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Expert Analysis: CCO Independent Conference Highlights of the 2022 ASCO Gastrointestinal Cancers Symposium (GICS)
  • CME

Manish A. Shah, MD
Rachna Shroff, MD
Released: April 20, 2022

Key Studies in Pancreas Cancer

Updated Activity/Safety of Adagrasib in PDAC and Other GI Tumors Harboring KRASG12C (KRYSTAL-1): Study Design

Rachna Shroff, MD:
Adagrasib, previously known as MRTX849, is a small-molecule inhibitor of KRASG12C that binds at the cysteine residue, locking the protein in an inactive form and inhibiting downstream signaling.19,20

At GICS 2022, Bekaii-Saab and colleagues21 reported updated activity and safety for adagrasib from a phase II cohort of patients with pancreas ductal adenocarcinoma (PDAC) and other GI cancers who had progressed on standard of care or who had no available standard of care (n = 30). The dose evaluated in this cohort was 600 mg twice daily given orally. The primary endpoint was ORR per RECIST v1.1. Secondary endpoints were DoR, PFS, OS, and safety.

KRYSTAL-1 Update: Baseline Characteristics

Rachna Shroff, MD:
The median age was 65.5 years (range: 40-89), and 12 patients (40%) were women. Most patients enrolled were White (67%), 17% were Asian, and 10% were Black or African American. In 80% of patients, the ECOG PS was 1. In total, 12 patients had PDAC, and 18 had other GI cancers. Of importance, only 10 of 12 patients with PDAC and 17 of the patients with other GI cancers were evaluable for efficacy. This was a heavily pretreated group of patients with a median of 2 prior systemic therapies, ranging from 1-5 prior therapies, and >83% had received ≥2 previous therapies.

KRYSTAL-1 Update: Efficacy in Unresectable or Metastatic PDAC

Rachna Shroff, MD:
Efficacy of adagrasib in the PDAC patient population was encouraging, with an ORR of 50%, which included 1 unconfirmed partial response. The DCR was 100%, the median time to response was 2.8 months, and the median DoR was approximately 7 months. Moreover, the median PFS was 6.6 months (95% CI:1.0-9.7). At the time of this report, 5 of the 10 evaluable patients with PDAC remained on treatment.

KRYSTAL-1 Update: Efficacy in Other GI Tumors

Rachna Shroff, MD:
Efficacy in the other GI cancers was similarly encouraging, with an ORR of 50% in patients with biliary tract cancers (n = 8), with 1 partial response each for GEJ and small-bowel cancer. As in patients with PDAC, the DCR also was 100%. The median time to response was 1.3 months, and the median DoR was approximately 8 months. The median PFS was 7.86 months (95% CI: 6.90-11.30). At the time of this report, 7 of the 11 evaluable patients remained on treatment.

KRYSTAL-1 Update: Safety Summary

Rachna Shroff, MD:
TRAEs of any grade were reported in 91% of patients with PDAC or other GI tumors (n = 30), most commonly nausea (48%), diarrhea (43%), vomiting (43%), and fatigue (29%). Grade 3/4 AEs were reported in 21% of patients. No deaths were reported on the study.

KRYSTAL-1 Update: Conclusions

Rachna Shroff, MD:
In patients with previously treated KRASG12C PDAC and other GI cancers—including GEJ, biliary tract, and small bowel cancer—adagrasib demonstrated antitumor activity and manageable safety. One half of patients with PDAC experienced a response, and DCR was seen in 100% of patients. Similarly, in other GI cancers, the ORR was 50%, and DCR also was 100%. In total, 16 patients remain on treatment. The KRYSTAL-1 study is ongoing (NCT03785249), and based on these data, investigators concluded that further evaluation of adagrasib in KRASG12C PDAC and GI cancers is warranted.

KRYSTAL-1 Update: Takeaways

Rachna Shroff, MD:
Although these are early data in a small population, this study provides proof of principle that we can target KRAS in pancreatic cancer. This is a landmark study that certainly raises hope for KRAS inhibition in GI cancers. Although KRASG12Cmutations are rare, this type of efficacy in a heavily pretreated population is encouraging.

