New ADCs Join NCCN Guidelines for Gynecologic Cancers Representing Step Forward

Antibody-drug conjugates (ADCs) are playing a larger role in the treatment of gynecologic cancer and new updates have been published regarding agents such as fam-trastuzumab deruxtecan-nxki (Enhertu, T-DXd) and mirvetuximab soravtansine-gynx (Elahere). These agents have introduced excitement and challenges too, according to Stephanie Gaillard, MD, PhD. Gaillard, who is a member of the Cervical and Uterine Cancer NCCN Guidelines Panel, noted that because the approvals require testing for specific molecular markers, challenges can present regarding tissue testing.

“The biggest change that we’ve seen in the past couple of years, and in particular this year, has been [with] the era of ADCs. We’re seeing some great responses to these therapies, longer durations of benefit, and multiple different drugs are available,” Gaillard said in an interview with OncLive®. “There’s mirvetuximab soravtansine for folate receptor alpha (FOLR1/FRα)-positive ovarian cancer, tisotumab vedotin-tftv [Tivdak] for cervical cancer, and T-DXd for any cancer that has high expression of HER2. Those have come to the fore and made it into the NCCN guidelines.”

The Most Notable NCCN Revisions in Ovarian Cancer1:

• For epithelial ovarian (including less common ovarian cancer)/fallopian tube/primary peritoneal cancer:

• Acceptable recurrence therapies:
  • Repotrectinib (Augtyro) was added to useful in certain circumstances regimens for those with NTRK fusion-positive tumors.
  • Preferred regimens, targeted therapy (single agents), were modified:
    • Mirvetuximab soravtansine was noted to be for those with FRα–expressing tumors (at least 75% positive tumor cells; category 1).
• Recurrence therapy for platinum-sensitive disease:
  • Mirvetuximab soravtansine/bevacizumab (Avastin) was added under useful in certain circumstances for FRα-expressing tumors (category 2B).
• Recurrence therapy for platinum-resistant disease:
  • Oral cyclophosphamide/pembrolizumab (Keytruda)/bevacizumab was added under other recommended regimens (category 2A).
  • T-DXd was added for HER2-positive tumors (immunohistochemistry [IHC] 3+ or 2+) under useful in certain circumstances (category 2A).
  • Mirvetuximab soravtansine/bevacizumab changed from a category 2B to a category 2A recommendation for FRα-expressing tumors.

• For stage II, III, and IV disease maintenance therapy:
  • Bevacizumab plus niraparib (Zejula) was added as a recommendation if patients cannot tolerate olaparib (Lynparza; category 2A).
• For grade 1 endometrioid carcinoma, low-grade serous carcinoma, and malignant germ cell/sex cord-stromal tumors:
  • Goserelin acetate was added as an option for hormonal therapy for patients with stage IC and stage II to IV disease.
• For low-grade serous carcinoma that is stage IC and stage II to IV:
  • Maintenance letrozole changed from a category 2B to a category 2A recommendation.
  • Tamoxifen was removed as a hormonal therapy option for low-grade serous carcinoma only.
• For the adjuvant treatment of stage II to IV malignant sex cord-stromal tumors:
  • Platinum-based chemotherapy changed from a category 2B to a category 2A recommendation.
• For primary therapy for stage I epithelial ovarian/fallopian tube/primary peritoneal diseases:
  • Paclitaxel/cisplatin was added under useful in certain circumstances (and also for stage II to IV disease; category 2A).
  • Docetaxel/oxaliplatin/bevacizumab plus maintenance bevacizumab was removed as a treatment option.
• For primary therapy for stage II to IV high-grade serous, endometrioid (grade 2/3), clear cell carcinoma, carcinosarcoma:
  • Intravenous/intraperitoneal paclitaxel/carboplatin was added as a recommendation under useful in certain circumstances (category 2A).

The Most Notable NCCN Revisions in Cervical Cancer2:

