLC. In that population, upward of 40% of patients have brain metastases at presentation. This is an unmet need for our patients. The prognosis is poor; the median overall survival [OS] is about 5 months.

It’s important for us to study agents that have activity in the brain. Adagrasib has an interesting property in that it inhibits the P-glycoprotein efflux pump. This is a transporter that usually pumps out drugs from the brain, and adagrasib directly inhibits it.

When we studied this drug preclinically in mouse models, we were able to see nice CNS concentration. In the clinic, when we administered this drug in patients at a regular dose of 600 mg [twice daily], which is the recommended phase 2 dose, we were able to do lumbar punctures in 2 patients in a phase 1b cohort specifically for patients with active and untreated brain metastases. The average Kp,uu unbound partition coefficient ratio was 0.47, suggesting that this drug has very good CNS penetration.

We also have seen clinical regression in patients. The intracranial ORR in the phase 1b cohort was 32%, which is similar to what we’ve seen extracranially. The CNS is going to be an active area of ongoing development of agents. In other targeted alterations such as 

, having drugs with significant CNS activity is critical. It’s similar in the 

Can you expand on the design of the phase 1b portion of the KRYSTAL-1 study and the overall trial objectives?

The KRYSTAL-1 study is a phase 1/2 [study including] dose escalation followed by expansion. We initially looked at just safety with the recommended phase 2 dose to understand the maximum tolerated dose. We rapidly escalated to 600 mg twice a day, and then we went into the expansion cohort, where all patients were treated at 600 mg twice a day.

Data [from cohort A of the phase 2 portion of that study] were presented at ASCO and were quite impressive. We saw a 43% objective response rate, a median progression-free survival [PFS] of about 6.5 months, and a median OS of 12.6 months.

This [cohort included] an additional 25 patients enrolled at the recommended phase 2 dose. These patients had active and untreated brain metastases. KRYSTAL-1 is the first study to look at patients with [with 

-G12C mutant NSCLC] and active and untreated brain metastases. We defined these patients as those who were clinically asymptomatic, were not on high doses of steroids, and were not on anti-epileptics. We excluded patients who had brainstem lesions, but we did allow patients who had leptomeningeal disease, if they were clinically asymptomatic.

An efficacy objective of this cohort study was to look at the intracranial response rate by modified [response assessment in neuro-oncology (RANO)] brain metastasis criteria. We also looked at extracranial response by RECIST v1.1 criteria. We wanted to look at safety and, if feasible, we also wanted to look at the CSF concentrations of the drug. We were able to do that in 2 patients.

What is important to know about patients with untreated CNS metastases?

We know from prior presentations of adagrasib that this drug was associated with a 33% intracranial response rate in patients with stable, treated brain metastases. With sotorasib, formerly known as AMG 510, we saw prior presentations of about a 13% response rate in patients with stable treated brain metastases. [Some] patients had prior radiation to the [brain] lesion, so it was difficult to identify whether the prior radiation or [adagrasib] caused the regression or response.

In the phase 1b cohort of adagrasib in the KRYSTAL-1 study, we specifically looked at patients who had active and untreated brain metastases. The response rate by the modified RANO brain metastasis criteria by a blinded independent review committee, was 32%. This was similar to the rate we saw extracranially, which was 37%, with an 88% concordance in responses in the brain, as well as responses in the chest and extracranially. A key [detail about this study] is that no significant, new CNS-specific adverse effects [AEs] were identified with this agent.

What has this study shown in terms of durability of responses?

The median intracranial OS was not yet reached in this study, which is exciting, because the median OS for patients with NSCLC with brain metastases is poor. At [a median follow-up of 6.6 months], the median intracranial PFS was 4.2 months. This is in line with what we would expect from this patient population.

We also saw patients who had prolonged responses to therapy. One of the patients who I personally treated had a durable long-term response to treatment of over 12 months. We’re seeing responses in the clinic, and we’re also seeing durability of those responses. Further data is needed to confirm these findings.

