A Look Back: What Happened With Amgen's KRAS G12D Clinical Trial in September 2019
Back in the fall of 2019, something quietly significant was happening in oncology — the kind of development that gets whispered about at medical conferences before it ever makes the evening news. Amgen, the same company that had made waves with its KRAS G12C inhibitor sotorasib, was turning its attention to a stubborn genetic target: KRAS G12D.
If you were following cancer research closely at the time, you probably remember the buzz. KRAS had been called "undruggable" for decades. That's why then AMG 510 (later named sotorasib) cracked the door open. And by September 2019, Amgen was pushing through it, looking specifically at G12D — a mutation that shows up in a huge number of pancreatic, colorectal, and lung cancers.
So what actually happened that month? And why does it still matter years later? Let's walk through it.
What Is KRAS G12D, and Why Is It Different From G12C?
Before we get into the trial itself, a quick primer — because this stuff is genuinely confusing if you haven't spent years in the field.
KRAS is a gene that makes a protein involved in cell growth. When it mutates, the protein gets stuck in the "on" position, telling cells to divide nonstop. Different mutations happen at different points in the protein — and those little variations matter more than you'd think.
G12C is a cysteine mutation. Drugs designed for G12C don't work well on G12D. G12D is an aspartate mutation. That single-letter difference in the amino acid changes everything about how a drug can bind to it. It's like trying to fit a key into a lock that's almost — but not quite — the same shape.
And here's the kicker: G12D is actually more common* than G12C in some of the deadliest cancers. Here's the thing — pancreatic ductal adenocarcinoma, for instance, is dominated by G12D mutations. Roughly 40% of pancreatic cancers carry it. So the need for a G12D-targeting drug isn't academic — it's life or death for a lot of patients.
Amgen's move into this space in 2019 was a direct response to that unmet need.
Why September 2019 Was a important Moment
You have to understand the context here. In mid-2019, the oncology world was still digesting the early clinical data on sotorasib (AMG 510). The drug was working — sometimes dramatically — in patients with KRAS G12C mutations, mostly in non-small cell lung cancer.
But every researcher in the field kept asking the same question: what about everyone else?*
The KRAS mutation universe is bigger than just G12C. In real terms, there are G12D, G12V, G13D, and others. Each one is its own puzzle. So when Amgen announced in September 2019 that it was moving a KRAS G12D inhibitor into the clinic, it wasn't just another pipeline update. It was proof that the G12C breakthrough wasn't a fluke — it was the start of something bigger.
The compound in question was AMG 718 (later known as MRTX1133 once it was licensed to Mirati, though Amgen's early work laid important groundwork). At the time, the early-phase trial was designed to test safety, find the right dose, and look for any early signs the drug was doing what it was supposed to do.
The Patient Population Being Targeted
This part really stuck with me. And the trial was deliberately enrolling patients with solid tumors known to harbor KRAS G12D mutations. That meant a lot of pancreatic cancer patients. A lot of colorectal cancer patients. People who, frankly, had very few good options.
What's interesting is that pancreatic cancer in particular has been one of the cruelest diagnoses in oncology. In real terms, the standard of care — chemotherapy regimens developed in the 1990s — still hasn't been meaningfully replaced. Because of that, five-year survival rates have barely budged in decades. So a targeted therapy aimed at the most common mutation in pancreatic cancer? That's a big deal, even at the earliest stages of clinical testing.
How the Trial Was Structured
Now, let's talk about how the actual study was designed, because early-phase oncology trials follow a pretty specific playbook.
Phase 1 Dose Escalation
The first part of the trial was classic dose-finding. Researchers start with a low dose in a small group of patients, watch for side effects, and gradually increase the dose in new cohorts. The goal is to find the maximum tolerated dose — the highest amount of the drug a person can handle without unacceptable toxicity.
This part is slow. In practice, painful, even. Patients in these early cohorts are often very sick, and many of them won't benefit. But without this step, nothing else can move forward.
Expansion Cohorts
Once a tolerable dose is identified, the trial opens up to more patients — usually grouped by tumor type. So you'd have a pancreatic cancer cohort, a colorectal cancer cohort, and so on. This is where researchers get their first real look at whether the drug is doing anything meaningful.
