Targeted Therapies Represent Core 2024 NCCN GI Cancer Guideline Advancements

Alan P. Venook, MD

Ushering more targeted therapies into the 2024 updates to the NCCN Clinical Practice Guidelines in Oncology for biliary tract cancers represented a notable advancement in the gastrointestinal (GI) cancer space, and new guideline specifications are coming for additional GI cancers, according to Alan P. Venook, MD. Venook, who is vice chair of the colon cancer and rectal cancer NCCN guidelines, and member of the biliary tract cancers NCCN guidelines, added that an appendix cancer guideline will be released shortly. He also highlighted that more clearly separating out certain diseases, such as gallbladder cancer from bile duct cancer from intrahepatic vs extrahepatic bile duct cancer are key upcoming changes as well.

“Our field in general, has been a bit slow with developments,” Venook said in an interview with OncLive®. “People should look for the appendix cancer guideline and that’ll be out in the next month or two. Creating a new guideline is a lot of effort, and we’ve been working on it for almost a year.”

The Most Notable 2024 NCCN Guideline Revisions in Rectal and Colon Cancers:^1,2

• The “Principles of Surgery” section has been extensively revised and renamed to “Principles of Surgery and Locoregional Therapies.”
  • Subsections were added under locoregional therapies:
    • Image-guided tumor ablation
    • Liver tumor ablation
    • Lung tumor ablation
    • Arterially directed embolic therapy
      • Hepatic transarterial radioembolization with yttrium-90 microspheres
      • Transarterial chemoembolization
    • External beam radiation therapy
    • Hepatic arterial infusion
• For the continuum of care with systemic therapy for advanced or metastatic disease that ismismatch repair–proficient (pMMR)/microsatellite stable (MSS), [or for mismatch repair–deficient (dMMR)/microsatellite instability–high (MSI-H]) or for a patient with a POLE/POLD1 mutation who is ineligible for or progressed on checkpoint inhibitor immunotherapy:
  • For second-line and subsequent therapy options (if not previously given):
    • Repotrectinib (Augtyro) was added (category 2A) for NTRK-positive tumors
  • The following regimens were added as second-line and subsequent therapy options (if not previously given) for those with KRAS/NRAS/BRAF wild-type disease who received previous therapy without oxaliplatin or irinotecan:
    • FOLFIRI (leucovorin, fluorouracil, and irinotecan) plus cetuximab (Erbitux) or panitumumab (Vectibix)
    • Cetuximab or panitumumab with or without irinotecan

Additional Notable 2024 NCCN Guideline Revisions in Colon Cancer:¹

• For the primary treatment of stage T1, N0 disease, endoscopic submucosal dissection was added as a treatment option
• For pMMR/MSS resectable synchronous liver-only and/or lung-only metastases:
  • The page was extensively revised by removing circumferential resection margin (CRM) and separating into 2 options: pathway with chemotherapy only, optional radiation therapy, and pathway with chemotherapy plus radiation therapy
• For dMMR/MSI-H resectable synchronous liver-only and/or lung-only metastases:
  • The page was extensively revised by removing CRM and creating one pathway for neoadjuvant treatment

The Most Notable 2024 NCCN Guideline Revisions in Biliary Tract Cancers:³

• For the primary treatment for unresectable and metastatic disease and subsequent-line therapy if disease progression occurs:
  • Repotrectinib was added (category 2A) for NTRK-positive disease
• For subsequent-line therapy if disease progression occurs:
  • Fam-trastuzumab deruxtecan-nxki (Enhertu) was added (category 2A) for HER2-positive (IHC 3+) tumors
• Fluoropyrimidine-based chemoradiation was reworded as chemoradiation in several sections
• The following other recommended regimens for systemic therapy were removed:
  • FOLFOX (fluorouracil, leucovorin, and oxaliplatin; also for adjuvant therapy)
  • Capecitabine plus oxaliplatin (also for adjuvant therapy)
  • Gemcitabine plus capecitabine
  • Gemcitabine plus cisplatin (also for adjuvant therapy)
  • Durvalumab (Imfinzi) plus gemcitabine and cisplatin
  • Gemcitabine plus cisplatin and albumin-bound paclitaxel (category 2B)
• For other recommended regimens for adjuvant therapy, capecitabine plus cisplatin (category 3) was removed
• For the primary treatment of unresectable and metastatic disease with systemic therapy:
  • Gemcitabine plus cisplatin and albumin-bound paclitaxel was removed from other recommended regimens (category 2B)
  • For subsequent-line therapy if disease progression occurs:
    • FOLFIRI changed from a category 2B to a category 2A recommendation
    • Lenvatinib (Lenvima) plus pembrolizumab (Keytruda) was removed from useful in certain circumstances (category 2B)
• For the subsequent-line treatment of unresectable and metastatic disease with targeted therapy if disease progression occurs:
  • Tucatinib (Tukysa) plus trastuzumab (Herceptin) was added for HER2-positive tumors (category 2A)
  • Adagrasib (Krazati) was added for KRAS G12C mutation-positive tumors (category 2A)