How did intracranial responses differ in those with target lesions vs those with non-target lesions?

We enrolled 25 patients onto the study, and [19] patients had RECIST v1.1–measurable disease. Of those, [15] had target and non-target lesions, and 4 patients had non-target lesions only. The response rates were similar [across these 2 groups]. The intracranial disease control rate was also similar across both cohorts.

When developing a prospective study measuring active and untreated CNS metastases, it’s important [to include patients with] target lesions. Moving forward, [trials with] adagrasib, as well as with other agents being studied in the brain, should have strict criteria for enrollment like we did.

Could you expand on the relationship between systemic and intracranial disease control?

Current KRAS G12C inhibitors are not as effective as some of the EGFR inhibitors that we see. With EGFR inhibitors, we’re seeing response rates in the 80% range. With ALK inhibitors, we’re also seeing response rates in the 80% range. In 

 G12C–mutant disease, we’re seeing responses in the 35%-45% range, so we still have a long way to go.

The intracranial response of 32% that we saw with adagrasib [in the KRYSTAL-1 study] appears low, but it’s similar to what we would expect from an extracranial response. If a patient has a 

 G12C mutation and is responding extracranially in the chest, they’re likely also going to respond in the brain. However, if they’re not responding in the chest, they will probably not derive benefit in the brain.

We do need to do more; we need to understand these agents better. We need to find better combination strategies in later lines without sacrificing or forgetting about the need for CNS activity.

What is important to know about the safety profile of adagrasib?

[In KRYSTAL-1], patients were treated in a fasted state at 600 mg twice a day with the capsule formulation [of adagrasib]. We did see higher rates of nausea, abdominal discomfort, and emesis. I’m hoping that with the formulation now as a tablet, these AEs will be less frequent, particularly in the fed state.

In clinical practice, most patients had these gastrointestinal AEs with adagrasib in the first 2 to 4 weeks of therapy, and then they significantly improved over time, either with some anti-emetics, or as the patient became more used to these AEs.

What do these data mean for patients with 

 G12C–mutated disease who have untreated CNS metastases, and how do you see this agent fitting into the treatment paradigm?

 G12C–mutant NSCLC, the current FDA-approved frontline regimens are chemotherapy and immunotherapy or immunotherapy alone. Chemotherapy does not have great CNS activity. Immunotherapy, particularly pembrolizumab [Keytruda], which is often used in the frontline setting, does have CNS activity.

There is an ongoing cohort in the phase 1 expansion study with sotorasib for patients with active and untreated CNS metastases. We’re looking forward to seeing that data. Additionally, we’ve shown that adagrasib does have CNS activity, but it’s not yet FDA approved. It has a PDUFA date of December 14, 2022.

An approval could change the potential landscape of this agent. Preclinically, the agent is robust because of its dose-dependent pharmacokinetics and its long half-life. Because of the CNS activity, particularly in a patient with active untreated CNS metastases, I would prefer to use adagrasib over sotorasib. However, according to the data that we currently have, if a patient is symptomatic, has vasogenic edema, has a centimeter or centimeter-and-a-half–sized lesion, or required steroids, I would recommend radiating that lesion prior to considering a systemic therapy.

What are the next steps with adagrasib and sotorasib?

The next step for these agents is to confirm their activity in a phase 3 study. Both sotorasib and adagrasib are being compared with docetaxel in the second line. [These agents] work in the second-line setting.

From there, the next logical step is asking: What if we move them to the frontline setting? Would patients respond longer and better? Both agents are now being studied in combination with a PD-1 inhibitor, pembrolizumab, and I look forward to seeing more results from these studies in the frontline setting, because there’s a potential role for these agents there.

Lastly, in the later lines in patients who’ve had progression on KRAS G12C inhibitors, the resistance landscape is diverse. Thinking about combination strategies, like potential combinations of upstream inhibitors such as SHIP2 inhibitors or SOS1 inhibitors or potential downstream inhibitors, might be an effective strategy for targeting some of those resistant clones.

