CME
Physicians: Maximum of 1.00 AMA PRA Category 1 Credit™
Released: October 25, 2022
Expiration: October 24, 2023
Heather Wakelee, MD:
In recent years, we have seen an explosion of novel targeted therapy for patients with advanced NSCLC and various driver mutations. The KRAS G12C mutation in NSCLC has become a very hot target with many therapeutic options available or in clinical trials.
Sotorasib is the first approved therapy specifically for patients with KRAS G12C–mutated advanced NSCLC (after ≥1 previous line of therapy) and it is a highly active agent. The phase Ib CodeBreaK100/101 study explored adding an immune checkpoint inhibitor—either atezolizumab or pembrolizumab—to sotorasib for patients with KRAS G12C–mutated NSCLC who received or refused previous standard therapies.14
The analysis of the CodeBreaK100/101 studies at the WCLC 2022 annual meeting included a cohort of patients who received combination therapy with sotorasib plus either atezolizumab or pembrolizumab (N = 58). In this analysis, 2 treatment approaches were included: one with a lead-in dose of sotorasib for 21 or 42 days before adding atezolizumab or pembrolizumab and the other beginning therapy with concurrent sotorasib plus atezolizumab or pembrolizumab. There was also a dose exploration to optimize sotorasib combination therapy. The primary endpoint was safety and key secondary endpoints included response rates, DoR, and pharmacokinetic information.14
In this trial with sotorasib, relatively high rates of hepatotoxicity were reported and most patients experienced treatment-related adverse events, but no grade 5 events occurred. As the dose of sotorasib increased in the concurrent treatment group, the risk of hepatotoxicity increased (approximately 40% of patients with a 120 mg or 360 mg dose vs ≥75% with higher doses), but the number of patients in each group was too small to make reliable comparisons.14
I think some caution is still needed as we look at these data and think about what this means for the combination of sotorasib with immune checkpoint inhibitors.
Heather Wakelee, MD:
When we look in detail at the adverse events associated with sotorasib lead‑in plus pembrolizumab, the most common treatment‑related adverse events were alanine aminotransferase and aspartate aminotransferase increases, alkaline phosphatase increases, and hepatotoxicity followed by diarrhea.14
Although these patient numbers are small, we need to be mindful of these toxicities.
Heather Wakelee, MD:
The combination of sotorasib and an immune checkpoint inhibitor produced relatively high rates of response: The ORR was 29% and the disease control rate was 83%. The depth of response was promising, with some striking CRs and PRs. The median DoR was approximately 18 months and some of the responders remained in response at the time of this analysis.14
Heather Wakelee, MD:
Based on these data, it is difficult to conclude whether the combination of sotorasib plus an immune checkpoint inhibitor is clearly better than what has been reported with sotorasib monotherapy. These efficacy data are certainly encouraging, but it is also a clear tradeoff with an increase in toxicity, particularly hepatotoxicity.
I am interested to see further exploration of this combination, but most patients with advanced NSCLC and KRAS G12C mutations will probably have had an immune checkpoint inhibitor in combination with chemotherapy as their first-line treatment. Based on these results, it is unclear if a combination of sotorasib and immune checkpoint inhibitor can reach the same response rate and DoR that we have seen with standard treatment with an immune checkpoint inhibitor plus chemotherapy.
Wade T. Iams, MD, MSCI:
I agree that this is not yet practice changing, but it does suggest that using the lead-in dosing may be a strategy that could help advance a combination of sotorasib plus an immune checkpoint inhibitor in additional trials. One additional consideration for these data that I would like to see in the future is whether patients who experienced hepatoxicity have improved clinical outcomes or worse outcomes and how this may affect the risk:benefit of this combination.
Wade T. Iams, MD, MSCI:
There has been some intriguing data that patients treated with KRAS G12C inhibitors, predominantly sotorasib, have quite heterogeneous mechanisms of resistance at progression. However, SHP2 seems to be a common denominator for several mechanisms of resistance that have been identified in various receptor tyrosine kinase pathways. One of the arms for the phase Ib CodeBreaK101 trial explored whether combining a SHP2 inhibitor with sotorasib can improve clinical results.
