Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Oncologists greet Lumakras: the world’s first KRAS inhibitor

The milestone approval for Amgen’s drug Lumakras will galvanize targeted therapy efforts against Ras oncoproteins and provides a powerful new last line of defense for patients with lung cancer.

Fewer than three years after starting clinical testing, Amgen’s drug Lumakras (sotorasib) received US Food and Drug Administration (FDA) approval for non-small-cell lung cancers that harbor KRAS G12C mutations. The drug is the first agent to block KRAS and is the result of a collective four decades of effort against a target once deemed ‘undruggable’. Although the emergence of resistance will require close monitoring, Lumakras not only adds a powerful new adjunct to conventional chemotherapy in lung cancer, but also is being tested as a first-line treatment, promising to open the way to inhibitors of other K-Ras variants more commonly found in human cancers.

Amgen’s recently-approved Lumakras targets cancers with KRAS G12C mutations. Credit: Simon Bradbrook/Springer Nature Limited

Scientists first identifiedKRAS (Kirsten rat sarcoma viral oncogene homolog) as a human oncogene in 1982. The protein is an isoform of the small GTP-binding protein Ras, which functions as a nucleotide-dependent switch for central cellular growth-signaling pathways. Mutated forms of KRAS are found in one-fifth of all human cancers, including 32% of non-small-cell lung cancers (NSCLCs), 40% of colorectal cancers (CRCs) and 85–90% of pancreatic cancers.

Lumakras has prompted initial sales forecasts of $1.8 billion. At an annual cost of $214,800 in the United States, it is not cheap. “That price is in line with other targeted therapies,” says Greg Friberg, Amgen’s vice president of medical affairs for Europe, Latin America, Middle East, Africa, and Canada. Tony Mok, however, of the Chinese University of Hong Kong—a past president of the International Association for the Study of Lung Cancer—says, “This is definitely prohibitive.” Only a few patients, he adds, will be able to afford it in countries lacking generalized reimbursement.

At a scientific level, the Lumakras approval is a coup for Amgen’s small-molecule drug discovery organization, given the intense level of competition to drug K-Ras in recent years. The small-molecule drug is a covalent inhibitor of K-Ras GTPase licensed for use in patients with NSCLC who have tumors carrying a glycine-to-cysteine substitution at codon 12 of KRAS (KRAS G12C) and have already failed at least one other therapy. It is approved for use with a companion diagnostic: Qiagen’s Therascreen KRAS RGQ PCR kit, a real-time qualitative PCR assay for use on the company’s Rotor-Gene Q MDx thermocycling instrument. The kit detects KRAS G12C and six other somatic mutations in the human KRAS oncogene, using DNA extracted from formalin-fixed, paraffin-embedded tumor tissue.

The approval is not just an important landmark in itself but also signals the start of a race to understand how to best use K-Ras inhibitors in combination to boost responses to therapy and at the same time slow tumor resistance from developing. It will energize efforts to discover potent inhibitors of other important K-Ras protein variants, particularly those encoded by KRAS G12D and KRAS G12V. The challenges involved in this next phase of development are just as complex as those that had to be overcome to get to this juncture. “We don’t know what the right strategy is going to be to maximize the efficacy of a drug like sotorasib when we think of combinations,” says Friberg.

The normal K-Ras protein cycles rapidly between an active ‘on’ state, when bound to guanosine triphosphate (GTP), and an inactive ‘off’ state, by dephosphorylating the nucleotide GTP to guanosine diphosphate (GDP). When active, it relays external growth signals from receptor tyrosine kinases to the cell’s nucleus through the MAPK–ERK or the PI3K–ATK pathways. Mutations cause the protein to signal excessively by locking it into an ‘always-on’ conformation, thus causing uncontrolled growth.