 G12C mutations in NSCLC would you like to impart to colleagues?

Test your patients in the frontline setting. You need to molecularly profile your patients. If you’re not obtaining NGS, you can’t identify the best possible treatments for your patients.

In the past, we always profiled our young, never-smoking patients, but 

 G12C occurs almost unanimously in patients who have smoked in the past. It’s no longer appropriate to select who you sequence or who you obtain NGS for; it needs to be done in all patients.

 is an oncogene and a driver alteration. If we target it and successfully inhibit it, we are benefitting and improving our patients’ quality of life and longevity. Thinking about the future, many inhibitors are being developed that may be even more potent than the covalent inhibitors that we have now in G12C.

Sabari JK, Spira AI, Heist RS, et al. Activity of adagrasib (MRTX849) in patients with KRASG12C-mutated NSCLC and active, untreated CNS metastases in the KRYSTAL-1 trial. 

. 2022;40(suppl 17):LBA9009 doi:10.1200/JCO.2022.40.17_suppl.LBA9009

Joshua K. Sabari, MD, discusses the significance of adagrasib as an agent with favorable central nervous system penetration and importance of performing next-generation sequencing in all patients with non–small cell lung cancer to detect KRAS G12C mutations. 

Adagrasib Elicits Responses in KRAS G12C–Mutant NSCLC

Efforts to unlock treatment modalities targeting 

 mutations have ebbed and flowed for patients with non–small cell lung (NSCLC) as investigators face resistance, intolerable toxicity profiles, and a lack of available binding pockets to guide treatment development.

 A rise in the identification of actionable genetic biomarkers have illuminated the prevalence of 

 G12C point mutations in patients with adenocarcinomas (13%) and up to 4% of patients with squamous NSCLC.

The development of direct inhibitors which form covalent bonds with cysteine 12 in the switch II binding pocket of the 

G12C protein have demonstrated the ability to irreversibly and selectively bind 

 Sotorasib (Lumakras) demonstrated early efficacy for patients with 

 G12C–mutant disease and was granted accelerated approval in 2021. Another agent, adagrasib, has demonstrated preclinical and early phase efficacy in patients with previously treated NSCLC with encouraging activity in patients with brain metastases.

G12C inhibitor and it [has evidence of efficacy] in NSCLC; there has been a lot of excitement about this agent for various reasons,” Alexander I. Spira, MD, PhD, FACP, codirector of Virginia Cancer Specialists Research Institute, director of the Thoracic and Phase I Program, and clinical assistant professor at Johns Hopkins School of Medicine, in Baltimore, Maryland, said in an interview with 

 G12C mutations act as oncogenic drivers and occur in approximately 14% of patients with NSCLC, predominantly adenocarcinomas,” Spira explained. “[Approximately] 27% to 42% of these patients will have CNS metastases at diagnosis. Adagrasib…was optimized for desired properties of a KRAS G12C inhibitor, including a long half-life, a [approximately] 23 hours, and dose-dependent pharmacokinetics,” he said adding that the agent “was designed with several things in mind, most notably it was designed to penetrate the central nervous system [CNS].”

CNS metastases are present in up to 42% of patients with 

 G12C-mutated NSCLC. With a median overall survival (OS) of approximately 5 months, patients with active, untreated CNS metastases represent a portion of patients with an unmet need.

Investigators recently published findings from the phase 2 cohort of the KRYSTAL-1 trial (NCT03785249) at the 2022 American Society of Clinical Oncology (ASCO) Annual Meeting, which were simultaneously published in the 

 These data demonstrated that adagrasib administered at 600 mg orally twice daily was safe and effective for patients who had received prior treatment with platinum-based chemotherapy and immunotherapy.

After a median follow-up of 12.9 months, the objective response rate (ORR) was 43% (95% CI, 33.5%-52.6%) among the 112 patients with measurable disease at baseline, which included 1 complete response (CR; 1%) and 47 partial responses (PRs; 42%). There were 41 patients with stable disease (SD; 37%) and 6 with progressive disease (5%) for a DCR of 80% (n = 89; 95% CI, 70.8%-86.5%).

