Randomized Trial Provides Biomarker and CNS Sotorasib Data in NSCLC

Timothy F. Burns, MD, PhD

Associate Professor of Medicine

Department of Medicine

Division of Hematology-Oncology

UPMC Hillman Cancer Center

Pittsburgh, PA

TARGETED ONCOLOGY: What data support the use of sotorasib (Lumakras) in patients with KRAS-mutated advanced non–small cell lung cancer (NSCLC)?

Sotorasib was approved [based on] CodeBreaK 100 [NCT03600883], which was essentially an expansion cohort looking at sotorasib at a recommended phase 2 dose of 960 mg. This was a mixed population, mostly patients with metastatic [disease], but a mix of first-, second-, and third-line patients. Most had received [prior platinum-based chemotherapy], almost a quarter had immunotherapy. We saw an objective response rate [ORR] of 37%.¹ The [median progression-free survival (PFS) of 6.8 months and overall survival (OS) of 12.5 months] numbers look very familiar because they're almost identical to what we see [median PFS, 6.5 months; median OS, 12.6 months] with adagrasib [Krazati].^1,2

How well did patients with NSCLC tolerate treatment with sotorasib?

It was interesting that in the phase 1 trial, they kept escalating the dose [of sotorasib]. They thought they were going to get to 180 mg and stop but they got to 960 mg. They [thought] 8 pills is [high, but] they did not reach the maximum tolerated dose. Its adverse event [AE] profile is better, maybe because they didn't push the drug as much [as adagrasib]. But sotorasib’s gastrointestinal [GI] toxicity seems to be lower [although] it still has liver toxicity. It can have many other AEs [including cough, dyspnea, musculoskeletal pain, fatigue, edema, and decreased appetite]. But mostly with these drugs it's GI [toxicity].³

What did 2-year follow-up on this trial show for this population?

The ORR with long-term follow-up was 41%.⁴ Duration of response was around 12 months. The [2-year update showed a similar] median PFS of 6.3 months and median OS of 12 months. It's better than we're doing [with second-line chemotherapy] but isn't [as good as] we see with other targeted therapies.

There has been some biomarker analysis of who may respond better or worse to these…. If you have a secondary RAS mutation, you probably should not be getting sotorasib or adagrasib. The KEAP1 mutation seems to be a [associated with bad outcomes]. There's still benefit across the board, but the benefit is definitely less in someone with a KEAP1 [mutation].

There was the most benefit in PD-L1­–negative patients but you do see benefit across the board. These were in small numbers of patients.

How did sotorasib perform in a randomized phase 3 trial vs chemotherapy in NSCLC?

The phase 3 [CodeBreaK 200 trial (NCT04303780)] had the largest number of patients. This trial randomly assigned [patients to receive] docetaxel vs sotorasib. Patients had no active brain metastases and had to have received [prior] chemotherapy and immunotherapy. It was a positive study, [meeting its primary end point of] PFS with an HR of 0.66, although docetaxel did better than we expected in this trial.⁵ There was no OS benefit, and that may be due to crossover. Many of these patients received sotorasib or adagrasib on the docetaxel arm [after progression], which makes sense.

The ORR was better than docetaxel but it's heading down [28.1% with sotorasib vs 13.2% with docetaxel]. People have asked me [why are the] response rates lower [than the phase 2 trial and I said], “Unfortunately, as we start to test these drugs in larger populations, response rates are not going to be in the 40s anymore.” We'll see what it is for adagrasib; those data are still pending, but at least…it is still [better than] docetaxel. These are these first generations of these drugs and as single agents, they have activity, and there are patients who can benefit for years with these. But we have to do better with trials and combinations.

[A biomarker analysis] came out at the 2023 American Society of Clinical Oncology Annual Meeting.⁶ We had a larger number of patients, so are there bad [mutations]? The consistent one, again, is KEAP1. [Patients with KEAP1 mutations] can still benefit. It's probably still better than docetaxel but your benefit can be a lot less with KEAP1. If you have an EGFR mutation, then doing single-agent sotorasib is probably not going to work, and it is similar in ERBB2 [HER2]…. But generally, across the board for most these mutations or co-mutations, they do well. We also see STK11, which often comes up. In the early studies we were worried about STK11, but these patients seem to still benefit.

In patients who were on the CodeBreaK 200 trial, their time to central nervous system [CNS] progression was much better with sotorasib [median, 11.6 months with sotorasib vs 6.0 months with docetaxel; HR, 0.63; 95% CI, 0.25-1.62; P = .17], as was their CNS PFS [median, 9.6 months with sotorasib vs 4.5 months with docetaxel; HR, 0.53; 95% CI, 0.28-1.03; P = .03] and there was a response rate similar to what we see systemically, maybe a little lower [8 out of 40 patients (20%) with intracranial complete response]….⁷ Both [KRAS inhibitors] have CNS activity. How much CNS activity they have is still yet to be determined, but it's safe to say it's probably in the ballpark of a systemic effect.

_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}