Despite its emblematic status as the most common oncogenic driver of cancer, K-Ras was long considered undruggable, in part because its surface lacked obvious pockets for allosteric inhibitors to bind. A new era in the hunt for K-Ras inhibitors began in 2013, when Kevan Shokat, of the University of California, San Francisco, and colleagues described an irreversible covalent inhibitor that selectively acts on the KRAS G12C mutated protein by targeting a sulfur group in the introduced cysteine, which is absent from the wild-type protein. This provided an initial toehold on the protein. The Switch II binding pocket Shokat’s group identified was accessible only when K-Ras was in its GDP-bound ‘off’ state, but this was enough to block signaling activity, as the presence of the inhibitor shifts the cell’s pool of K-Ras proteins from the active to the inactive state.

Even before the publication of that study, Amgen had also been “noodling around” with similar concepts, says Margaret Chu-Moyer, vice president of research at Amgen, who leads the chemistry group that discovered Lumakras. Other covalent kinase inhibitors, such as the Bruton’s tyrosine kinase inhibitor Imbruvica (ibrutinib), also work by trapping cysteine residues, she says. “That was part of the story too.” After uncovering some initial leads, Amgen widened the hunt for potent K-Ras G12C inhibitors by entering a collaboration with Carmot Therapeutics, which gave it access to large libraries containing tens of thousands of covalent inhibitors. In addition to targeting the Switch II pocket, the Amgen team also focused on binding a cryptic pocket formed by a histidine residue at position 95. “It’s almost like Play-Doh—if you don’t put your thumb in it you don’t know it’s there,” says Chu-Moyer. Targeting that contact point as well boosted the potency of its drug leads. “Sotorasib is the only G12C inhibitor that opens that pocket,” she says.

In the clinic, Lumakras has, so far, proved to be a promising—though by no means curative—therapy for patients seeking second-line therapy for NSCLC who are otherwise lacking viable treatment options. In the CodeBreaK 100 phase 1/2 single-arm trial that secured its approval, Lumakras attained an overall response rate of 37.1%, including 4 complete responses (3.2%) in the 126 patients who received the drug. Median progression-free survival and median overall survival were 6.8 months and 12.5 months, respectively.

“There is no doubt that the phase 2 clinical data is practice-changing, and I consider these findings, in a heavily pretreated population—with 81% of patients having previously progressed on both platinum chemotherapy and PD-1 axis inhibitors—as a major milestone in the clinical management of patients with KRAS G12C mutated non-small-cell lung cancer,” says Ferdinandos Skoulidis, of MD Anderson Cancer Center, who was the lead author on the study. The previous standard of care, docetaxel or docetaxel plus Cyramza (ramucirumab), a vascular endothelial growth factor receptor 2 inhibitor, provides about 2.8 months progression-free survival and overall survival ranging from 8 to 10 months. Mok says the Lumakras data are “very encouraging,” but they are still immature. “Whether it really extends the survival benefit is debatable. Twelve months survival is good for KRAS, but it’s not a randomized study, it’s a selected population.”

“We should also bear in mind that this level of efficacy does not come at the expense of substantial toxicity or compromised quality of life, which is, in many instances, the case with standard-of-care cytotoxic chemotherapy with docetaxel,” says Skoulidis.

Patients’ differing responses to Lumakras may be influenced by several factors, including the presence of additional mutations in their cancers, the level of DNA damage they have sustained—it can be particularly extensive in smokers, and the activity of resistance mechanisms that can limit the drug’s efficacy. The CodeBreaK 100 study provided an initial glimpse of responses to Lumakras of patients with co-occurring mutations in the genes encoding STK11 (serine/threonine kinase 11) and KEAP1 (Kelch-like ECH-associated protein 1), both of which encode tumor suppressors. “Patients with co-mutations in STK11, but without concurrent mutations in KEAP1, appear to derive increased benefit from sotorasib,” says Skoulidis. Patients in this subgroup attained an overall response rate of 50%, median progression-free survival of 11 months, and median overall survival of 15.3 months—which, he says, “is certainly remarkable data for a molecular subgroup that is otherwise refractory to standard-of-care therapy.” The study was not statistically powered to evaluate these observations, however, and they will need to be confirmed in further studies.