“Responses appear to be deep, with 75% of responders having a greater than 50% tumor reduction,” Spira said.

Moreover, the median time to response with the KRAS G12C inhibitor was 1.4 months (range, 0.9-7.2) and median duration of response was 8.5 months (95% CI, 6.2-13.8). Spira noted that as of the data cut-off, treatment was ongoing in half of patients who experienced a response (n = 24) and 33% (n = 16) have maintained their response.

The median progression-free survival (PFS) was 6.5 months (95% CI, 4.7-8.4), with 6- and 12-month PFS rates of 52% and 29%, respectively. After a median follow-up of 15.6 months, median overall survival (OS) was 12.6 months (95% CI, 9.2-19.2), with 6- and 12-month OS rates of 71% and 51%, respectively.

The investigators further evaluated intracranial activity among 33 patients with adequately treated, stable central nervous system (CNS) metastases. The intracranial ORR was 33% (n = 11; 95% CI, 18%-52%), which included 5 CRs (15%) and 6 PRs (18%). There were 17 patients with SD (52%) for a DCR of 85% (n = 28; 95% CI, 68%-95%). The median intracranial PFS was 5.4 months (95% CI, 3.3-11.6).

“We saw some patients with pretreated brain metastases continue to have some response,” Spira said noting that there were patients who received no prior radiation therapy and that brain metastases were treated with just chemotherapy or immunotherapy. These patients were defined by investigators as those who had asymptomatic, neurologically stable brain lesions, including focal leptomeningeal disease and cerebellar metastases, but excluding patients with brainstem lesions.

In terms of safety, Spira noted that overall, the agent was well-tolerated and that adverse effects (AEs) were manageable with dose reductions. “There were significant number of patients that got dose reductions but only 16% of patients discontinued, so if [patients] don’t tolerate it dose reducing seems to work,” he said.

In the overall population of patients who received adagrasib in KRYSTAL-1, treatment-related AEs (TRAEs) of any grade occurred in 113 patients (97%), of which 50 (43%) were grade 3/4 in severity. The most frequent any-grade TRAEs were diarrhea (63%), nausea (62%), vomiting (47%), fatigue (41%), ALT increase (28%), blood creatinine increase (26%), AST increase (25%), and decreased appetite (24%). Among patients with grade 3/4 TRAEs, the most common reported events were elevated lipase levels (6.0%) and anemia (5.2%). Two grade 5 events occurred: cardiac failure and pulmonary hemorrhage.2,3 TRAEs led to dose reductions in 60 patients (52%), interruptions in 71 (61%), and discontinuation in 8 (7%).

An analysis of patients in the phase 1b cohort of KRYSTAL-1 with active, untreated CNS metastases at baseline (n = 25), also presented the 2022 ASCO Annual Meeting, showed that patients who received adagrasib 600 mg twice daily had durable CNS-specific activity. At a median follow-up of 6.6 months, 19 patients had radiographically evaluable disease for intracranial ORR—15 with target lesions and 4 with nontarget lesions only.

 Patients were assessed using modified Response Assessment in Neuro-Oncology Brain Metastases (mRANO-BM) criteria via blinded independent central review.

Among all evaluable patients, intracranial ORR was 32% (95% CI, 12.6%-56.6%) comprising a 16% CR rate and a 16% partial response (PR) rate.4 Moreover, 53% of patients had stable disease and disease control rate (DCR) was 84% (95% CI, 60.4%-96.6%). Among the 15 patients with target lesions, intracranial ORR was 27%, with a CR rate of 7%, a PR rate of 20%, and a DCR of 80%. Finally, among patients with nontarget lesions, 2 patients had a CR for an intracranial ORR of 50%. The remaining 2 patients in this cohort had stable disease for a DCR of 100%.

