What are your top takeaways from ASCO GI 2023?

Top 3 radiation oncology studies:

1. Abstract 489- NRG/RTOG 1112 presented at ASTRO but only phase III study to establish the role of liver SBRT in HCC; will SBRT supplant radioembolization given the 3 negative phase III studies for radioembolization in contrast to this positive study for SBRT
2. Abstract 6: Do nonoperative modality (NOM) treatments of rectal cancer compromise the chance of cure? Final surgical salvage results from OPERA phase 3 randomised trial (NCT02505750).
3. LBA492: Canadian Cancer Trials Group HE.1: A phase III study of palliative radiotherapy for symptomatic hepatocellular carcinoma and liver metastases: establishes the role of palliative single fraction RT for symptomatic HCC and liver mets.

Notable non-radiation oncology trials:

1. LBA661: NAPOLI-3: A randomized, open-label phase 3 study of liposomal irinotecan + 5-fluorouracil/leucovorin + oxaliplatin (NALIRIFOX) versus nab-paclitaxel + gemcitabine in treatment-naïve patients with metastatic pancreatic ductal adenocarcinoma (mPDAC). Comparison of essentially a FOLFIRINOX type regimen with nab-paclitaxel for metastatic pancreas- improvement in OS and PFS.
2. LBA490: SWOG 1815: A phase III randomized trial of gemcitabine, cisplatin, and nab-paclitaxel versus gemcitabine and cisplatin in newly diagnosed, advanced biliary tract cancers. Note that this was a negative trial. Confirms the TOPAZ-1 regimen of Durva/gem/CDDP as 1st line SOC in advanced biliary cancer.

1. NALIRIFOX vs Gem/Abraxane in advanced pancreatic cancer: Minor improvement in mOS and unclear if similar results would have been seen with FOLFIRINOX vs Gem/Abraxane. Until future head-to-head trials of FOLFIRINOX vs Gem/Abraxane are reported (PASS-01 and PRECISION PROMISE), this trial likely makes NALIRIFOX the preferred 1st-line regimen for advanced pancreatic cancer.
2. SWOG-1815: No benefit from Gem/Cis/Abraxane vs Gem/Cis. With this negative trial, Gem/Cis/Durva further solidified as first-line standard for advanced biliary. Perhaps the higher response rate could suggest Gem/Cis/Abraxane can be considered for patients with locally advanced disease needing response to get to surgery, but the difference is likely insufficient given the greater toxicity.
3. Updated results of Agenus’s botensilimab and balstilimab as immunotherapy for MSS colon: 23% ORR and 76% DCR with responses appearing durable.
4. Zolbetuximab with FOLFOX for CLDN18.2 positive gastroesophageal: Addition of Zolbetuximab with 2m OS benefit. How will this drug fit in with our current standard of FOLFOX+PD1?

