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Spotlight

This roundtable series examines options for patients with 

 G12C-mutated non–small cell lung cancer, as discussed by key opinion leaders and participants at virtual live events.

Later-Line KRAS-Targeted Treatments Available in Lung Cancer

Targeted Oncology: What data support the use of sotorasib (Lumakras) in patients with non–small cell lung cancer (NSCLC) and a 

: The CodeBreaK 100 study [NCT03600883] was a registrational phase 2 study. Similar to adagrasib [Krazati], this was a study that was done for sotorasib, which was the other TKI [tyrosine kinase inhibitor]. Both these drugs were developed simultaneously, but this one reported out first and got an accelerated FDA approval earlier than adagrasib. This was a study where sotorasib was administered orally at 960 mg once a day until disease progression. Eligibility for this trial was for patients with locally advanced or metastatic NSCLC who progressed on prior lines of therapy. On this study, no more than 3 prior lines were allowed, whereas [the study of] adagrasib took a lot of more heavily pretreated patients.

They had a much sicker population in that study.

 The primary end point was of CodeBreaK 100 very similar to the other study, with objective response rate [ORR] being looked at.

The patients were mostly White; both of these studies show that disparity, [with] very small amounts of African American or any other patient populations included.

 They had ECOG [performance status] of 0 or 1, [the majority were] former smokers, most had adenocarcinoma, [and most had] metastatic disease. The patients in this trial were mostly failing primary [or second] lines of therapy.

What were the efficacy and adverse events (AEs) seen in this trial?

The ORR [overall response rate] was approximately 37%.

 Between the 2 drugs, [an ORR] between 30% to 40% is what you expect. There were 4 complete responses [CRs] on the study but most patients had partial response [(PR) 33.9%] or stable disease [43.5%]. The median duration of response [DOR] was 11.1 months, a median progression-free survival [PFS] of 6.8 months, and a median overall survival [OS] of 12.5 months. There were very similar data with both of the drugs except that [the KRYSTAL-1] study had much sicker patients, and there were more data reported out on the CNS [central nervous system] benefits.

It had a very similar AE profile [to adagrasib, including] gastrointestinal, hepatobiliary, respiratory AEs; fatigue was significant.

Twelve percent of these patients had grade 3 or 4 hepatotoxicity, so if you give patients these drugs, that is something I watch very closely based on my experience using the drug.

What was explored in the 2023 update from the CodeBreaK 100 trial?

They reported 2-year response rates subsequent to [the prior data were investigated]. The CR rate was 3% and PR rate was 38%, for an ORR of 41%. The longer the patient stays on sotorasib, the ORR goes up…if they are able to tolerate the drug and don't have progression upfront.

 Stable disease was seen in 43% of patients, DOR was approximately 1 year, and 73% of those who responded [did so] for at least than 6 months.

They did a post hoc biomarker analysis to see if there was any breakdown in terms of response with co-mutations. If they had PD-L1 expression less than 1%, those patients tended to do better than patients who had 1% and above.

In the co-mutation setting, patients who had 

 mutation continue to do poorly as they do with lots of other drugs.

 mutations did not do well, whereas some of the other mutations did not make much of a difference. These numbers [of patients] are not high enough and so clinically, I don't change practice based on these data, but it's just interesting to see. That's where the science is going, to see if you can pick out the patients that will respond well based on the co-mutation that they have. Those patients with 

 don't do well on the immunotherapy/chemotherapy combination drug treatments upfront.

They pulled some data [which] is all post hoc; I would not change practice based on it, but it's interesting to see that patients who were older tended to have a better median OS, 13.6 months [vs 11.5 months in patients under 65 years].

 Patients who had a better ECOG performance status of 0 did better [than those with performance status of 1; 22.5 months median OS vs 9.5 months, respectively]. Patients with fewer prior lines of therapy did better. Interestingly, patients who had [received] PD-L1 therapy [within 3 months of] switching to the next drug did not do as well, but these are not data that I would change my practice based on.

How did the CodeBreak 200 trial support the use of sotorasib in the second line of treatment?

CodeBreaK 200 [NCT04303780], which was recently reported, is the phase 3 study. It was an open-label phase 3 study with 345 patients with a 

 G12C mutation who progressed and were randomly assigned to sotorasib vs docetaxel. Adagrasib has a phase 3 trial that's ongoing whereas sotorasib has already reported head-to-head comparison with docetaxel. The primary end point was PFS and a secondary end point was overall survival, but the trial was not powered to report that out. It met the primary end point with a median PFS for sotorasib of 5.6 months vs 4.5 months for docetaxel, so it was not much different, but it was a positive study. [However,] it did not show an OS benefit in the phase 3 study compared with docetaxel. Forty-six patients crossed over from docetaxel to sotorasib per protocol on progression.

The ORR with sotorasib was 28.1% vs 13.2% with docetaxel. The disease control rate was better numerically, 82.5% with sotorasib vs 60.3% with docetaxel. The median duration of response was 8.6 months with sotorasib vs 6.8 months with docetaxel. Does this translate into an OS benefit? We have not seen that.

