Breakthroughs at ASCO 2019 –The First KRAS Inhibitor And Progress In Established Drug Targets
By Dr. Nina Lapke, Biomedical Informatics Scientist of ACT Genomics
Mutated KRAS – undruggable no more
KRAS has been known as a crucial cancer driver for decades, and its inhibition could have tremendous benefits for affected cancer patients. Unfortunately, KRAS is not yet established as a direct drug target in the clinic. This is not for lack of trying – KRAS simply appeared “undruggable”. The main difficulty to inhibit mutant KRAS was the insufficient binding of drug molecules to its surface, which lacks apparent binding structures.
However, KRAS inhibitor AMG 510 achieves just that – it binds to a cysteine residue of a common KRAS mutation subtype, KRAS G12C. Binding is inactivating and irreversible . KRAS G12C is present in about 13% of non-small cell lung cancers and 3-5% of colorectal cancers. First-In-Human results from a Phase 1 study enrolling 35 patients were presented at the ASCO Annual Meeting in June 2019 [1, 2]. Results were particularly encouraging for the ten evaluable non-small cell lung cancer patients, with response and disease control rates of 50% and 90%.
The study likely represents a milestone of clinical KRAS targeting. Although Amgen’s AMG 510 has a head start, a second KRAS G12C inhibitor (MRTX849 from Mirati Therapeutics) is already being tested in the clinic . Results regarding the performance of MRTX849 are eagerly awaited.
Highly selective MET inhibitors improve outcomes in lung cancer
Among important cancer drivers in non-small cell lung cancer patients, other than KRAS mutations, are the less common alterations of receptor tyrosine kinase MET. Those MET driver alterations include MET exon 14 skipping (METex14) mutations, occurring in 3-4% of patients. Although METex14 mutations can be used to guide tailored treatment, response rates with the available multikinase inhibitor crizotinib have been moderate (30-40%) .
Now, new results from two lung cancer studies with highly selective MET inhibitors, tepotinib and capmatinib, were presented at ASCO 2019 [5, 6]. In the tepotinib study, 85 patients with METex14 mutations were enrolled. Reported overall response rates were substantial and ranged between 42% and 64%, depending on the sample used for mutation detection and the method of response assessment . For capmatinib, 97 patients were evaluable, and response rates were 71% for treatment naïve patients and 39% for patients with 1-2 prior lines of treatment .
The encouraging response rates, together with the favorable safety profile that was observed for both drugs, raise hopes for improving treatment of patients with METex14 mutations.
Antibody therapy coming of age – the promise of Fc-engineered anti-HER2
Trastuzumab has long been established as the standard-of-care agent in HER2-positive breast cancer. However, current anti-HER2 therapy might not yet use its full potential. The reason is that HER2-expressing cancer cells flagged by the antibodies are not optimally recognized and destroyed by the immune system. This is particularly relevant for patients carrying a low-affinity allele for CD16A, an immune receptor that recognizes the non-HER2 binding (Fc) part of trastuzumab .
To achieve higher drug efficacy, another HER2-specific antibody, margetuximab, was Fc-engineered to better bind both the low- and high-affinity alleles of CD16A. The SOPHIA trial compared margetuximab and trastuzumab in patients with pre-treated HER2 positive breast cancer . In 437 patients who had at least one low-affinity allele of CD16A, treatment with margetuximab prolonged progression-free survival (PFS) by almost two months, compared to trastuzumab (median PFS: 6.9 versus 5.1 months, P=0.005) [8, 9]. In contrast, among patients who did not carry a low-affinity CD16A allele, there was no significant difference in median PFS between margetuximab and trastuzumab treatment (median PFS: 4.8 versus 5.6 months, P=0.110).
The results illustrate the potential of Fc-engineering to improve clinical outcomes for patients treated with antibodies that - among other anti-cancer mechanisms - flag tumor cells for destruction by the immune system. Such cancer cell-binding antibodies are widely used in the clinic, and HER2 is only one of their targets. Therefore, the appealing approach of Fc-engineering to meet the needs of patients depending on their immune receptor alleles will likely be extended beyond anti-HER2 therapy. In fact, a second Fc-engineered antibody binding to cancer cell surface molecule B7-H3, enoblituzumab, is already tested in the clinic .
2. Fakih M et al., Journal of Clinical Oncology 2019; 37: 3003-3003
4. Guo R et al., Journal of Clinical Oncology 2019; 37: 9006-9006
5. Paik PK et al., Journal of Clinical Oncology 2019; 37: 9005-9005
6. Wolf J et al., Journal of Clinical Oncology 2019; 37: 9004-9004
7. Gavin PG et al., JAMA Oncol 2017; 3: 335-341
8. Rugo HS et al., Journal of Clinical Oncology 2019; 37: 1000-1000