First Data of Sotorasib in Patients With Pancreas Cancer and KRASG12C Mutation (CodeBreaK100)

Rachna Shroff, MD:
CodeBreaK100 is a multicenter, open-label phase I/II clinical trial enrolling patients with advanced solid tumors and a KRASG12C mutation. At the ASCO monthly plenary in February 2022, Strickler and colleagues22 presented first data of sotorasib in pancreas cancer. Patients were required to have an ECOG PS ≤2 and disease progression on standard systemic therapy or have no appropriate standard therapy available. Patients received 960 mg of sotorasib until disease progression, intolerance, or consent withdrawal. The primary endpoint for the phase II trial was ORR per RECIST v1.1. Secondary endpoints included DoR, DCR, PFS, OS, time to response, and safety.

First Data of Sotorasib in KRAS p.G12C–Positive Pancreas Cancer: Baseline Characteristics

Rachna Shroff, MD:
The median age in this study was 65.5 years (range: 41-81), and 23.7% of patients were women. The ECOG PS was ≥1 in approximately 68% of patients, and 97% of tumors had adenocarcinoma histology. Of importance, >55% of patients had stage IV disease at diagnosis, and 44.7% had metastatic disease at 1 body site. The most frequent sites for tumor metastasis were the liver (81.6%), lung (42.1%), bone (10.5%), and brain (2.6).

First Data of Sotorasib in KRAS p.G12C–Positive Pancreas Cancer: Prior Therapies

Rachna Shroff, MD:
This also was a heavily pretreated patient population with a median of 2 prior anticancer therapies, ranging from 1-8. All patients had received CT. Approximately 76% of patients had received FOLFIRINOX, and approximately 66% of patents had received gemcitabine plus nab-paclitaxel.

First Data of Sotorasib in KRAS p.G12C–positive Pancreas Cancer: Efficacy Summary

Rachna Shroff, MD:
Patients with KRAS G12C–positive pancreas cancer achieved a centrally confirmed ORR of 21.1% with a median DoR of 5.7 months. In the 38 patients receiving treatment to date, the DCR was quite remarkable at 84.2%.

After a median follow-up of 16.8 months, the median PFS was 4.0 months (95% CI: 2.8-5.6), and the median OS was 6.9 months (95% CI: 5.0-9.1).

First Data of Sotorasib in KRASG12C–Positive Pancreas Cancer: Safety Summary

Rachna Shroff, MD:
Overall, sotorasib was well tolerated, with 42.1% of patients experiencing any-grade TRAEs. Grade ≥3 AEs were reported in approximately 16% of patients. The most common grade 3 AEs reported were diarrhea (5.3%), fatigue (5.3%), abdominal pain (2.6%), alanine/aspartate aminotransferase elevation (2.6%), pleural effusion (2.6%), and pulmonary embolism (2.6%).

AEs led to dose reduction or interruption in 13.2% of patients, and approximately 8% of patients developed serious AEs. There were no grade 4 AEs, and no treatment-related deaths were reported.

First Data of Sotorasib in KRAS p.G12C–Positive Pancreas Cancer: Conclusion

Rachna Shroff, MD:
The first results of the CodeBreaK100 trial in patients with pancreas cancer and KRASG12C mutation show that sotorasib is well tolerated and has encouraging activity in patients with heavily pretreated pancreas cancer. At the recommended phase II dose of 960 mg daily, the centrally confirmed ORR was 21.1%, and DCR was 84.2%. Based on these results, investigators propose that further evaluation of sotorasib is warranted in this population of high unmet need.

First Data of Sotorasib in KRAS G12C–Positive Pancreas Cancer: Takeaways

Rachna Shroff, MD:
CodeBreak100 is the second study to show the efficacy of KRASG12C inhibitors in refractory pancreatic cancer. The study showed an ORR of 21.1%. Although lower than in the KRYSTAL-1 study, this included a larger sample size. Nonetheless, in this heavily refractory patient population, efficacy is quite promising and lends further support to our ability to target KRAS in this deadly disease.

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