1. SUNLIGHT study: This is a phase III global study for metastatic colorectal cancer patients who had previous 1-2 lines of chemotherapy to get randomized (1:1) to either TAS102 alone or TAS102 plus bevacizumab. The primary endpoint of the study is overall survival (OS). This study enrolled 492 patients globally. The median OS and progression-free survival were 10.8 months and 5.6 months in the TAS102/bevacizumab arm compared to 7.5 months and 2.4 months in the TAS102 single agent arm respectively (HR 0.61, 95% CI 0.49-0.77, p<0.001 for OS; HR 0.44, 95% CI 0.36-0.54, p<0.001 for PFS). This study's results further confirmed survival benefits seen in the earlier phase II study and the absolute survival benefits for more than 3 months in both OS and PFS are clinically meaningful. So TAS102 plus bevacizumab should be considered a new standard for patients with refractory mCRC who are going to start TAS102 treatment without contraindication for bevacizumab. In the US, this combination has been listed as an option in the NCCN guidelines since 2021 (actually this study did not recruit well in the US due to this) so it may be not necessarily practice-changing in the US but certainly, we are glad the positive phase III study confirmed our practice.
2. SPOTLIGHT study: This is a global, randomized, double blinded, placebo-controlled phase III study evaluating first line mFOLFOX plus zolbetuximab (a Claudin 18.2‒targeted antibody) or placebo for patients with Claudin 18.2‒positive, HER2-negative locally advanced unresectable or metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma with primary endpoint of PFD. A total of 565 patients were enrolled in the study, zolbetuximab improved median PFS from 8.67 months to 10.61 months (HR 0.751, 95% confidence interval 0.589-0.942, p=0.0066). Median OS was also better in the zolbetuximab arm (18.23 vs. 15.54 months, HR 0.75, 95% CI 0.601-0.936, p=0.0053). This study demonstrated that Claudin 18.2 is a good target in gastric or GEJ adenocarcinoma. However, the study may not be practice-changing yet. First, this study regimen did not have immunotherapy as one component (like the Checkmate 649 regimen), given the FDA approval of nivolumab with chemo in the first-line setting, will patients and providers go for zolbetuximab without immunotherapy? According to the presenter, they evaluated the PD-L1 CPS in the study (not reported in the details but was mentioned during the Q&A, about 13% of patients were PD-L1 CPS>=5). Maybe we need to wait for further study to have the immunotherapy component or subgroup analysis. Second, currently, no FDA-approved Claudin 18.2 test is available yet and a different study has a different definition for Claudin 18.2 positivity, and this study used moderate-to-strong Claudin 18.2 staining in >=75% tumor cells (possibly need further confirmation for such cutoff).
3. NAPOLI-3 study: This is a randomized, open-label phase 3 study of liposomal irinotecan +5 FU/leucovorin plus oxaliplatin (NALIRIFOX) versus gemcitabine plus Nab-paclitaxel as 1st-line treatment for metastatic pancreatic ductal adenocarcinoma patients. The study enrolled 770 patients and met its primary endpoints of OS at median follow of 16.1 months. The mOS in the NALIRIFOX arm was 11.1 months compared to 9.2 months in the gemcitabine plus Nab- paclitaxel arm (HR 0.83, 95% CI 0.70-0.99, p=0.04). mPFS also favored NALIRIFOX arm (7.4 months vs. 5.6 months, HR 0.69, 95% CI 058-0.83, p<0.001). Both arms had similar percentages of TEAEs. This study demonstrated NALIRIFOX is an active regimen as a first line treatment for metastatic pancreatic cancer with better OS compared to gemcitabine plus Nab-paclitaxel. However, most providers believe FOLFIRINOX is possibly better than gemcitabine plus Nab-paclitaxel based on the OS numbers seen in the original PRODIG study, the MPACT, the PRODIGE 24, and APACT studies). Triplet chemotherapy should be considered as standard of care for these patients who can tolerate. Meanwhile, we still do not know if NALIRIFOX is better than FOLFIRINOX (especially the mFOLFIRINOX regimen from the PRODIGE 24 study which is relatively easier for patients to tolerate).

1. I think the GAP (gem cis abraxane) presentation by Dr. @Dr. First Last was a good takeaway - more didn't equal more when it comes to efficacy but did add more toxicity. The question in my practice is whether there is still a role for this regimen in the subsets of patients who did better- gallbladder, locally advanced. For instance, would we do this prior to surgery?
2. The zolbetuximab data was also interesting. I think the questions in clinical practice will be how to proceed in patients who are claudin positive but also candidates for immunotherapy.