What biomarker analysis was done in the randomized study population?

They broke the data down with all the co-mutations. It seemed like sotorasib retained its overall response benefit [vs docetaxel] across the key mutations.

, they all tend to respond, so unlike immunotherapy, these drugs work despite the co-mutations. But these are small numbers and are not practice changing in my opinion.

They looked at some intracranial efficacy as well because patients with 

 G12C [mutations] have CNS progression. In this study they saw the time to CNS progression was in patients who got sotorasib, 11.6 months vs 6.0 months in docetaxel [HR; 0.63; 95% CI, 0.25-1.62; 

 = .17], and CNS PFS was also better in the sotorasib arm vs docetaxel [9.6 months vs 4.5 months median PFS, respectively; HR, 0.53; 95% CI, 0.28-1.03; 

The AEs were very similar. The big ones are the [elevated] liver function test results, fatigue, and diarrhea.

A big percentage of these patients had any-grade AEs which are not to be ignored. Even grade 1 diarrhea that happens for a long time is very distressing to the patient. I don't tend to ignore that, and I don't just look at the grade 3 and 4 AEs. I also look at grade 1 and 2 AEs. [The trial also showed sotorasib is associated with] the other AEs that you expect with TKIs.

1. Skoulidis F, Li BT, Dy GK, et al. Sotorasib for lung cancers with 

. 2021;384(25):2371-2381. doi:10.1056/NEJMoa2103695

2. Jänne PA, Riely GJ, Gadgeel SM, et al. Adagrasib in non-small-cell lung cancer harboring a 

. 2022;387(2):120-131. doi:10.1056/NEJMoa2204619

3. Lumakras. Prescribing information. Amgen; 2021. Accessed September 26, 2023. 

4. Dy GK, Govindan R, Velcheti V, et al. Long-term outcomes and molecular correlates of sotorasib efficacy in patients with pretreated 

 G12C-mutated non-small-cell lung cancer: 2-year analysis of CodeBreaK 100. 

. 2023;41(18):3311-3317. doi:10.1200/JCO.22.02524

5. de Langen AJ, Johnson ML, Mazieres J, et al. Sotorasib versus docetaxel for previously treated non-small-cell lung cancer with KRASG12C mutation: a randomised, open-label, phase 3 trial. 

. 2023;401(10378):733-746. doi:10.1016/S0140-6736(23)00221-0

6. Skoulidis F, De Langen A, Paz-Ares LG, et al. Biomarker subgroup analyses of CodeBreaK 200, a phase 3 trial of sotorasib versus (vs) docetaxel in patients (pts) with pretreated 

 G12C-mutated advanced non-small cell lung cancer (NSCLC). 

. 2023;41(suppl 16):9008. doi:10.1200/JCO.2023.41.16_suppl.9008

7. Dingemans AMC, Syrigos K, Livi L, et al. Intracranial efficacy of sotorasib versus docetaxel in pretreated 

 G12C-mutated advanced non-small cell lung cancer (NSCLC): practice-informing data from a global, phase 3, randomized, controlled trial (RCT). 

. 2023;41(suppl 17):LBA9016. doi:10.1200/JCO.2023.41.17_suppl.LBA9016

Analyses Probe into Co-Mutation Activity of Sotorasib in KRAS-Mutant NSCLC

Targeted Oncology: What do the National Comprehensive Cancer Network (NCCN) guidelines recommend for patients with non–small cell lung cancer (NSCLC) and a 

Per NCCN guidelines…in patients with the 

 G12C mutations who have adenocarcinoma or squamous cell carcinoma in the second line—so they have progressed on frontline therapy—we have 2 drugs currently approved: sotorasib [Lumakras] and adagrasib [Krazati].

 One was approved in 2021, the other in 2022. Both of the approvals are for second line and [later] in patients in this scenario.

Why were these drugs studied in the second line and later, whereas other targeted inhibitors are moving to the frontline setting?

A lot of them started in second and third line because it takes a lot of justification to bring any drug to frontline. With 

 G12C inhibitors, it's because we've had so many treatments in preclinical studies that have not worked. There was more reluctance in bringing it up front, knowing that all the drugs historically tested in trials were not effective. That’s one of the reasons. We'll go through some of the data where even in second and third line or the subsequent lines, the data are not [strong enough]. It's not the FLAURA trial [NCT02296125] of osimertinib [Tagrisso]. That's not the level of data we're seeing where [want to] take this to the front line. There are ongoing trials trying to do that, but even the data in subsequent lines are not as impressive as we want it to be. They're great drugs, but not to that level where I'm ready to jump to front line.

What is the significance of the KRYSTAL-1 study (NCT03785249) in this setting?

KRYSTAL-1 is a phase 2 study with adagrasib. It's a registrational phase 2 cohort. It was used as a monotherapy in patients with metastatic disease who had prior therapy with a PD-L1 [inhibitor] plus or minus chemotherapy, in sequence or together. They permitted inclusion of patients with stable CNS [central nervous system] metastases. Patients received 600 mg twice a day [in the form of] a capsule, and patients were fasting. The primary end point was overall response rate [ORR], and the secondary end points were duration of response [DOR], progression-free survival [PFS], and overall survival [OS].