One arm of the phase Ib CodeBreaK101 trial explored a combination of sotorasib and the SHP2 inhibitor RMC-4630 with escalating doses in patients with advanced solid tumors with KRAS G12C mutations who have received previous systemic therapy for advanced disease (N = 27). In this cohort of patients, previous KRAS G12C inhibitor therapy was allowed. In patients with NSCLC and KRAS G12C mutations (n = 11), a previous systemic therapy included PD-1/PD-L1 inhibitors and/or platinum-based chemotherapy and targeted therapy.
The primary endpoint was safety and key secondary endpoints included response information, PFS, OS, and pharmacokinetics.15
Wade T. Iams, MD, MSCI:
Among the 11 patients with NSCLC and KRAS G12C mutations, the baseline characteristics were as expected and well balanced compared with the total patient population, except for Eastern Cooperative Oncology Group performance status. Nearly one half of the patients with NSCLC received a previous KRAS G12C inhibitor: either sotorasib or adagrasib.15
When interpreting the results of this analysis, it is important to remember that one half of these patients had received a previous KRAS G12C inhibitor and one half were KRAS G12C inhibitor naive.
Wade T. Iams, MD, MSCI:
Approximately one quarter of the patients who received sotorasib plus RMC-4630 experienced grade 3 treatment‑related adverse events, but no grade 4/5 events were reported.15 Authors divided the treatment-related adverse events into those attributed to sotorasib, those attributed to RMC-4630, and those attributed to both sotorasib and RMC-4630. Attribution can be difficult, but we can see that rates of these adverse events were balanced between each group.
The most commonly reported treatment‑related adverse events reported with this combination included edema, diarrhea, dry mouth, and fatigue. Diarrhea is frequently reported in the clinic with KRAS G12C inhibitors along with hepatotoxicity, and this was recapitulated in this trial as well.
Wade T. Iams, MD, MSCI:
When treatment‑related adverse events were assessed by dose escalation cohort, grade 3 treatment-related adverse events occurred in 36% of patients receiving RMC-4630 200 mg vs 17% for 100 mg. The mean duration on a combination therapy was 3.1 months, and there were no clinically meaningful drug–drug interactions observed between sotorasib and RMC-4630.15
Wade T. Iams, MD, MSCI:
Among the 11 patients with NSCLC and KRAS G12C mutations, the response rate with sotorasib plus RMC-4630 was 27% for all patients and 50% for patients who had not previously received a KRAS G12C inhibitor.15 These data suggest that it may be beneficial to consider an approach similar to what is currently recommended for BRAF inhibitor/MEK inhibitor combinations, which is to use a combination approach upfront vs adding a SHP2 inhibitor at the time of acquired resistance to KRAS G12C inhibition.
Wade T. Iams, MD, MSCI:
Although this is a small number of patients with NSCLC, two thirds of patients with a PR had an ongoing response at a median follow-up of 5.8 months, suggesting the potential for a long-term response.15
These data suggest that targeting this mechanism of resistance by adding a SHP2 inhibitor to sotorasib may be a successful approach in the future.
Wade T. Iams, MD, MSCI:
Overall, the combination of the SHP2 inhibitor RMC-4630 with sotorasib was well tolerated, with expected adverse events including edema, diarrhea, and hepatotoxicity. The clinical efficacy with this combination was promising but was notably higher among patients who had not yet received a KRAS G12C inhibitor.
This report represents an intriguing movement forward but requires further evaluation.
Heather Wakelee, MD:
I agree that it is an interesting idea to target SHP2, which is a novel pathway to target in oncology, to think about how we can prevent resistance to KRAS G12C inhibitors from developing. Although these preliminary data are promising, I think that understanding more about the DoR is critical. Whether adding a SHP2 inhibitor to a KRAS G12C inhibitor increases the response rate, if it helps that response be more durable, then we are showing a meaningful step forward in reducing the chance resistance occurring. I look forward to seeing more long-term data from this and other studies for this combination approach.
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