1. For patients with FIGO stage III to IVA disease:
   1. Pembrolizumab may be added to chemoradiation.
2. For local/regional recurrence, therapy for relapse:
   1. The no prior radiation therapy or failure outside of previously treated field pathway was revised to note individualizedexternal beam radiation therapy (EBRT) plus concurrent platinum-containing chemotherapy with or without brachytherapy should be given.
   2. For patients who received prior radiation therapy and have central disease:
      1. Individualized EBRT with or without concurrent platinum-containing chemotherapy was added as an option.
   3. For patients who received prior radiation therapy and have noncentral disease:
      1. A revision was made for individualized EBRT to be given with or without concurrent platinum-containing chemotherapy rather than systemic therapy.
      2. Best supportive care was added as an option.
3. For systemic therapy for cervical cancer that is squamous cell carcinoma, adenocarcinoma, or adenosquamous carcinoma:
   1. A new section was added under chemoradiation with the following as other recommended regimens if cisplatin and carboplatin are unavailable:
      1. Capecitabine/mitomycin
      2. Gemcitabine
      3. Paclitaxel
   2. For second-line or subsequent therapy of recurrent or metastatic disease:
      1. Cemiplimab-rwlc (Libtayo) was added as a preferred regimen.
      2. Irinotecan changed from a category 2B to a category 2A other recommended regimen.
      3. T-DXd was added as useful in certain circumstances for those with HER2-positive tumors (IHC 3+ or 2+).
      4. Single-agent larotrectinib (Vitrakvi) and entrectinib (Rozlytrek) changed from category 2B to category 2A useful in certain circumstances recommendations for NTRK fusion-positive tumors.
4. For second-line or subsequent therapy of recurrent or metastatic small cell neuroendocrine carcinoma of the cervix:
   1. Irinotecan changed from a category 2B to a category 2A other recommended regimen.

In the interview, Gaillard detailed NCCN guideline updates for cervical, uterine, and ovarian cancers and highlighted challenges when determining treatment eligibility with molecular markers. Gaillard is the director of gynecologic cancer trials, codirector of the Development Therapeutics/Phase I Clinical Trials Program, and an associate professor of oncology at Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins in Baltimore, Maryland.

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

Gaillard: [Something] that was included in the [cervical cancer] NCCN guidelines this year was the addition of other recommended regimens for chemoradiation if the preferred chemotherapy is not available. With the shortages in chemotherapy recently, particularly cisplatin and carboplatin, we needed to think about alternatives when those were in short supply. [That was an] important change that went into the NCCN guidelines.

One of the recent exciting updates to the [footnotes of the] cervical cancer guidelines has been the addition of pembrolizumab with chemoradiation for patients with stage III to IVA disease based on FIGO 2014 staging. However, since the staging system used for the phase 3 KEYNOTE-A18 study [NCT04221945] was FIGO 2014 and it’s not the staging system that’s currently in use by pathologists, making that conversion to determine whether a patient is eligible to receive pembrolizumab in combination with chemotherapy can be a challenge.

Have you faced any challenges in integrating these changes into your practice?

One of the things that is challenging with some of the ADCs is the requirement for a particular molecular profile to be eligible for the treatment. For example, to be eligible for mirvetuximab soravtansine the tumor tissue has to test positive on the companion diagnostic test for FOLR1 and for T-DXd it needs to have an elevated level of HER2 expression by IHC. Because testing for these markers is new and not yet integrated into standard pathology evaluations, we’re often having to go back to the tumor tissue and request additional assessments. Then the question is, should we test the original tumor or obtain a new biopsy? Also, the length of time it may take to test the tissue can be a problem when trying to make quick treatment decisions for patients.

How do you communicate guideline changes to your patients when they are receiving treatment?

It depends on the situation. If the recommendation is immediately relevant, for example if it changes the patient’s current treatment plan, I would bring it up as soon as possible; I would have them [come to] clinic [to] discuss the pros and cons of the recommendation and how it influences their current treatment plan. Oftentimes, the recommendations will not immediately impact them but [may] change a future plan for treatment. [Therefore], I may bring it up when we’re closer to needing to make that decision. Sometimes patients have heard about the update or the new therapeutic option and are asking [me about] it—then I’ll tell them where it fits into that anticipated future plan.

What advancements are you looking forward to seeing in the future for patients with gynecologic malignancies?

There are a lot of exciting clinical trials being performed right now for patients with gynecologic cancers, and we’re excited to see what the future holds in terms of treatment options. There’s a big emphasis right now on studies with ADCs, immunotherapies, [and] other targeted therapies, and hopefully we’ll continue to be able to move away from the traditional approaches that we’ve taken in the past.

References

1. NCCN. Clinical Practice Guidelines in Oncology. Ovarian cancer including fallopian tube cancer and primary peritoneal cancer, version 3.2024. Accessed November 20, 2024. https://www.nccn.org/professionals/physician_gls/pdf/ovarian.pdf
2. NCCN. Clinical Practice Guidelines in Oncology. Cervical cancer, version 4.2024. Accessed November 20, 2024. https://www.nccn.org/professionals/physician_gls/pdf/cervical.pdf