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The year 2013 saw a number of "firsts:" The first Black president of the U.S. was sworn in for a second term; the first non-European Catholic Pope was elected in over 1,000 years; a British royal couple welcomed the first of three children; and a "identified allele-specific covalent inhibitors of KRAS^G12C, the first direct inhibitors of oncogenic KRAS."

That "breakthrough study has ushered in a new era of precision oncology and medicinal chemistry: direct inhibitors of mutant RAS," wrote Jia Luo, MD, of Dana-Farber Cancer Institute in Boston, and co-authors in ASCO's 2022 . "RAS alterations are the most common activating lesions in human cancers, and KRAS is the most common oncogene-driven form of NSCLC [non-small-cell lung cancer], accounting for one-quarter of these cancers."

But unlike with EGFR or ALK, success with KRAS-targeting agents has been mixed, the authors noted, pointing out that KRAS-driven lung cancers can benefit from PD-L1 blockade therapy, but wins tend to be limited to a subset of patients with KRAS-driven lung cancers, so "the search for small-molecule inhibitors of mutant KRAS has continued, with little progress until recently."

Luo and colleagues highlighted two agents that have made serious headway in the disease: The FDA-approved, (Lumakras), which offered meaningful outcomes in several CodeBreak trials -- a "moment" that Luo's group said "marked the first targeted drug approval for mutant KRAS ... historically considered to be undruggable" -- and the FDA-labeled breakthrough therapy designation of , which is being tested in an ongoing confirmatory phase III trial (estimated 2024).

One reason for the FDA backing sotorasib was the CodeBreak 100 trial, and in a presentation at the 2022 American Association for Cancer Research (AACR) meeting, Grace Dy, MD, of Roswell Park Comprehensive Cancer Center in Buffalo, New York, discussed results from the 2-year analysis of the trial. Also at AACR, Mark Awad, MD, PhD, also of Dana-Farber, shared his take on the future of KRAS-targeting agents.

What were some of the main findings from CodeBreak 100?

Dy: Based on data from the component of the CodeBreak 100 study, sotorasib showed an objective response rate [ORR] of 37%, median progression-free survival [PFS] of 6.8 months, and median overall survival [OS] of 12.5 months ... after a median follow-up of 15 months.

How was the 2-year analysis conducted?

Dy: The for our analysis ... pooled and combined data from patients in the portion of the trial, adding 48 patients who received 960 mg daily of sotorasib, a similar dose to patients who were treated in the phase II component of the trial, for a total of 174 patients for safety and long-term follow up analysis. Median follow-up for OS in this cohort is 25 months at the data cut off in February [2022].

This is a global study enrolling patients over 52 centers across 10 countries in four continents ... Most patients were former smokers or current smokers with two median prior lines of therapy, and more than 80% of patients who were enrolled received both prior platinum-based chemotherapy and an immune checkpoint inhibitor [ICI].

What were some of the main outcomes?

Dy: Central review of response showed an ORR in this combined cohort of 40.7%, complete response [CR] rate of 2.9%, partial response [PR] of 37.8%, and overall disease control rate of 83.7%, with the median PFS of 6.3 months.

[For the] time to response among patients who had PR or CR, the median time to response was 6 weeks, with 70% of patients having experienced a response at their first imaging scan. The median duration of response was 12.3 months, and the Kaplan Meier-estimated percent of responders who remained in response for 12 months or longer was 50.6%. Median OS is 12.5 months, with 1-year OS landmark analysis of 51%. And ... for the first time we report the 2-year OS achieved [with] one out of three patients remaining alive at the initiation of sotorasib treatment.

In the exploratory subgroup analysis, we sought to compare patients who achieved long-term benefit as defined by a median PFS of at least 12 months versus patients who had early progression as defined by PFS of ≤3 months.

Patients who meet the criteria for long-term benefit represented about a quarter of the entire efficacy analysis set, mostly represented by patients who had response, in contrast to patients who had early progression; these were represented mostly by patients who did not sustain a response.