Patients were predominantly white [83.6%], had ECOG performance status of 0 or 1, and were mostly former or current smokers.

 Interestingly, the histology they included in this trial is predominantly adenocarcinoma [with] a small percent of squamous cell carcinoma [2.6%]. Most of the patients had metastatic disease [vs 11.2% with locally advanced disease]. For some of the patients, this was their [fifth] line of therapy. In [12.1%] of patients on the study [adagrasib was the fifth or later] line of therapy. It’s unusual for a lot of clinical trials to have that. They included a [mix] of patients with bone, CNS, adrenal, and liver metastases.

What were the efficacy outcomes of this trial?

The ORR with the single agent in this heavily pretreated patient population was 42.9%. One patient had a complete response, but most patients had partial responses [42.0%] and stable disease [36.6%], which I think is decent if somebody is [treated in the] third line or later. There was disease control in 79.5% of patients, the median PFS was 6.5 months, and the median OS was 12.6 months at the time of data cutoff [median follow-up: 12.9 months for PFS; 15.6 months for OS].

 G12C mutation is associated [with CNS metastases]. Anywhere between 27% to 40% of patients have CNS metastases at presentation or at some point during the disease course.

 I think that's a good way to test for efficacy of these drugs, and that's often where a lot of our patients fail. In preclinical models, adagrasib showed a clinically meaningful penetration into the cerebrospinal fluid with a brain-to-plasma concentration of 0.47, which is comparable with a lot of the other TKIs that have approval in patients with CNS metastases, so it is a good drug with CNS penetration.

They looked at a post hoc evaluation of the best intracranial response in these patients, and 33.3% of patients had confirmed intracranial response.

 The median duration of intracranial response was 11.2 months, and the median intracranial PFS was 5.4 months in [42] patients who had CNS metastases at baseline. These are data signaling this could be a good drug for patients who have CNS metastases.

As an aside, the group looked at a cohort of about 25 patients who had untreated CNS metastases and put them on adagrasib and had very similar good responses.

 These were patients with metastases that were not treated with radiation. They excluded patients with cerebellar or brainstem metastases or leptomeningeal disease, but most of the brain metastases were included and saw some good responses.

What toxicities were seen with adagrasib in this trial?

We [sometimes think that if] it's an oral medicine, it's relatively safer. That's not always the case. These drugs come with a significant amount of toxicity that you expect with tyrosine kinase inhibitors [TKIs]. For most patients, it was gastrointestinal toxicities, where approximately 70% of patients had some form of diarrhea.

 Fatigue was a [common] adverse event, and…I want to highlight the liver toxicity. Hepatotoxicity was seen at any grade in 37% of patients but grade 3 and 4 [occurred in] 10%, which is a significantly high amount of hepatotoxicity and something that we should be aware of when giving these patients these drugs.

 G12C inhibitor in a patient with brain metastases vs radiotherapy or other approaches?

I extrapolate a lot of this from how I treat patients with 

 mutations. As of now, the data that we're seeing is off of a phase 2 study, and the 25 patients whom I talked about are a subset of those patients. I would not change current practice based on that. The way these data help me is, if somebody has CNS metastases, I would…send them for radiation therapy referral or neurosurgery referral based on what's appropriate to treat that CNS metastasis. But then if I have to pick a drug to give that patient, would I prefer docetaxel vs an oral TKI, one of these 2 drugs [sotorasib and adagrasib]. I would prefer the oral TKI because I know docetaxel does not have good CNS penetration, but these drugs do, and there could be some benefit in that patient population. It is something that I would use after I treat the CNS metastasis. There are a lot of patients who might have micrometastatic disease in the CNS that's not always visible on the MRI. If this is a patient where I am suspecting that highly, then I would be more inclined to pick the TKI if they can take it.

1. NCCN. Clinical Practice Guidelines in Oncology. Non­–small cell lung cancer, version 5.2023. Accessed November 27, 2023. 

2. Jänne PA, Riely GJ, Gadgeel SM, et al. Adagrasib in non-small-cell lung cancer harboring a KRASG12C mutation. 

3. Sabari JK, Velcheti V, Shimizu K, et al. Activity of adagrasib (MRTX849) in brain metastases: preclinical models and clinical data from patients with krasg12c-mutant non-small cell lung cancer. 

. 2022;28(15):3318-3328. doi:10.1158/1078-0432.CCR-22-0383

4. Negrao MV, Spira AI, Heist RS, et al. Intracranial efficacy of adagrasib in patients from the KRYSTAL-1 trial with 

-mutated non–small-cell lung cancer who have untreated CNS metastases. 

. 2023;41(28):4472-4477. doi:10.1200/JCO.23.00046

During a Targeted Oncology™ Case-Based Roundtable™ event, Devika Das, MD, discussed the role of KRAS inhibitors and the outcome of the KRYSTAL-1 trial in patients with non–small cell lung cancer. This is the first of 2 articles based on this event. 