1. SPOTLIGHT study (Shitara et al.) - For patients with unresectable/metastatic GEJ/gastric adenocarcinoma with positive CLDN18.2 expression, the addition of Zolbetuximab (mAb targeting CLDN18.2) to frontline FOLFOX chemotherapy improved PFS from 8.67 to 10.61 most (HR 0.751) and OS from 15.54 to 18.23 most (HR 0.75). Overall response rates were relatively similar (~60%). Highlights another targetable molecular marker in GEJ/gastric cancer, which may impact first line treatment options, though CLDN18.2 is only positive in about 1/3 of patients. Still unclear what treatment would be more appropriate in the frontline setting for HER2 negative disease if both CLDN18.2 positive and PDL1 positive, but possibly higher PDL1 expression may favor combination chemotherapy with Nivolumab.
2. NAPOLI-3 study (Wainberg et al.) - Patients with metastatic pancreatic adenocarcinoma were randomized to NALIRIFOX (aka FOLFIRINOX but with liposomal irinotecan instead) or Gemcitabine/nab-Paclitaxel. OS was significantly improved from 9.2 to 11.1 months (HR 0.83) with NALIRIFOX, with improvement of PFS as well from 5.6 to 7.4 months (HR 0.69). Response rates were 41.8% NALIRIFOX vs 3.2% Gem/nab-P. There were significantly higher cytopenias rates with Gem/nab-P (likely due to 3 weeks on/ 1 week off dosing), but a much higher rate of diarrhea with NALIRIFOX (any grade 70.5%, gr 3-4 20.3%). Overall NALIRIFOX would be favored over Gem/nab-P, but how much better is this than FOLFIRINOX, and at what added cost?
3. SWOG 1815 study (Shroff et al.) - Though phase 2 results were promising, the addition of nab-Paclitaxel to Gemcitabine/Cisplatin in the frontline setting for advanced cholangiocarcinoma and gallbladder cancer did not significantly improve overall survival or progression free survival. However, there is a suggestion of greater benefit/response for locally advanced (vs metastatic) disease as well as gallbladder cancer, warranting further study. Overall, for most patients with advanced disease, Gemcitabine/Cisplatin + Durvalumab would remain the standard based on TOPAZ-1.
4. SUNLIGHT study (Tabernero et al.) - Phase 3 study evaluating 3rd line treatment with TAS102 + Bevacizumab vs TAS102 alone in patients with metastatic colorectal adenocarcinoma. OS improved from 7.5 to 10.8 months (HR 0.61), and PFS from 2.4 to 5.6 months (HR 0.44) with the addition of Bevacizumab to TAS 102. About 25% of patients did not have prior anti-VEGF therapy; unclear if there was any difference in magnitude of benefit for those receiving prior anti-VEGF vs those who did not receive prior anti-VEGF therapy. Overall, TAS102 + Bev should be established as a standard regimen in the 3rd line and beyond setting for mCRC.

1. SUNLIGHT trial showing Lonsurf (TAS-102) plus bevacizumab provides a survival advantage in 3rd line colorectal cancer treatment.
2. Phase 1 trial of botensilimab/balstilimab (“bot/bal”) in MSS colorectal cancer – this is a subgroup that has been almost impossible to see any response to immunotherapy, so this is a very promising regimen to move forward to phase 3 trials.
3. Dawson et al. with 8 Gy x 1 whole liver radiation to patients with HCC or liver mets who have pain, prior to proceeding with best supportive care. This showed a survival and QOL advantage and I think shows a role for liver radiation prior to referral to hospice.

1. SPOTLIGHT – the benefits of adding zolbetuximab to mFOLFOX6 for claudin 18.2+ G/GEJ adenocarcinoma underscored the need to test for his biomarker as part of a fully informed approach to upper GI malignancy, including her2, PDL1, MMR, and FGFR2
2. MOUNTAINEER-03 – the accelerated FDA approval for a her2-directed therapy (tucatinib + trastuzumab) in colon cancer emphasizes the importance of “making every cancer a rare cancer”, i.e. splitting highly prevalent malignancies into smaller, more actionable subgroups
3. SWOG-1815 – it’s important to acknowledge when a long-awaited trial is negative; despite high hopes, the triplet of gemcitabine/cisplatin/nab-paclitaxel did not demonstrate significant survival benefit over the gemcitabine/cisplatin doublet that we have long used as a backbone in biliary tract cancer; that said, BTC remains the example par excellence of the GI cancer that benefits from next-generation sequencing to surface targetable mutations.

1. Canadian Cancer Trials Group HE.1: A phase III study of palliative radiotherapy for symptomatic hepatocellular carcinoma and liver metastases.

This multi-center, phase III trial randomized patients with painful hepatocellular carcinoma (HCC) or liver metastases (LM) 1:1 to BSC alone or with single fraction RT (8 Gy) to whole liver or near whole liver. The results showed that a single fraction RT improves hepatic pain in the majority of patients with end-stage HCC or liver metastases, with a trend to improved survival.

1. Celiac plexus radiosurgery for pain management in advanced cancer: An international phase II trial, health-related quality of life (HRQOL) outcomes.

The results showed that celiac plexus SBRT with 24 Gy in 1 fraction decreases pain and opioid use amongst patients with pancreatic cancer and other tumors invading the celiac axis. The treatment appears to improve HRQOL.

1. Long-term results from NRG-GI002: A phase II clinical trial platform using total neoadjuvant therapy (TNT) in locally advanced rectal cancer (LARC)

This 3-arm phase II trial demonstrated that pembrolizumab but not veliparib, when added to TNT, was associated with improved 3-year overall survival but not DFS.

1. NRG/RTOG 1112. This was also presented at 2022 ASTRO (discussion posted here).