NEW YORK – Researchers from Memorial Sloan Kettering have identified potential causes of resistance to KRAS inhibitor sotorasib (Amgen's Lumakras) and are exploring combination strategies to overcome that resistance.
The researchers have begun a Phase Ib/II master protocol trial, dubbed CodeBreaK 101, to explore the activity of sotorasib in combination with other drugs, including a MEK inhibitor, a SHP2 allosteric inhibitor, a PD-L1 inhibitor, a pan-ErbB tyrosine kinase inhibitor, and an EGFR inhibitor, in patients with advanced KRAS G12C-mutant solid tumors.
Prior research from MSK and Amgen, published in Nature, suggested that drugs targeting ERK pathway intermediates could overcome resistance to KRAS inhibition and supports the combinations being assessed in this Phase Ib/II trial.
Sotorasib became the first KRAS inhibitor to reach the market when it was approved in the US last year for previously treated, locally advanced or metastatic non-small cell lung cancer patients whose tumors harbor a KRAS G12C mutation. Other drugmakers are eager to emulate Amgen's success and enter the space. Mirati Therapeutics, for example, is evaluating the KRAS G12C inhibitor adagrasib in a Phase I/II trial in KRAS G12C-mutant NSCLC, colorectal cancer, and other solid tumors.
However, a portion of patients, despite harboring KRAS G12C mutations in their tumors, are resistant, or become refractory, to KRAS inhibitors. Previous studies have explored these mechanisms of resistance, including research from the Dana-Farber Cancer Institute, and uncovered a diverse landscape of resistance alterations.
Similarly, in the Nature study, researchers from MSK delved further into the resistance mechanisms that might limit patients' ability to respond to KRAS inhibitors. They analyzed liquid biopsy or tissue data from 43 patients before and after treatment with sotorasib. Thirty-six of those patients had NSCLC, three had colorectal cancer, and four had other cancer types. In 27 patients, treatment-emergent alterations were identified.
These included mutations in KRAS, NRAS, BRAF, EGFR, FGFR2, MET, MYC, IDH1/2, PTEN, and PI3K. Yonina Murciano-Goroff, an author of the paper and a medical oncologist at MSK, noted that even among patients who had the same pretreatment KRAS G12C mutation and received the same KRAS inhibitor there was a diversity of resistance alterations.
The researchers further explored the association between resistance to sotorasib, which inhibits KRAS G12C, and the emergent KRAS or NRAS mutations, dubbed secondary RAS mutations, using cell lines. The secondary RAS alterations seen in patients included KRAS G12D, G12V, G12F, and V8L mutations; low-level KRAS copy number gain; and NRAS Q61L and G13V mutations.
"Our results show that there is no one mutation that causes resistance to KRAS G12C inhibition in all cases," Murciano-Goroff said. "We found mutations in a number of genes, including KRAS, NRAS, and BRAF. These results are in some ways challenging as they suggest that there may not be a 'one-sized fits all' strategy for addressing resistance to KRAS G12C inhibition."
In the cell lines research, Murciano-Goroff and colleagues found the secondary RAS mutations reduced the antiproliferative effects of KRAS inhibitors sotorasib and Mirati Therapeutics' adagrasib, which contributed to the cancer cells becoming resistant to KRAS G12C inhibition. The researchers then investigated the therapeutic vulnerabilities in KRAS G12C-resistant tumors, finding that ERK signaling intermediates, including SHOC2, ERK2, NRAS, CRAF, and BRAF, were depleted in cells treated with sotorasib.
Based on that finding, researchers tested the activity of sotorasib with drugs that target these ERK intermediates, including the MEK inhibitor trametinib (Novartis' Mekinist), Novartis' RAF dimer inhibitor LXH254, and Selleckchem's ERK inhibitor SCH984. They found that the combination of drugs that blocked ERK signaling and KRAS G12C led to more durable pathway inhibition and a more pronounced antiproliferative effect in the KRAS G12C-resistant cell lines compared to each drug alone.
"The lack of a dominant resistance alteration poses a challenge in determining an all-inclusive treatment strategy for patients who progress on [KRAS] G12C inhibitor monotherapy … if druggable, treatment-emergent variants can inform the choice of downstream therapy," the authors wrote in the Nature paper. "Our data suggest that co-targeting ERK signaling intermediates alongside KRAS G12C may prolong the benefit of therapy in the setting of emergent hotspot mutations in RAS or BRAF." However, they noted that prospective clinical trials were needed to confirm these initial findings.
This is precisely what's underway now in the ongoing CodeBreaK 101 trials. "Research collaborations have provided insights into these mechanisms of resistance enabling Amgen to initiate a master protocol where we are exploring over 10 rational combinations in the clinic," an Amgen spokesperson said in a comment. "These include combinations with targeted therapies, chemotherapy and immunotherapy."
In the study, researchers at MSK and Amgen are exploring these combinations in more than 1,200 patients with KRAS G12C-mutant solid tumors that have progressed and spread after prior treatment, including treatment with KRAS G12C inhibitors. Early data from the trial, released in October, has already demonstrated the activity of some of the combinations identified in the Nature study in patients who have become resistant to KRAS G12C inhibition.
For example, among seven colorectal cancer patients who previously received KRAS inhibitor treatment but then got on sotorasib and the MEK inhibitor trametinib, one achieved a partial response and six achieved disease control. Only three NSCLC patients in the analysis had previously received a KRAS G12C inhibitor, and two achieved disease control on treatment with sotorasib and trametinib.
Other early data from CodeBreaK 101, presented in September, showed sotorasib in combination with EGFR inhibitor panitumumab (Amgen's Vectibix) had activity in heavily pretreated patients with KRAS-mutant colorectal cancer. The objective response rate in this 26-patient cohort, which included five patients who had prior sotorasib treatment, was 27 percent to the combination therapy. Among the five patients who had previous KRAS inhibitor treatment, four achieved stable disease on the combination.
"Understanding how resistance develops to these allele specific inhibitors is key to providing better care for patients with these mutations," Murciano-Goroff said. "Ultimately, our paper underscores the value of biomarker-driven clinical trials and research as we work to improve care for patients treated with [KRAS] G12C inhibitors who develop resistance and to tailor treatments for individual patients."