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Updates in the GI Cancers with Dr Axel Grothey

Presentation by Dr Axel Grothey, MD West Cancer Center

At the 2023 Total Health Spring Oncology Review and Renew Conference, Dr Axel Grothey from West Cancer Center provided an update on the GI cancers from the most recent American Society for Clinical Oncology (ASCO) Gastrointestinal Cancers Symposium. Dr Grothey focused on the topic of targeted therapies and precision medicine approaches in GI cancer, with highlights for some of the more practice changing developments over the past year. He noted a range of cellular biomarkers, and positive predictive markers in GI cancers, such as human epidermal growth factors 2 (HER2) and fibroblast growth factor receptor (FGFR) 2b, which can be targets for therapy.

Gastro-Esophageal Junction (GEJ) Cancers

In the setting of GEJ cancers, Dr Grothey noted a new biomarker, Claudin 18.2 (CLDN 18.2) which has been targeted with an antibody called zolbetuximab. In the SPOTLIGHT trial, zolbetuximab was used in combination with an established chemotherapy regimen, modified FOLFOX6, or mFOLFOX6. This was a phase III study of patients with inoperable (unresectable) or metastatic gastric or gastroesophageal junction (G/GEJ) cancers. Dr Grothey noted that CLDN 18.2 is expressed on the surface of G/GEJ cancers, and this makes it a promising target for therapy. It is believed that zolbetuximab binds to CLDN 18.2 on cancer cells, and in so doing, causes the tumor cells to be attacked by the immune system through antibody-dependent and independent mechanisms. Since the target of zolbetuximab is CLDN 18.2, patients were screened in the trial for CLDN 18.2 expression in their cancers, and Dr Grothey noted that, in fact, a sizable proportion of the patients in the study were positive for CLDN expression (38%).

The primary endpoint of this large trial (>500 patients) was progression-free survival (PFS), which significantly favored the use of zolbetuximab + mFOLFOX6 over placebo + mFOLFOX6 with a 24-month PFS rate of 24% vs. 15% and a statistically significant hazard ratio (HR) for PFS of 0.751 (P=0.0066). Notably, the secondary endpoint of overall survival (OS) also favored the use of zolbetuximab, with a median OS of 18.23 vs. 15.54 months and an HR of 0.750 (P=0.0053). Dr Grothey noted that, despite these positive findings, the response rate (RR) and the duration of response (DoR) was surprisingly similar between the groups. In terms of adverse events (AEs), Dr Grothey noted that, owing to the expression of CLDN 18.2 on cancer cells, as well as other gastric cells, the primary “on-target” AEs associated with zolbetuximab were nausea, vomiting and decreased appetite. Some of the key take-home points which Dr Grothey summarized from the SPOTLIGHT trial are summarized in Box 1.

BOX 1. Gastro-Esophageal Junction Cancer: SPOTLIGHT

· Zolbetuximab, an anti-Claudin 18.2 (CLDN18.2) directed treatment, in combination with FOLFOX, is emerging as new SOC in advanced CLDN18.2 positive GE/ GEJ cancers.

· This agent adds to an increasing list of molecular targets for patients with GE/GEJ cancers, such as HER2 and FGFR 2b.

· The treatment landscape is rapidly changing in GE/GEJ cancers.

Pancreatic Cancer

For pancreatic cancer, Dr Grothey highlighted results from the NAPOLI 3 trial. This was a randomized, open-label study that examined the efficacy and safety of a triple chemotherapy regimen called NALIRFOX (liposomal irinotecan + 5-fluorouracil/leucovorin + oxaliplatin) as compared with a standard chemotherapy regimen of nab-paclitaxel + gemcitabine (Gem+NabP) for patients having previously untreated metastatic pancreatic ductal adenocarcinoma. The results showed a statistically significant benefit of NALIRIFOX, with an OS of 11.1 months versus 9.2 months with Gem+NabP (HR=0.83; P=0.04), and the median PFS was also significantly improved with NALIRIFOX (7.4 vs. 5.6 months; HR=0.69; P<0.0001) suggesting this was the more active of the regimens. The objective response rate (ORR) was also better for NALIRIFOX versus Gem+NabP (41.8% vs. 36.2%). Dr Grothey noted there did not appear to be a major difference between the two regimens in terms of toxicity profile, and therefore efficacy data are more important to consider in the overall results. Dr Grothey noted some key points for NAPOLI 3, summarized in Box 2.

BOX 2. Pancreatic Cancer: NAPOLI 3

· Results from NAPOLI 3 suggest NALIRIFOX is superior to Gemcitabine + Nab-paclitaxel in first-line (1L) metastatic pancreatic ductal adenocarcinoma.

· Questions remain, however as to how effective the NALIRIFOX regimen is compared to other 1L regimens such as FOLFIRINOX (which, in another trial also showed an 11.1-month OS benefit).

· Owing in part to a higher cost of the NALIRIFOX regimen, Dr Grothey suggested that FOLFIRINOX would remain as his first line regimen in the 1L metastatic setting.

Metastatic Colorectal Cancer

Dr Grothey also reviewed results from SUNLIGHT, a phase III study, which examined the use of trifluridine/tipiracil (also called TAS-102) in combination with bevacizumab for third line treatment of treatment refractory, metastatic colorectal cancer. Patients in the study needed to have received two prior treatment regimens. The primary endpoint, OS showed significant improvement with the triple combination as compared with trifluridine/tipiracil alone (median OS 10.8 vs. 7.5 months; HR=0.61; P<0.001). Dr Grothey suggested that this finding was not unexpected, as bevacizumab, a therapy directed against vascular endothelial growth factor (VEGF) has previously been shown to enhance the efficacy of drugs in the same class as TAS-102 in prior studies, and he suggested SUNLIGHT results could change the current standard of care. Secondary endpoints of PFS 5.6 vs 2.4 months (HR=0.44; P<0.0001), RR, 6.3% vs. 0.9%, and disease control rate (DCR, 77 vs 47%) also favored the triple combination as compared to trifluridine/tipiracil, and a benefit of the regimen was observed in all relevant patient subgroups. Dr Grothey further suggested the results prove a benefit of continued VEGF pathway inhibition beyond progression. The key takeaways from SUNLIGHT, summarized by Dr Grothey are shown in Box 3.

BOX 3. Metastatic Colorectal Cancer: SUNLIGHT

· TAS-102, used in combination with the anti-VEGF therapy bevacizumab is the new standard of care for metastatic CRC.

· Owing to its tolerability, this regimen should be considered over other less tolerated treatments such as regorafenib.

· Results from SUNLIGHT confirm a benefit of continued VEGF inhibition beyond progression.


Speaker Disclosure Information: Dr Grothey listed no disclosures for this presentation.

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