In the interview, Venook described challenges with implementing NCCN guidelines into practice in rectal, colon, and biliary tract cancers, as well as advancements in these areas from 2024. He is the Madden Family Distinguished Professorship in Medical Oncology and Translational Research at UCSF, the Shorenstein Associate Director for Program Development at the Helen Diller Family Comprehensive Cancer Center, and a professor in the Department of Medicine at UCSF in San Francisco, California.

Venook also provided insights on NCCN guideline updates in hepatocellular carcinoma (HCC) and next steps in the field in a concurrent article. He is a member of the HCC NCCN guideline panel.

OncLive: What 2024 NCCN guideline updates in biliary tract cancer have had an immediate influence on how you practice?

Biliary tract cancer is a little different [than other tumor types]. For years we had no tissue banks because it’s very hard to collect tissue in these patients. Once we did [collect tissue], we figured out that there are a couple of mutations that can be targeted and that’s very exciting. Over the past couple of years, we’ve added IDH1 inhibitors as well as FGFR fusion inhibitors. There are a couple of targeted therapies that work in biliary tract cancer and that’s exciting news.

The other thing that the guidelines are doing is trying to separate out more clearly gallbladder cancer from bile duct cancer from intrahepatic vs extrahepatic bile duct cancer. Historically, we’ve lumped them together and we now know that they should be separated.

What were notable 2024 NCCN guideline revisions in colon cancer?

In colorectal cancer [CRC], we’re creating a new guideline for appendix cancer. It’s a lot of effort to create a new guideline, but we’re just now putting the finishing touches on it. It’ll be posted most likely in the next couple of months, and that’s very important because appendix cancer is a unique disease—it's perhaps the one disease that’s amenable to hyperthermic intraperitoneal chemotherapy, to tumor debulking. That’s a huge change in the guidelines for CRC. Historically, colorectal, anal, and appendix [cancers] were all lumped together, as well as small bowel. A few years ago, we created a small bowel guideline, and now we’re creating an appendix guideline.

Have you faced any challenges integrating updates to guidelines in your practice?

The challenge is always, are we ahead of the insurers? It’s a bit of a chicken-and-egg [situation]. The guidelines are to a great extent the metric that insurers use in determining what they cover, and if we happen to be ahead of the insurers [issues can occur]. For example, last year, there were a couple of advances in rectal cancer where we learned that not every [patient] needs surgery [and] not every [patient] needs radiation—2 studies came out [showing that]. Therefore, we changed the frequency of MRI follow-up for these patients because we have to monitor them very closely. Some insurers weren’t up to speed on that, even though we changed the guidelines, and some practitioners couldn’t get insurance coverage of the MRI because the insurers were not caught up on the guidelines.

I can’t emphasize enough how these are living documents and how rapidly they can change. Our goal is to stay on top of it and stay ahead. After all, if there are advances and we’re not getting them out to patients, we’re not helping. That’s what our emphasis has been on.

How do you communicate guideline changes to your patients who are currently receiving treatment?

Rarely do they have an impact [but] one of the challenges is a spin-off of that question: What do you do when you know that there’s a change coming in the guidelines, but it’s not public yet, and the patient presents to you when you know the change might be applicable to them? That’s an ethical challenge. Let’s say it’s not for public consumption, but if I know [something] and need my colleagues to understand why I’m making a decision or in a tumor board [scenario], [the question of] how you deal with proprietary information [comes into play].

My view is I default to doing what I think is best for the patient, but it’s dicey trying to be careful about maintaining confidentiality on some of these [updates]. It’s more important that patients be given the best options if I think there’s a development that, even if it’s not public yet, the guidelines demonstrate should be used. It can be an ethical predicament.

References

1. NCCN. Clinical Practice Guidelines in Oncology. Colon cancer, version 5.2024. Accessed November 18, 2024. https://www.nccn.org/professionals/physician_gls/pdf/colon.pdf
2. NCCN. Clinical Practice Guidelines in Oncology. Rectal cancer, version 4.2024. Accessed November 18, 2024. https://www.nccn.org/professionals/physician_gls/pdf/rectal.pdf
3. NCCN. Clinical Practice Guidelines in Oncology. Biliary tract cancers, version 4.2024. Accessed November 18, 2024. https://www.nccn.org/professionals/physician_gls/pdf/btc.pdf