For the biomarker analysis, between 60% and 70% of the patients had tissue or blood available for further investigation at baseline ... These two patient subgroups are very similar in terms of age, gender, median prior lines of therapy, status in terms of pre-metastases at baseline, or tumor mutation burden.

For patients who achieved long-term benefit, proportionately slightly less patients received both platinum-based chemotherapy and ICI, though ... at least 70% received both.

What about adverse events [AEs]?

Dy: With regards to treatment-related AEs [TRAEs] ... there are no surprises. Most TRAEs were grade 1 or 2 in severity, namely diarrhea, liver-enzyme abnormality, or nausea. About 21% of patients encountered grade 3 or 4 toxicities; 22% required treatment interruption or dose modification. But only 6% required treatment discontinuation. There were no fatal TRAEs.

We also sought to look at patients who were remaining on treatment for over a year, and this represented about one quarter of the entire cohort ... there were no surprises in terms of late toxicities. And in fact, there were no grade 3 or 4 TRAEs, save for one patient who had hemolytic anemia.

Of note, there were no treatment discontinuations among these patients who remained on treatment after 1 year of therapy, supporting the clinical observation that sotorasib therapy is very manageable in terms of AEs, minimal or no cumulative toxicity, or late toxicity, in contrast to what we would expect with docetaxel.

What about PD-L1 expression and KRAS^G12C frequency?

Dy: With regards to PDL-1 expression by central testing, long-term benefit is achieved across all PDL-1 expression levels, including tumors with PDL-1 low levels. Examining the genomic profile ... patients with KEAP1 wild-type tumors, patients received long-term benefit regardless of the presence of STK11 co-mutation. While long-term benefit is also observed among a fraction of patients with KEAP1 mutation, proportionately this occurred at the lower rate compared to patients who were KEAP1 wild-type.

Examining KRAS^G12C, variant allele frequency in both tissue and blood ... there is no significant difference in terms of tissue variant allele frequency among patient subgroups. However, lower plasma ctDNA [circulating tumor DNA] levels of baseline was more commonly observed in patients who achieved long-term benefit. Plasma baseline ctDNA levels were correlated with the tumor burden as assessed by measuring the sum of the baseline diameters for target measurements.

What are some of the take-home messages from the trial?

Awad: In the last decade, we've seen improvements in targeted therapies for lung cancer ... [with] earlier-generation drugs targeting genes such as EGFR, ALK, RET, and HER2 ... KRAS can be added to this list as a druggable target.

We've seen the updated response data [from CodeBreak 100] showing response rate of 40.7%, so slightly higher than what we had seen with the reporting last year, and a median PFS of about 6.3 months.

So significant headway for this molecularly defined subgroup of lung cancer, but not quite the response rate that we're used to seeing with some of our other classes, and not quite the duration of PFS that we're using to seeing with EGFR and ALK.

With adagrasib, we're seeing a comparable response rate of about 45%, so roughly on par with what we've seen with sotorasib, and this raises the question: 'Are we hitting a therapeutic ceiling with G12C inhibitor monotherapy?' To borrow this motto from the patient advocacy subgroup: Can we kick cancer's KRAS harder? Will we see improved efficacy with novel KRAS^G12C inhibitors?

There are a number of drugs currently in clinical development ... [but] ... are we going to see improvements in response rate and PFS with any of these agents, or are we limited by what we can achieve by monotherapy? Are we going to see any improved efficacy with some of these novel agents?

G12C inhibitors represent an amazing advance in the treatment of KRAS lung cancers ... but the therapeutic efficacy of these G12C inhibitors is currently limited by several things including patient factors, intrinsic biology, and the emergence of complex resistance mechanisms, and will therefore need new approaches to delayed-over-time drug resistance to hopefully keep kicking cancer's KRAS.

Read the review here and expert commentary about it here.