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GI Cancers FAQ
Experts Discuss Key Questions in Treating Advanced GI Cancers

Released: March 21, 2023

Christopher H. Lieu
Christopher H. Lieu, MD
John Marshall
John Marshall, MD
Manish Shah
Manish Shah, MD
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Key Takeaways
  • Specific patients with advanced HER2-positive gastric cancer may benefit from a triplet regimen of pembrolizumab, trastuzumab, and chemotherapy.
  • Tucatinib was approved recently in combination with trastuzumab for RAS wild-type, HER2-positive unresectable or metastatic colorectal cancer that has progressed following treatment with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy.
  • Zolbetuximab is an investigational antibody to Claudin 18.2 that appears to improve outcomes when combined with chemotherapy in patients with advanced Claudin 18.2–positive, HER2-negative gastric/gastroesophageal junction cancers.

In this commentary adapted from a live satellite symposium at the 2023 American Society of Clinical Oncology Gastrointestinal Cancers Symposium, Christopher H. Lieu, MD; John L. Marshall, MD; and Manish Shah, MD, address key questions on the management of colorectal cancer (CRC), gastric cancer/gastroesophageal junction (GEJ) cancer, and pancreatic cancer.

How do you manage patients with HER2-positive metastatic CRC?

John L. Marshall, MD:
I had a 66-year-old female patient diagnosed with stage II rectosigmoid colon cancer 4 years ago who received surgery. She was given no adjuvant therapy and was lost to follow-up during the pandemic. When she returned to the clinic with weight loss, a CT scan showed small, bilateral lung lesions and peritoneal lesions. The biopsy was positive for adenocarcinoma. Of importance, the tumor was microsatellite stable (MSS) and RAS/RAF wild-type but HER2 positive (3+).

Christopher H. Lieu, MD:
MSS is important because it has ramifications for immunotherapy. When I see a patient with wild-type RAS and RAF, I know to look for HER2 amplification, as this is more observed commonly in this population and has treatment implications.

John L. Marshall, MD:
This patient with HER2-amplified metastatic CRC received first-line capecitabine plus oxaliplatin and bevacizumab, which she tolerated poorly. She was switched to capecitabine and bevacizumab but eventually progressed with new liver lesions.

Christopher H. Lieu, MD:
One option that might be considered for her that recently received accelerated approval by the FDA would be the combination of tucatinib and trastuzumab. The global, open-label phase II MOUNTAINEER trial evaluated the efficacy and safety of tucatinib in combination with trastuzumab in 84 patients with HER2-positive, RAS wild-type, chemotherapy-refractory metastatic CRC. In results presented at the 2022 European Society for Medical Oncology World Congress on Gastrointestinal Cancer, the overall response rate (ORR) in this heavily pretreated population was nearly 40%, with an impressive median progression-free survival (PFS) of 8 months and a median overall survival (OS) of 24 months. Based on this, tucatinib, a selective tyrosine kinase inhibitor of HER2, received accelerated FDA approval in combination with trastuzumab for the treatment of adult patients with RAS wild-type, HER2-positive unresectable or metastatic CRC that has progressed following treatment with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy. Other guideline-listed options for previously treated, RAS wild-type, HER2-positive advanced CRC include trastuzumab plus pertuzumab or lapatinib or trastuzumab deruxtecan.

Dr Marshall, the case patient did not do well on her first-line treatment. How do you sequence therapy in patients like this?

John L. Marshall, MD:
This patient case was from my practice. I was not excited about irinotecan as second-line therapy; in terms of tolerance and efficacy, the numbers you showed for tucatinib and trastuzumab were better than one might expect for FOLFIRI. Of note, I would not consider EGFR-targeted therapy in a patient with HER2-positive CRC. So, I certainly would consider HER2-targeted therapy for this patient.

Manish Shah, MD:
Physicians should remember that if a targeted approach like this does not work, they can fall back on previous standards of care such as FOLFIRI plus cetuximab.

Christopher H. Lieu, MD:
Dr Shah, would you ever consider trastuzumab deruxtecan (T-DXd) for a patient with HER2-low metastatic CRC?

Manish Shah, MD:
T-DXd is a novel antibody–drug conjugate that comprises a humanized anti-HER2 monoclonal antibody (with the same amino acid sequence as trastuzumab) linked to a topoisomerase I inhibitor payload. One phase II study of T-DXd in colon cancer has included patients with HER2-low disease. Unfortunately, the efficacy in HER2-low metastatic CRC was lower than that observed in advanced HER2-low breast cancer. In my opinion, to use T-DXd in gastrointestinal (GI) cancers, the tumor should be strongly HER2 positive (immunohistochemistry [IHC] 3+ or 2+).

How do you manage patients with HER2-positive advanced gastric cancer?

Manish Shah, MD:
Let’s look at a case. I had a 57-year-old man present with progressive dysphagia and a 15-pound weight loss who eventually was diagnosed with an invasive, moderately differentiated GEJ adenocarcinoma. A biopsy showed the tumor to be mismatch repair (MMR) proficient and strongly HER2 positive (IHC 3+). We treated him with chemoradiotherapy plus surgery, and he achieved a pathologic complete response (pCR). However, as is the case with 5% to 7% of patients, despite his pCR, he recurred with a 2-cm liver lesion. A biopsy confirmed the lesion was metastatic adenocarcinoma, consistent with his primary esophageal cancer, including similar molecular profiling with HER2 positivity (IHC 3+) and MMR proficiency. The PD-L1 combined positive score was 10.