Endpoints and What Researchers Were Watching
The primary endpoint in a Phase 1 like this is safety. But everyone involved is also keeping a close eye on secondary endpoints — things like objective response rate, disease control rate, and progression-free survival. Day to day, translational endpoints matter too: does the drug engage its target? Are KRAS signaling pathways getting turned off in the tumor?
Want to learn more? We recommend is water more dense than oil and acs med chem lett impact factor for further reading.
In September 2019, the trial was in the very early innings. So the dose escalation was still ongoing. Real efficacy data was still a ways off.
What Most People Got Wrong About the Announcement
Here's something I want to flag, because I saw a lot of confusion online at the time — and honestly, I still see it in retrospective write-ups.
A lot of headlines and tweets implied that Amgen had cured* KRAS G12D or that the trial was already showing dramatic results. Because of that, it wasn't. In September 2019, the drug had entered the clinic. That's it. That alone was newsworthy because the science was hard, but it was a starting point, not a finish line.
Another thing people got wrong: the assumption that a G12C drug would automatically work for G12D. It doesn't. The binding chemistry is different. The shape of the protein surface is different. Amgen had to essentially start from scratch on the medicinal chemistry side, and that's part of why this work took so long.
The Bigger Picture: What This Trial Was Really About
Step back for a second, because there's a layer to this that's easy to miss.
The September 2019 trial wasn't just about one drug. Which means it was a proof of concept for an entire class of therapies. If a G12D inhibitor could be developed and moved into the clinic, it would validate the idea that the "undruggable" label on KRAS was permanently retired. It would mean that biotechs and pharma companies across the industry could keep building on this foundation.
And they did. By the early 2020s, multiple G12D programs were in development — from Mirati Therapeutics, from Revolution Medicines, from Bristol Myers Squibb, from Genentech. Now, the field expanded fast. None of that happens without Amgen being willing to take the early risk.
Practical Takeaways for Patients and Families
If you're reading this because you or someone you love is facing a KRAS G12D-mutated cancer, here's what's actually useful to know.
The September 2019 trial is part of a much longer story. ClinicalTrials.Also, that trial contributed to the foundation that has led to ongoing studies — including combination therapies, next-generation inhibitors, and trials exploring G12D in colorectal cancer specifically. gov remains the best real-time resource for finding open studies.
Genomic testing matters. Plus, a lot. If a tumor hasn't been sequenced for KRAS mutations — including the specific subtype — that's the first conversation to have with an oncologist. Treatment decisions are increasingly being made at the molecular level, and knowing the exact mutation changes the options.
And patience, unfortunately, is part of the process. Here's the thing — drug development is slow. In real terms, announcements that look like breakthroughs often take years to translate into approved therapies. But the direction is right.
Frequently Asked Questions
Was the Amgen KRAS G12D trial successful in September 2019? Not in the way most people would define "successful." The drug had entered the clinic, but efficacy data wasn't available yet. The trial was in early Phase 1 dose escalation.
What types of cancer were included in the trial? Primarily solid tumors known to harbor KRAS G12D mutations — including
pancreatic, colorectal, and non-small cell lung cancer.
How long did it take to develop this drug candidate? From the initial structural biology work in the mid-2010s to the first patient dosed in September 2019, approximately four to five years of intensive medicinal chemistry and preclinical development preceded the clinical trial.
Is this drug approved? As of the most recent data, AMG 510 (sotorasib) received FDA approval in May 2021 for KRAS G12C-mutated NSCLC, but the G12D-specific candidate remained in clinical development, with ongoing trials continuing to evaluate its safety and efficacy profile.
Why focus on KRAS at all? Because it's one of the most frequently mutated oncogenes in human cancer. Roughly one in four human cancers harbors some form of RAS mutation, and G12D alone accounts for a significant percentage of those cases.
Looking Forward
Here's the thing about the September 2019 trial represents something larger than a single clinical milestone. Practically speaking, it represents the moment when the field collectively decided that KRAS G12D was worth targeting as seriously as G12C had been. That decision has shaped oncology drug development for the better part of a decade.
The path from undruggable to clinical candidate was never going to be short. But the work that Amgen and its competitors have put in over the past decade is finally bearing fruit in ways that were almost unimaginable when researchers first started poking at the KRAS protein in the 1980s. For patients with G12D-mutated cancers, that work is the only thing standing between them and another treatment option that might actually work.
The story of KRAS G12D inhibitors is still being written. The September 2019 trial was a crucial early chapter — not the conclusion, but the proof that a conclusion was possible.