Median OS in this population was not reached.4 Investigators reported that intracranial DOR was not reached (95% CI, 4.1-not estimable [NE]), and median intracranial PFS was 4.2 months (95% CI, 3.8-NE) in this patient population.

Further, investigators reported the concordance between systemic and intracranial disease control was 88% (14 of 16 patients evaluable).4 Systemic ORR, using RECIST 1.1 criteria, was 37% (95% CI, 16.3%-61.6%), and systemic DCR was 79% (95% CI, 54.4%-93.9%).4 Median systemic DOR was 9.6 months (95% CI, 2.7-9.6), and median systemic PFS was 5.6 months (95% CI, 3.8-11.0).

The safety profile of adagrasib in this cohort was consistent with the overall population and no new safety signals were observed.4 Any grade TRAEs were observed in 96%. The most frequent TRAEs (any grade ≥ 40%) included nausea (80%), diarrhea (80%), vomiting (44%), and AST increase (40%). Grade 1/2 TRAEs occurred in 60% of patients; no grade 4/5 TRAEs were reported. TRAEs led to dose reduction or interruption in 12 (48%) patients and discontinuation in 1 (4%) patient. The CNS-specific TRAEs included dizziness (all grade, 20%; grade 3, 8%) and grade 1/2 aphasia and insomnia reported in 1 patient.

KRYSTAL-12 Pushes Adagrasib Into the Spotlight

Building on the foundation of observations gained from the phase 1/2 study, investigators are comparing single-agent adagrasib head-to-head with standard-of-care docetaxel in the phase 3 KRYSTAL-12 trial (NCT04685135).

Investigators plan to enroll approximately 340 participants with previously treated unresectable locally advanced or metastatic 

 Prior treatment must include a platinum-containing regimen and a checkpoint inhibitor for advanced or metastatic disease and may not include prior treatment with a KRAS G12C inhibitor, such as sotorasib. Patients are also ineligible if they have active brain metastases.

Specimens from either the primary or metastatic tumors must be available—either archival or newly obtained—for central laboratory testing of 

 G12C mutations and for additional correlative gene alterations.

Participants will be randomly assigned 2:1 to either adagrasib 600 mg twice daily administered orally or docetaxel 75 mg/m

 every 3 weeks. Stratification factors include region (US/Canada vs other countries) and administration or prior platinum-based chemotherapy and anti–PD-1/PD-L1 therapy (sequential vs concurrent).

The primary end point of the study is PFS. Secondary end points include OS, safety, ORR, and 1-year OS rates. Additionally, patient-reported outcomes using the lung cancer symptom scale and quality-of-life assessments using the European Quality of Life 5 Dimensions Questionnaire will be administered.

As the treatment landscape for patients with NSCLC with actionable oncogenic driver mutations continues to expand exponentially, Spira noted that integrating these therapies into practice will rely on testing. A new drug application was submitted by Mirati Therapeutics, Inc based on data from KRYSTAL-1. The FDA is expected to make a decision on the application in December 2022.

“There is a currently an FDA-approved agent, sotorasib, so [if adagrasib is approved] will have 2 [agents] in our armamentarium and that’s great,” Spira said. “I think a lot of the information that will come out [will help us determine] which [may be] better for certain patients [and determine] how important the CNS activity is, which [could] be a differentiator for adagrasib.”

Continued enrollment on clinical trials and increasing testing for actionable mutations are the key to continued successes for this patient population. “We can’t make better drugs without patients enrolling in studies,” Spira said. “We have all these [actionable] mutations and we’re still only testing approximately 75% of patients for 

 and that has been around for [approximately] 10 years. [Testing rates are] even less for 

. The bottom line is we need to test all our patients for all mutations but include 

de la Fuente EC, Garcia MEO, Rueda AG, Lage Y, Garrido P.Targeting KRAS in non-small cell lung cancer. 

