AMG 510, AbGn-107 Prove to Be Effective, Tolerable in GI Cancers

The novel KRAS G12C inhibitor AMG 510, along with the antibody-drug conjugate (ADC), AbGn-107, have demonstrated efficacy and tolerability in early-phase studies of patients with KRAS G12C-mutated colorectal cancer (CRC) and gastrointestinal (GI) cancers, respectively, according to Andrew L. Coveler, MD.

In the first-in-human, phase 1 CodeBreak 100 study, AMG 510 was evaluated in patients with advanced solid tumors that harbored a KRAS G12C mutation, including a subgroup of heavily pretreated patients with CRC (n = 42). After a median follow-up of 7.9 months (range, 4.2-15.9), results of the interim analysis showed that stable disease was maintained for a median 4.2 months.¹ The median progression-free survival (PFS) was 4.0 months and median overall survival (OS) was 10.1 months. Tumor shrinkage was observed in 18 of 39 patients, with available post-baseline tumor data across all doses.

Coveler added that the agent was well tolerated, and no dose-limiting toxicities were observed.

Another agent of interest with intriguing data in a first-in-human, phase 1 study is AbGn-107, which demonstrated activity in patients with heavily pretreated pancreatic, biliary, and gastric cancers.²

“The take-home message of these studies is that [a lot of the progress being made] in other tumor types is hopefully coming to gastrointestinal cancer, such as effective targeted therapies, much like the KRAS G12C inhibitor,” said Coveler. “Bringing immunotherapy to the pancreas cancer [space] has been a significant challenge, so, hopefully, that will be moving forward. Finally, ADCs which have been useful in some other diseases, such as HER2-positive breast cancers and lymphoma, will hopefully be able to move [forward in] other solid tumors.”

In an interview with OncLive, Coveler, director of the Pancreatic Cancer Specialty Clinic, Seattle Cancer Care Alliance; an associate professor of medical oncology, University of Washington (UW) School of Medicine; a physician with UW Medicine; and an associate professor, Clinical Research Division, Fred Hutchinson Cancer Research Center, discussed next steps for these agents in future clinical trials.

OncLive: Could you discuss the rationale for exploring AMG 510 in CRC?

Coveler: AMG 510 is really the first KRAS G12C inhibitor to be moved into patients in the GI space. KRAS, up until now, has been the undruggable enzyme, so inhibiting KRAS is thought to be useful in colon cancer because about 40% of colon cancer has a KRAS mutation. Most of them aren't KRAS G12C mutations, but the proof of concept is to see if inhibiting KRAS in colon cancer is beneficial to patients. Eventually, it will be used in combination with other medications, such as EGFR inhibitors, including cetuximab (Erbitux) and panitumumab (Vectibix). If a patient has a KRAS mutation—one of the driving mutations in CRC—there is [sometimes a] resistance to EGFR inhibitors.

Could you speak about the patient population that was included in this study?

In the entire study, there are various patient populations that include essentially anyone with a KRAS G12C mutation. In the poster that was presented at [the 2020 ASCO Virtual Scientific Program], all of the patients had heavily pretreated CRC. [These patients have] gone through the standard treatments of 5-fluorouracil (5-FU), irinotecan, and oxaliplatin [FOLFIRI], and received single-agent AMG 510.

Has AMG 510 shown efficacy in other studies?

Where AMG 510 has so far gotten the most press, in truth, is in patients with lung cancer with a KRAS G12C mutation. Lung cancer has several different specific enzymes that have been found to drive the cancer, such as ALK and ROS1. In those settings, agents such as AMG 510have had good responses; the lung cancer cohort has done well.

What phase 1 findings were presented at the 2020 ASCO Virtual Scientific Program?
The study comprised about 42 patients with CRC and were heavily pretreated. Although there were about 3 patients who responded [to the regimen], there were also about 29 or 30 patients who achieved disease control and had stable disease, which gives at least a hint of activity for targeting this enzyme. As we move forward, the [next steps] are going to be combination therapy and looking to see how this agent works in combination with other medications.

What is the safety profile of this agent?

Overall, it's a very well tolerated oral medication. In a phase 1 study, you typically look for dose-limiting toxicities and [this agent] didn't have any of those. Most of the AEs are mild as far as safety goes, with diarrhea being the most common followed by fatigue and some other GI AEs, such as nausea. [There were] some other laboratory abnormalities, but overall it is very well tolerated.

Switching gears, you were also a co-author of the phase 1 study with AbGn-107. Could you talk about the rationale for this agent in GI malignancies?

AbGn-107 is an ADC. The idea here is to take a very potent chemotherapy that is known [within the field] and is something that we can't actually give to patients intravenously because it's too toxic. [Instead], we bind it to an antibody that will bring that drug directly to the cancer cells. The target is variously expressed on different cancers, but it seems to be mostly expressed in pancreas, biliary, and gastric cancer, although it is not [commonly expressed in] CRC. But that expression [can hopefully] bring high potent chemotherapy directly to a cancer cell.

What were the findings, as well as the safety profile of AbGn-107?

The findings of this study were that, overall, the drug was very well tolerated. The dose-limiting toxicity really became hematologic through low white blood cell counts—that was the biggest AE. There were some other minor AEs, including some enzyme elevations and joint aching that were manageable, but the [main factor] that limited [dosage] had to do with white blood cell count or neutropenia.

What are the next steps for these studies?

For AMG 510, there is a robust developmental path of trying that drug in combination with other agents. Moving forward, a lot of that is somewhat available on Clinicaltrials.gov to see what future combinations are available. [AbGn-107], which had minor responses for 6 patients, had patients with pancreas cancer who experienced durable disease control for longer than expected and will potentially be seen in the future with combination studies.

References

1. Fakih M, Desai J, Kuboki Y, et al. CodeBreak 100: Activity of AMG 510, a novel small molecule inhibitor of KRASG12C, in patients with advanced colorectal cancer. J Clin Oncol. 2020;38(suppl 15; abstr 4018). doi:10.1200/JCO.2020.38.15_suppl.4018
2. Ko AH, Coveler AL, Schlechter BL, et al. Phase I, first-in-human study of AbGn-107, a novel antibody-drug conjugate (ADC), in patients with gastric, colorectal, pancreatic or biliary cancers. J Clin Oncol. 2020;38(suppl 15; abstr e16771). doi:10.1200/JCO.2020.38.15_suppl.e16771