Patients with non-small cell lung cancer (NSCLC) treated with the KRASG12C inhibitor sotorasib (Lumakras®; Amgen; previously known as AMG 510) had a two-year overall survival rate of 32.5%, according to data from the CodeBreaK 100 clinical trial presented during the Annual Meeting of the American Association for Clinical Research (AACR), held April 8-13, 2022 in New Orleans, LA.[1]

Sotorasib is the first and only KRASG12C inhibitor to-date to show long-term clinical benefit and overall survival in patients with NSCLC harboring the KRASG12C mutation.

Based on the primary analysis from this trial, which was sponsored Amgen, the U.S. Food and Drug Administration (FDA) approved sotorasib in May 2021 for the treatment of patients with locally advanced or metastatic NSCLC whose tumors harbor the KRASG12C mutation and who have received prior therapies.

Changing treatment paradigm
“Since the FDA approval almost a year ago, sotorasib has changed the treatment paradigm for patients with advanced non-small-cell lung cancer who harbor the KRASG12C mutation,” said Grace Dy, M.D., chief, thoracic oncology, Roswell Park Comprehensive Cancer Center. “The durable efficacy and positive benefit-risk profile seen in the two-year analysis of CodeBreaK 100 highlight the important role this innovative targeted therapy can offer long-term.”

“Longer-term follow-up data are important to better define the safety and efficacy of sotorasib since it is the first-in-class KRASG12C inhibitor therapy to be approved for this patient population,” said presenter Dy further noted.

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“For this particular analysis, we also sought to determine whether there are potential biomarkers that can identify patients who will derive long-term benefit from sotorasib treatment,” she said.

Trial design
Dy and colleagues analyzed data from 174 patients who received sotorasib in the combined phase I and phase II studies of the trial. Most patients had received an average of two prior lines of therapy, including anti-PD-1 or anti-PD-L1 immunotherapy and platinum-based chemotherapy.

Grace K. Dy, MD, chief of thoracic oncology and professor of oncology at Roswell Park Comprehensive Cancer Center, Buffalo, New York: “Two-year follow up of the CodeBreaK 100 clinical trial demonstrated prolonged tumor responses and a favorable safety profile.”

In this updated analysis, which included NSCLC patients receiving the FDA-approved dose of sotorasib at 960 mg daily, 40.7% of patients experienced a partial or complete response to sotorasib, with a median duration of response of 12.3 months.

The median progression-free survival (PFS) and overall survival (OS) were 6.3 months and 12.5 months, respectively. The overall survival rate was 50.8% after one year of treatment and 32.5% after two years.

Long-term treatment with sotorasib was well tolerated, with mild and manageable toxicities and no new safety concerns in patients continuing onto sotorasib beyond one year.

“Given that the majority of NSCLC patients enrolled had previously received immunotherapy and platinum-based chemotherapy, it is notable that the two-year overall survival rate was almost 33%, which is very favorable in comparison to historical control treatment,” Dy explained.

“For example, the two-year overall survival rate in patients with non-squamous NSCLC treated with the chemotherapy agent docetaxel with or without the anti-VEGFR antibody therapy ramucirumab as second-line treatment is expected to range between 15 and 22 percent,” she added.

“The survival outcomes and toxicity profile make sotorasib the treatment of choice compared to salvage chemotherapy in patients who did not respond to previous therapies,” Dy said.

Earlier in the treatment
In addition, prolonged tumor response was independent of PD-L1 expression and was also observed in tumors with low PD-L1 levels.

“Our findings also provide a rationale for studies that investigate the incorporation of sotorasib earlier in the treatment course to improve the outcomes for NSCLC patients who are less likely to benefit from immunotherapy,” Dy added.

The investigators performed additional analyses on both tumor and blood samples to identify biomarker profiles associated with durable clinical benefit. These studies showed that prolonged clinical benefit was observed regardless of tumor mutation burden, PDL1 expression, and STK11 co-mutation status.

“We are pleased with these latest results from the CodeBreaK 100 study, which represent the longest follow-up of patients treated with a KRASG12C inhibitor and confirm rapid, deep, and durable responses in patients receiving sotorasib,” concluded. David M. Reese, M.D., executive vice president of Research and Development at Amgen.

Study limitations
The limitations of this study include that CodeBreaK 100 is a single-arm, non-randomized trial. A randomized, global phase III trial (CodeBreaK 200) is ongoing that includes docetaxel as the comparator.

“We eagerly await the results of the phase III study, which likely will be available later this year, and expect that they will confirm our findings from CodeBreaK 100,” Dy concluded.

Clinical trials
A Phase 1/2, Study Evaluating the Safety, Tolerability, PK, and Efficacy of Sotorasib (AMG 510) in Subjects With Solid Tumors With a Specific KRAS Mutation (CodeBreaK 100) – NCT03600883
Study to Compare AMG 510 “Proposed INN Sotorasib” With Docetaxel in Non-small Cell Lung Cancer (NSCLC) (CodeBreak 200) – NCT04303780

Highlights of prescribing information
Sotorasib (Lumakras®; Amgen)(Prescription Information)

Dy GK, Govindan R, Velcheti V, Falchook GS, Italiano A, Wolf J, Sacher AG, Takahashi T, Ramalingam SS, Dooms C, Kim DW, Addeo A, Desai J, Schuler M, Tomasini P, Tran Q, Jones S, Ang A, Anderson A, Hindoyan AA, Hong DS, Li BT. Long-term outcomes with sotorasib in pretreated KRASp.G12C-mutated NSCLC: 2-year analysis of CodeBreaK100 In: Proceedings of the 113th Annual Meeting of the American Association for Cancer Research; 2021 April 8-13; New Orleans LA. Philadelphia (PA): AACR; 2022. Abstract nr CT008

Feature image: 2017 Annual Meeting of the American Association for Cancer Research. Photo courtesy: © 2017 – 2022 AACR/Todd Buchanan. Used with permission.

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