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

Devika Das, MD

Associate Professor

UAB Medicine

Birmingham, AL

LINK TO PART 1

Targeted Oncology: What data support the use of sotorasib (Lumakras) in patients with non–small cell lung cancer (NSCLC) and a KRAS G12C mutation?

DEVIKA DAS, MD: 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.¹ They had a much sicker population in that study.² 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.¹ 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%.¹ 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.³ 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.⁴ 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.⁴

In the co-mutation setting, patients who had KEAP1 mutation continue to do poorly as they do with lots of other drugs.⁴ Patients with ROS1 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 STK11/KEAP1 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].⁴ 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 KRAS 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.⁵

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.⁶ [With] the other mutations like STK11 and KEAP1, 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 KRAS 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; P = .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; P = .03].⁷

The AEs were very similar. The big ones are the [elevated] liver function test results, fatigue, and diarrhea.⁵ 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.

_References:

_{1. Skoulidis F, Li BT, Dy GK, et al. Sotorasib for lung cancers with KRAS p.G12C mutation. N Engl J Med. 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 KRASG12C mutation. N Engl J Med. 2022;387(2):120-131. doi:10.1056/NEJMoa2204619}

_{3. Lumakras. Prescribing information. Amgen; 2021. Accessed September 26, 2023. https://tinyurl.com/mr266wu4}

_{4. Dy GK, Govindan R, Velcheti V, et al. Long-term outcomes and molecular correlates of sotorasib efficacy in patients with pretreated KRAS G12C-mutated non-small-cell lung cancer: 2-year analysis of CodeBreaK 100. J Clin Oncol. 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. Lancet. 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 KRAS G12C-mutated advanced non-small cell lung cancer (NSCLC). J Clin Oncol. 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 KRAS G12C-mutated advanced non-small cell lung cancer (NSCLC): practice-informing data from a global, phase 3, randomized, controlled trial (RCT). J Clin Oncol. 2023;41(suppl 17):LBA9016. doi:10.1200/JCO.2023.41.17_suppl.LBA9016}