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"Resistance is futile." There's debate about which science fiction offering that iconic line came from -- was it "Doctor Who," "Space: 1999," or a '90s-era "Star Trek" movie? What's less debatable, though, is that patients with non-small cell lung cancer (NSCLC) who are on immune checkpoint inhibitors (ICIs) have a very high likelihood of acquiring treatment resistance. But the mechanisms of acquired resistance to ICI in NSCLC are largely unknown, stated Mark M. Awad, MD, PhD, of Dana-Farber Cancer Institute in Boston, and colleagues.

Of course, that doesn't render ICIs in NSCLC futile. If anything, "resistance is fundamental" to refining treatment options and boosting outcomes. To that end, Awad's group performed comprehensive genomic profiling and immunophenotypic characterization on samples from 82 patients with NSCLC, matching pre- and post-ICI biopsies. The team compared those findings with a control group who received non-ICI intervening therapies between biopsies (predominantly targeted therapies).

As the researchers reported in the , they identified "putative resistance mutations" in more than a quarter of the ICI-treated cases, including acquired loss-of-function mutations in STK11, B2M, APC, MTOR, KEAP1, and JAK1/2. None of these acquired alterations were seen in controls.

There was a significant decrease in HLA class I expression in the immunotherapy cohort at the time of acquired resistance compared with the chemotherapy and the targeted therapy cohorts.

The researchers also found driver mutations in KRAS in over a third of the cases, and for patients who got intervening targeted therapies, a little over 3% had acquired mutations in KRAS. Among gene-level copy gains, acquired high-level amplification was found in almost 4% of KRAS mutations in ICI-resistant samples.

In an accompanying , Brian S. Henick, MD, of Columbia University Irving Medical Center in New York City, and colleagues asked how the results can be leveraged to enhance patient care today. "Post-treatment biopsy, although recommended for patients treated with targeted therapies, is rarely done in the case of ICI resistance," the editorials noted. "Yet, these results suggest that rebiopsy may reveal new genomic alterations that are informative or with new approaches might be targetable."

The researchers used KRAS G12C inhibitors as an example, Henick and colleagues said, noting that these agents have "accelerated approval only in the second line, and appear to induce responses regardless of STK11 comutations -- which may be acquired with ICI resistance. As our therapeutic options grow, such data are crucial to deciding between future therapies."

On a related topic, Stephen V. Liu, MD, of the Lombardi Comprehensive Cancer Center at Georgetown University in Washington, D.C., speaking in April 2024 at an , discussed why KRAS has proven to be an elusive target in lung cancer care. Here are some of his remarks.

Would you share some background on KRAS mutation in NSCLC?

Liu: The KRAS mutation has been known about for a long time; it was one of the first oncogenes described, and identified in lung cancer in 1983. So it was about 4 decades until we saw targeted agents for KRAS.

Why did it take so long? Well, it's not because it was rare. About one in three NSCLC cases will harbor a KRAS mutation. There's an interesting geographic variation. In Asia, it's a little less common, at about 14%, but certainly not rare.

Now within KRAS, there is profound heterogeneity, starting with the mutation itself. KRAS mutations cluster in codons 12, 13, and 61. In lung cancer, about 80% are going to be in codon 12. The most common KRAS mutation in lung cancer is KRAS G12C, accounting for about 40% of KRAS mutations.

Why is G12C a little more common in lung cancer? Well, there's a biochemical reason for it. If we think back to our biochemistry days, KRAS G12C represents a switch from the amino acid glycine, or G, to cysteine, or C. And if we think of these amino acids in terms of the nucleotides that form the amino acids, glycine is a GGT or GGC and cysteine is a TGT or TGC.

So to go from G to C, to go from glycine to cysteine, we have to swap out a G nucleotide, or a guanine, with a thymine. And that G to T swap is what we call a transversion. And transversion changes are generally reflective of exposure to aromatic hydrocarbons, which are present in cigarette smoke.

What agents are currently FDA approved for the treatment of NSCLC with KRAS G12C mutation?

Liu: We have not one, but two agents now receiving FDA accelerated approval for the treatment of KRAS G12C NSCLC: sotorasib (Lumakras) and adagrasib (Krazati). Sotorasib in the study, adagrasib shortly afterwards in the , both showing response rates hovering around 40% with a progression-free survival of about 6 to 7 months. We were seeing clear activity. We now have KRAS inhibitors.

Why is this mutation so challenging to target?

Liu: This mutation is typically the result of exposure to cigarettes. KRAS is a very challenging target, although different from some of the other areas where we've had early success. It's a small protein. And it has a relatively smooth surface -- meaning not a lot of pockets for our drugs to bind to.

So if we take a receptor like EGFR, we can design a drug like osimertinib (Tagrisso), where it prefers to bind to osimertinib than to its ATP [adenosine triphosphate] -- harder in the case of GTP, particularly KRAS, which is a much stronger affinity for GTP, binding on the order of 20 picomolar. So that's about a million-fold difference. We would need to design a drug that had that much stronger affinity. Right now, it's simply beyond our capabilities. We can't design a drug that's going to outcompete GTP for that binding site.

What are some other ways to potentially target KRAS?

Liu: We think of KRAS not as a transmembrane receptor tyrosine kinase, but as an intracellular membrane-bound molecule. And so we looked at ways to untether RAS. The real advance came from at UCSF [University of California San Francisco], using a tethering process called disulfide screening.

KRAS-mutant lung cancer can respond and often does respond well to immunotherapy -- in some cases, better than KRAS wild-type. So our standard there is immunotherapy, because, quite simply, immunotherapy offers a greater potential of durable benefit, long-term survival, while the response rates we see with targeted therapy are impressive and the tolerability is impressive.

So what we need are markers not just of efficacy of these drugs, but which patients with a KRAS-mutant lung cancer will be best served with just immunotherapy, a PD-1 or PD-L1 inhibitor, dual checkpoint inhibition, alone or with chemotherapy. Who should receive the standard treatment and will do very well?

And just as importantly, who's not going to achieve long-term survival with those standard approaches and deserves a chance at something better? We're still learning about resistance to KRAS inhibitors.

Read the study here and expert commentary about it here.