. 2022;11:792635. doi:10.3389/fonc.2021.792635

Spira AI, Riely GJ, Gadgeel SM, et al. KRYSTAL-1: activity and safety of adagrasib (MRTX849) in patients with advanced/metastatic non-small cell lung cancer (NSCLC) harboring a KRAS G12C mutation. 

. 2022;40(suppl 16):9002 doi:10.1200/JCO.2022.40.16_suppl.9002

Jänne PA, Riely G, Gadgee SM, et al. Adagrasib in non–small-cell lung cancer harboring a 

. Published online ahead of print June 3, 2022. doi:10.1056/NEJMoa2204619

. 2022;40(suppl 17):LBA9009. doi:10.1200/JCO.2022.40.17_suppl.LBA9009

Phase 3 study of MRTX849 (adagrasib) vs docetaxel in patients with advanced non-small cell lung cancer with KRAS G12C mutation (KRYSTAL-12). ClinicalTrials.gov. Updated June 9, 2022. Accessed June 17, 2022. 

https://clinicaltrials.gov/ct2/show/NCT04685135

Mok TSK, Lawler WE, Shum MK, et al. KRYSTAL-12: a randomized phase 3 study of adagrasib (MRTX849) versus docetaxel in patients (pts) with previously treated non-small-cell lung cancer (NSCLC) with KRASG12C mutation. 

. 2021;39(suppl 15):TPS9129. doi:10.1200/JCO.2021.39.15_suppl.TPS9129

U.S. Food and Drug Administration (FDA) accepts Mirati Therapeutics’ new drug application for adagrasib as treatment of previously treated KRASG12C-mutated non-small cell lung cancer. News release. Mirati Therapeutics, Inc. February 15, 2022. Accessed June 17, 2022. bit.ly/3xEn1ya

Efforts to unlock treatment modalities targeting KRAS mutations have ebbed and flowed for patients with non–small cell lung as investigators face resistance, intolerable toxicity profiles, and a lack of available binding pockets to guide treatment development.

KRYSTAL-12 Investigators Seek to Confirm Adagrasib’s Role in KRAS G12C–Mutant NSCLC

Alexander I. Spira, MD, PhD, FACP, research institute director, Thoracic and Phase 1 Trial Program, Virginia Cancer Specialists Research Institute, Virginia Cancer Specialists, clinical assistant professor, Johns Hopkins University, discusses the activity of adagrasib (MRTX 849) in patients with non–small cell lung cancer (NSCLC) and central nervous system (CNS) metastases.

The phase 2 KRYSTAL-1 trial (NCT03785249) evaluated adagrasib in patients with advanced/metastatic NSCLC whose tumors harbored 

 G12C mutations, with or without CNS metastases. Data presented at the 2022 ASCO Annual Meeting showed that among 33 patients with treated, stable CNS metastases, the intracranial overall response rate was 33%, including a complete response rate of 15%, a partial response of 18%, and a stable disease rate of 52%.

An analysis of patients with active, untreated CNS metastases at baseline (n = 25), also presented the 2022 ASCO Annual Meeting, showed that patients who received adagrasib at 600 mg twice daily had durable CNS-specific activity. At a median follow-up of 6.6 months, 19 patients have radiographically evaluable disease for intracranial ORR—15 with target lesions and 4 with nontarget lesions only. Among all evaluable patients the intracranial ORR was 32% comprising a 16% CR rate and a 16% partial response rate.

In May 2021, the FDA approved sotorasib (Lumakras) for patients with NSCLC harboring 

 G12C mutations who have received at least 1 prior systemic therapy, Spira explains.

However, adagrasib represents another potential tool in this armamentarium, and this is the first agent to display evidence of any CNS activity in the patient population, which is a differentiator from sotorasib and other treatments, Spira adds. Patients in this population often present with CNS metastases or progress to the brain, so this agent could help fulfill an unmet need, Spira concludes.

Alexander I. Spira, MD, PhD, FACP, discusses the activity of adagrasib in patients with non–small cell lung cancer and central nervous system metastases.

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