Summary
- Mirati’s KRAS inhibitor MRTX-849 will likely fail as a second line monotherapy in KRAS-mutant NSCLC.
- Consensus is emerging that Amgen’s AMG-510, with an identical mechanism of action, will likely release disappointing data this summer.
- Attempts to combine '849 with other targeted therapies will also likely fail: KRAS-mutant cancers exhibit heterogeneity, resulting in a wide variety of resistance mechanisms that can't be identified in advance.
- There is little credible scientific rationale for trying to combine ‘849 with checkpoint inhibition, and the attempt will almost certainly fail, given that KRAS-mutant tumors are already quite susceptible to CPIs, and it will prove extraordinarily difficult to enhance that effect.
- Mirati's other drug, sitravatinib, has shown almost zero single-agent activity, and the attempt to combine the drug with checkpoint inhibition in checkpoint-refractory patients is a futile attempt at salvaging a failure, hence the weak Ph2 data, unrealistic endpoint extrapolations, and 2 years with no updates.
We are short shares of Mirati Therapeutics (NASDAQ:MRTX), a $4.6bn clinical-stage biopharmaceutical company whose lead drug candidate, MRTX-849, is a small-molecule KRAS inhibitor (KRASi). The KRAS protein plays a critical role in cell proliferation and differentiation, and mutations of the gene that encode it are present in one of seven tumors, and in over 30 percent of lung adenocarcinomas. Cracking KRAS has long been one of the holy grails of cancer research, and in the last year, both Amgen (NASDAQ:AMGN) and Mirati have suggested they’re close.
Both companies have released Phase I data showing that their respective KRASi are capable of shrinking tumors in second-line treatment of patients with KRAS-mutated non-small-cell lung cancer (NSCLC). The compounds also seem to work as intended: by inhibiting the signaling activity of the specific KRAS mutant (KRAS G12C) that accounts for ~12-14% of all NSCLC diagnoses. As the only pure KRAS proxy, Mirati’s market value has soared. But lost in the euphoria is a realistic assessment of the data and its implications for Mirati. While Amgen’s AMG-510 and Mirati’s MRTX-849 have indeed induced responses in NSCLC patients, it’s becoming clear that the response rate is low and the duration of these responses is incredibly short-lived. That makes approval of the drugs as single agent therapies extremely unlikely, even in second line treatment.
As the clinical futility of these KRASi as monotherapy is slowly recognized, the emphasis of the research – and anticipation – is shifting towards their use in a variety of combination therapies, both in first- and second-line treatment. But the data and research are not encouraging. Recent data on the efficacy of checkpoint inhibitors in KRAS-mutant NSCLC strongly suggests that combining them with KRAS inhibition would do nothing to enhance their already robust effect and could even be detrimental. Research has also recently revealed considerable heterogeneity in KRAS-mutant tumors, which utilize a wider range of molecular pathways to continue proliferating than had been previously assumed. The upshot is that successful combinations of ‘849 with other targeted therapies are unattainable because it’s impossible to know in which patients they will be effective. If that weren’t enough, combination attempts are also all but certain to encounter toxicity issues.