We chose to treat him with first-line pembrolizumab, trastuzumab, and chemotherapy based on results from the practice-changing KEYNOTE-811 study. KEYNOTE-811 was a randomized phase III trial of trastuzumab plus chemotherapy (either 5-fluorouracil/cisplatin or oxaliplatin and capecitabine) with either placebo or pembrolizumab for 264 patients with HER2-positive advanced gastric or GEJ adenocarcinoma and no prior treatment for advanced disease. Results showed a remarkable ORR of 74% in the pembrolizumab arm vs 52% with placebo, which led to FDA accelerated approval of the triplet in this setting.

The case patient did have a strong response but ultimately progressed. A repeat biopsy showed the tumor remained HER2 positive (IHC 3+). We chose to treat him with T-DXd, which is now approved by the FDA for second-line use after prior trastuzumab in advanced gastric or GEJ cancers based on the phase II DESTINY-Gastric01 study. In this trial, 188 patients with HER2-positive locally advanced/metastatic gastric or GEJ cancer with progressive disease on at least 2 previous regimens were randomized to receive T-DXd or physician’s choice of chemotherapy (irinotecan or paclitaxel). In terms of efficacy, the response rate and survival were remarkable for later-line treatment of advanced gastric/GEJ cancer. The ORR was 51% with T-DXd vs 14% with chemotherapy; correspondingly, median OS was 12.5 months vs 8.9 months, respectively.

Dr Marshall, given that approximately one quarter of patients will lose their HER2 expression after first-line HER2-targeted treatment, do you rebiopsy patients who receive trastuzumab and then progress?

John L. Marshall, MD:
Ultimately, I think we need to be retesting these patients for HER2 amplification.

Do you use olaparib as maintenance therapy in specific patients with metastatic pancreatic cancer?

Manish Shah, MD:
Yes, despite the lack of an OS benefit in the POLO trial. POLO was a randomized, double-blind phase III trial of maintenance therapy with the PARP inhibitor olaparib vs placebo in patients with metastatic pancreatic cancer and a deleterious/suspected deleterious germline BRCA1/2 mutation (N = 154). Eligible patients had undergone at least 16 weeks of first-line platinum-based therapy (mainly FOLFIRINOX) without progression. In the primary analysis of POLO, median PFS was significantly improved with olaparib maintenance therapy: 7.4 months vs 3.8 months with placebo (HR: 0.53; P = .0038). Updated data, however, showed no median OS difference between treatment groups (HR: 0.83; P = .3487).

John L. Marshall, MD:
I also use olaparib as maintenance for patients like those in POLO, and some do quite well. In my practice, if a tumor is positive for a somatic BRCA1/2 mutation, I will do germline testing. However, I would use olaparib even without the germline confirmation.

Manish Shah, MD:
Dr Marshall, what is your preferred frontline chemotherapy regimen for patients with pancreatic cancer and a BRCA1/2 mutation?

John L. Marshall, MD:
I prefer the doublet of gemcitabine plus cisplatin in this situation. I find it to be less burdensome for the patient than FOLFIRINOX administration, which involves a 2-day pump, growth factors, and more.

What are recent findings with Claudin 18.2–targeted agents in GI cancers?

Manish Shah, MD:
I am excited by the ongoing development of targeted therapies, and zolbetuximab is particularly promising. Zolbetuximab is an antibody to Claudin 18.2, a structural component of intercellular tight junctions that is not routinely expressed in most normal tissue but broadly expressed in several tumor types, including gastric/GEJ cancers. The phase II FAST study was a randomized trial of first-line zolbetuximab plus CAPOX chemotherapy in patients with advanced Claudin 18.2–positive gastric/GEJ adenocarcinoma. Results showed a median PFS of 9.0 months with zolbetuximab vs 5.7 months with chemotherapy and a median OS of 16.5 months vs 8.9 months, respectively.

At ASCO GI 2023, Shitara and colleagues presented results from the phase III SPOTLIGHT study of the addition of zolbetuximab to mFOLFOX6 in patients with previously untreated, Claudin 18.2–positive, HER2-negative advanced gastric/GEJ adenocarcinoma. Notably, 38.5% of assessable patients who were screened for this study were Claudin 18.2 positive.  Results showed that the addition of zolbetuximab to mFOLFOX6 improved both PFS and OS vs mFOLFOX6 plus placebo: Median PFS was 10.6 months vs 8.7 months, respectively, and median OS was 18.2 months vs 15.5 months. The phase III GLOW trial has similarly evaluated the addition of zolbetuximab to CAPOX in the same population, with a press release suggesting significant PFS and OS benefits with zolbetuximab. Some of the main adverse events to monitor for with zolbetuximab are nausea and vomiting; because Claudin 18.2 is expressed in the gastric epithelium, this is an on-target effect.

Because Claudin 18.2 is now a validated target, multiple drugs and drug classes (antibody–drug conjugates, including EO-3021; monoclonal and bispecific antibodies, including TST001; and CAR T‑cells, such as CT041) are being developed to target this marker.

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