At present, Amgen’s main development thrust remains in the second-line setting, where it is testing Lumakras in combination with ten different agents, including the Mek inhibitor Mekinist (trametinib), several immune checkpoint inhibitors, more kinase inhibitors and a number of drugs acting through various other mechanisms. “By the end of the year, we’re going to release some combination data,” says Amgen’s Friberg. At this point, it is too early to predict which are most likely to be the most effective, notwithstanding the extensive preclinical work that informed the study protocol. “The truth is the cell lines will often point us in the right direction, but they don’t give us the answers,” Friberg says.

Even so, preclinical data have already served to heighten expectations with respect to certain combinations. “There is now substantial evidence that Ras itself drives a number of mechanisms that stifle the immune response,” says Channing Der, of the University of North Carolina at Chapel Hill, one of the pioneers of Ras research. “When you use these inhibitors, you get two for the price of one: you inhibit a driver of cancer growth, but you also inhibit a driver of immune resistance.”

As with any targeted therapy, resistance to Lumakras will inevitably emerge, and understanding the underlying mechanisms will help to inform the choice of appropriate combination partners and to maintain the drug’s utility. A recent study from the Dana-Farber Cancer Institute that analyzed the mutational profiles of cancers in a phase 1/2 trial of Mirati Therapeutics’ adagrasib, another small-molecule inhibitor of K-Ras G12C, has shown that myriad resistance mechanisms are involved. The study, led by Andrew Aguirre of Dana-Farber and The Broad Institute of MIT and Harvard, identified secondary mutations in KRAS, including new mutations that eliminate the original G12C mutation and additional activating mutations in the second KRAS allele. They also identified bypass mutations in other components of the receptor tyrosine kinase–Ras–MAPK pathway, including MET amplifications, activating mutations in NRAS, BRAF, MAP2K1 and RET, oncogenic fusions involving ALK, RET, BRAF, RAF1 and FGFR3, and loss-of-function mutations in NF1 and PTEN. The study authors conclude that KRAS G12C inhibition “leads to strong selective pressures and convergent evolution of multiple distinct mechanisms of resistance.” Their findings are in agreement with Amgen’s own analyses of patient profiles conducted during trials of Lumakras. “There’s no one resistance pathway that seems to be common to any of the patients,” says Friberg.

The full picture could become even more complex, once these therapies are administered to large patient populations. The Dana-Farber analysis concerned only 38 patients—27 with NSCLC, 10 with colorectal cancer and 1 with appendiceal cancer. The group identified at least one putative resistance mechanism in seventeen of these, but not all of the driver mutations were identified, says Der. “This has been certainly a fascinating, but perhaps a bit troubling, glimpse into the realities of targeted therapy—that resistance will always arise,” Der says. “It is an outcome that is essentially hardwired into targeted therapies.” The current position of K-Ras G12C inhibitors in the treatment algorithm may be a contributor. “Some of the mutation burden that is seen in these patients could well have arisen from the chemotherapy that they were subjected to,” he says. “This is pure speculation, but it’s entirely possible that resistance mechanisms might not arise as quickly if this becomes first-line treatment.”

The CodeBreaK 100 study provides preliminary evidence in support of this view. It included a small subgroup of 13 patients who were refractory to checkpoint inhibitor therapy but who were still naïve to chemotherapy. These attained an overall response rate of 69%, well above what was seen in the overall study population. Amgen has, says Friberg, initiated a biomarker-guided monotherapy trial study in first-line patients who respond poorly to current therapy, to establish whether any may fare better on Lumakras. It is one of many new avenues of research that have opened up in the wake of this landmark drug approval (Table 1).

Table 1 KRAS-targeting therapies in development

Author information



Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Sheridan, C. Oncologists greet Lumakras: the world’s first KRAS inhibitor. Nat Biotechnol 39, 1032–1034 (2021).

Download citation


Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing