NCCN Continuing Education
Target Audience: This activity is designed to meet the educational needs of oncologists, nurses, pharmacists, and other healthcare professionals who manage patients with cancer.
Accreditation Statements
In support of improving patient care, National Comprehensive Cancer Network (NCCN) is jointly accredited by the Accreditation Council for Continuing Medical Education (ACCME), the Accreditation Council for Pharmacy Education (ACPE), and the American Nurses Credentialing Center (ANCC), to provide continuing education for the healthcare team.
Physicians: NCCN designates this journal-based CME activity for a maximum of 1.0 AMA PRA Category 1 CreditTM. Physicians should claim only the credit commensurate with the extent of their participation in the activity.
Nurses: NCCN designates this educational activity for a maximum of 1.0 contact hour.
Pharmacists: NCCN designates this knowledge-based continuing education activity for 1.0 contact hour (0.1 CEUs) of continuing education credit. UAN: JA4008196-0000-23-012-H01-P
PAs: NCCN has been authorized by the American Academy of PAs (AAPA) to award AAPA Category 1 CME credit for activities planned in accordance with AAPA CME Criteria. This activity is designated for 1.0 AAPA Category 1 CME credit. Approval is valid until December 10, 2024. PAs should only claim credit commensurate with the extent of their participation.
All clinicians completing this activity will be issued a certificate of participation. To participate in this journal CE activity: (1) review the educational content; (2) take the posttest with a 66% minimum passing score and complete the evaluation at https://education.nccn.org/node/92953; and (3) view/print certificate.
Pharmacists: You must complete the posttest and evaluation within 30 days of the activity. Continuing pharmacy education credit is reported to the CPE Monitor once you have completed the posttest and evaluation and claimed your credits. Before completing these requirements, be sure your NCCN profile has been updated with your NAPB e-profile ID and date of birth. Your credit cannot be reported without this information. If you have any questions, please email education@nccn.org.
Release date: December 10, 2023; Expiration date:December 10, 2024
Learning Objectives:
Upon completion of this activity, participants will be able to:
• Integrate into professional practice the updates to the NCCN Guidelines for Cervical Cancer
• Describe the rationale behind the decision-making process for developing the NCCN Guidelines for Cervical Cancer
Disclosure of Relevant Financial Relationships
None of the planners for this educational activity have relevant financial relationship(s) to disclose with ineligible companies whose primary business is producing, marketing, selling, reselling, or distributing healthcare products used by or on patients.
Individuals Who Provided Content Development and/or Authorship Assistance:
The faculty listed below have no relevant financial relationship(s) with ineligible companies to disclose.
Catheryn M. Yashar, MD, Panel Vice Chair
Nicole R. McMillian, MS, CHES, Senior Guidelines Coordinator, NCCN
Shaili Aggarwal, PhD, Oncology Scientist/Medical Writer, NCCN
Sara Espinosa, PhD, Oncology Scientist, Medical Writer
The faculty listed below have the following relevant financial relationship(s) with ineligible companies to disclose. All of the relevant financial relationships listed for these individuals have been mitigated.
Nadeem R. Abu-Rustum, MD, Panel Chair, has disclosed receiving grant/research support from GRAIL.
To view all of the conflicts of interest for the NCCN Guidelines panel, go to NCCN.org/guidelines/guidelines-panels-and-disclosure/disclosure-panels
This activity is supported by educational grants from AstraZeneca; Exact Sciences; Novartis; and Taiho Oncology, Inc. This activity is supported by an independent educational grant from Daiichi Sankyo. This activity is supported by independent medical education grants from Illumina, Inc. and Regeneron Pharmaceuticals, Inc.
Overview
An estimated 13,960 new cases of carcinoma of the uterine cervix (ie, cervical cancer) will be diagnosed in the United States in 2023, and an estimated 4,310 people will die of the disease.1 Overall, cervical cancer rates are decreasing in the United States, although incidence remains high among Hispanic/Latino, Black, and Asian populations.2–5 In 2020, the global new cases of and deaths from cervical cancer were estimated to be 604,127 and 341,831, respectively.6 It is the fourth most common cancer in individuals assigned female at birth worldwide,7,8 with 85% of cases occurring in developing countries, where cervical cancer is a leading cause of cancer death in individuals assigned female at birth.6,9 Squamous cell carcinoma (SCC), adenocarcinoma (AC), and adenosquamous carcinoma (ASC) are the 3 common histologies of cervical cancer. SCC accounts for approximately 80% of all cervical cancers and AC accounts for approximately 20%. In developed countries, the substantial decline in incidence and mortality of SCC of the cervix is presumed to be the result of effective screening and higher HPV vaccination coverage, although racial, ethnic, and geographic disparities exist.2,3,10–12 However, AC and ASC of the cervix have increased over the past 3 decades, probably because cervical cytologic screening methods are less effective for AC/ASC because the lesions are located deeper than the ectocervix.13–17 The ASC subtype is rare and accounts for approximately 5% to 6% of all cervical carcinomas. Presently, there is no difference in treatment between SCC and AC/ASC cervical cancer subtypes, although the clinical features and prognosis of disease vary considerably between these subtypes.
Persistent HPV infection is a major factor in the development of cervical cancer.18,19 The incidence of cervical cancer appears to be related to the prevalence of HPV in the population. In countries with a high incidence of cervical cancer, the prevalence of chronic HPV is approximately 10% to 20%, whereas in low-incidence countries it is 5% to 10%.7 Screening methods using HPV testing may increase detection of adenocarcinoma. Vaccination with HPV vaccines may also decrease the incidence of both SCC and AC.15,20 Although most studies report that most cervical cancers are caused by HPV, approximately 5% of the tumors are reported as HPV-independent tumors.21,22 In 2020, the WHO updated the Female Genital Tumors classification of cervical cancer by subdividing the cervical cancer lesions into HPV-associated and HPV-independent tumors based on new pathologic findings.23 Among these subtypes, HPV-associated SCC is the most prevalent, with very rare occurrences of HPV-independent SCC. The HPV-independent AC subtype has a less favorable prognosis compared with HPV-associated AC. The NCCN Cervical Cancer Panel acknowledges that although the prior versions of the WHO classification discussed these tumors based on morphologic features, the integration of the immunohistochemical and molecular profiles has led to a better classification system, which is now adapted in the 2020 WHO Classification of Female Genital Tumors for cervical cancer.23
Regardless of cancer subtype and HPV infection status, primary treatment with curative intent for patients with cervical cancer typically consists of surgery, chemoradiation, or a combination of these treatments; options vary by cancer stage. These NCCN Guidelines Insights highlight the recent updates to the systemic therapy options for the treatment of cervical cancer.
Systemic Therapy Recommendations for Cervical Cancer
Chemoradiation for Locally Advanced Cervical Cancer
Concurrent chemoradiation, using platinum-containing chemotherapy (cisplatin alone [preferred] or cisplatin/fluorouracil), is the treatment of choice for stages IB3, II, III, and IVA disease based on the results of randomized clinical trials.24–29 These trials have shown that the use of concurrent chemoradiation results in a 30% to 50% decrease in the risk of death compared with radiotherapy (RT) alone. Long-term follow-up of 3 trials has confirmed that concurrent cisplatin-containing chemoradiation improves progression-free survival (PFS) and overall survival (OS) when compared with RT with (or without) hydroxyurea.30–32 In the NCCN Guidelines, cisplatin remains the preferred radiosensitizing agent in the primary treatment of patients with locally advanced cervical cancer when used concomitantly with external-beam RT. The guidelines recommend carboplatin as a preferred radiosensitizing agent for patients who are cisplatin-intolerant.33 The NCCN Cervical Cancer Panel recently included alternative radiosensitizing agents that could be considered for use only when cisplatin and carboplatin are unavailable (see CERV-F 1 of 3, above). The options of capecitabine/mitomycin, gemcitabine, and paclitaxel were added under “Other Recommended Regimens” as radiosensitizers based on a few early-phase studies that have shown their efficacy and tolerability when administered concomitantly with radiation.34–36
A phase III randomized trial enrolling 926 patients with locally advanced cervical cancer of stage II–IVA evaluated the efficacy of RT + concurrent chemotherapy consisting of oral 5-fluorouracil/mitomycin compared with RT only, RT + adjuvant chemotherapy (5-fluorouracil), or RT + concurrent chemoradiotherapy + adjuvant chemotherapy.34 Although acute side effects were more prevalent in the concurrent arm and the OS was not significant between the arms, the RT + concurrent chemotherapy arm showed the least locoregional recurrence and the highest 5-year disease-free survival (DFS) when compared with the other arms. In particular, the differences in DFS and OS rates were highly significant when comparing the concurrent chemoradiation arm with the RT-only arm (P=.0001). Several studies have shown that although 5-fluorouracil/mitomycin combined with RT was effective, the combination is also associated with relatively higher toxicity rates and should be used with caution.37,38 The efficacy and safety of gemcitabine combined with pelvic radiation was tested in 19 patients with chemotherapy-naïve, advanced stage IIIB cervical cancer and showed a complete response (CR) of 89.5% and partial response (PR) of 5.3%, for an overall response rate (ORR) of 94.7%. The OS at a median follow-up time of 19.9 months was 100%, with a DFS of 84.2%. Due to gemcitabine’s high potency as a radiosensitizer, it requires reduced dosing when used concurrently with radiation to avoid radiation toxicity.35 In a comparative study, the disease control and toxicity profile were found to be similar between cisplatin and gemcitabine.39 The benefit of paclitaxel alone as a radiosensitizer has not been extensively studied in the literature and there are only a few known preclinical or early-phase studies of its efficacy. In a pilot study to evaluate paclitaxel with RT, CR was achieved by 8 of 13 patients with locally advanced cervical cancer and by 4 of 6 patients treated with a recurrent disease.40 Although chemoradiation is tolerated, acute and long-term side effects have been reported.41–43 Due to significant toxicity concerns associated with these agents, the panel continues to prefer cisplatin or carboplatin as preferred agents over other nonplatinum chemoradiation regimens. The NCCN panel has noted for all chemoradiation agents that the cost and toxicity profiles of these radiosensitizing agents should be considered when selecting an appropriate regimen for treatment, and has strongly expressed that this is especially critical when these regimens are being used for extended-field RT where toxicities may be more severe (CERV-F 1A of 3, page 1228).
First-Line Systemic Therapy Options for Recurrent or Metastatic Cervical Cancer
The estimated 5-year survival rate for patients with early-stage cervical cancer is >90%, whereas the curative options for advanced-stage disease are limited.44 Systemic therapy with or without radiation forms the basis of treatment for patients with recurrent or metastatic disease.
Chemotherapy as First-Line Therapy
Cisplatin has been considered the most effective agent for metastatic cervical cancer. However, most patients who develop metastatic disease have received concurrent cisplatin/RT as primary treatment and may no longer be sensitive to single-agent platinum therapy.45,46 The combination of platinum-based chemotherapy (cisplatin or carboplatin)/paclitaxel/bevacizumab has been extensively investigated in clinical studies, and these combinations are among the preferred, first-line treatment options for patients with recurrent/metastatic cervical cancer in the NCCN Guidelines. In addition, the panel has continued to recommend other platinum-containing combination regimens, such as cisplatin/paclitaxel (category 1), carboplatin/paclitaxel (category 1), topotecan/paclitaxel/bevacizumab (category 1), topotecan/paclitaxel, and cisplatin/topotecan as appropriate alternate options for certain patients in the “Other Recommended Regimens” category.45–50 The panel also recommends single-agent cisplatin and carboplatin as other recommended regimens. In previous versions of the guidelines, cisplatin appeared in the “Preferred, First-Line Single-Agent” category. However, based on the panel’s clinical judgement, as more effective treatment options are increasingly being available in the first-line setting, platinum-based single-agent chemotherapy has been reserved as alternate options under “Other Recommended Regimens.”
Pembrolizumab Plus Chemotherapy With or Without Bevacizumab as First-Line Therapy
Over the years, systemic therapy options for cervical cancer have undergone a paradigm shift due to the growing number of newer treatment options available with meaningful improvement in survival rates. In addition, because the importance of testing for the presence of certain biomarkers in advanced disease is well recognized, the availability of several agents targeting these specific biomarkers has led to improved outcomes in patients. Several new biomarker-based immune-oncologic agents have been added to the guidelines for the management of recurrent/metastatic cervical cancer in recent years. Currently, the guidelines include 2 immunotherapy-based regimens as preferred, first-line therapy options for the treatment of PD-L1–positive recurrent or metastatic cervical cancer. Pembrolizumab combined with chemotherapy, with or without bevacizumab, is the preferred, category 1 treatment option based on the results of the KEYNOTE-826 study.51 In the primary analysis of the phase III KEYNOTE-826 trial, which enrolled 617 patients (548 with PD-L1–positive combined positive score [CPS] ≥1 tumors; 317 with CPS ≥10) with previously untreated persistent, recurrent, or metastatic cervical cancer, the addition of pembrolizumab to chemotherapy with or without bevacizumab improved PFS and OS compared with the placebo group (PFS: 10.4 vs 8.2 months, respectively; hazard ratio [HR], 0.65; 95% CI, 0.53–0.79; P<.001, and OS at 24 months: 50.4% vs 40.4%, respectively; HR, 0.67; 95% CI, 0.54–0.84; P<.001). The ORR was significantly higher in the pembrolizumab arm compared with the placebo group among the patients with PD-L1–positive (CPS ≥1) tumors (68.1% vs 50.2%). Based on the results of the KEYNOTE-826 trial, the FDA approved pembrolizumab in combination with chemotherapy, with or without bevacizumab, for patients with persistent, recurrent, or metastatic cervical cancer whose tumors express PD-L1 (CPS ≥1). In the final, updated analysis of the trial presented at the 2023 ASCO Annual Meeting, the addition of pembrolizumab to chemotherapy with or without bevacizumab continued to show significant survival benefits in patients with PD-L1–positive (CPS ≥1) tumors at a median follow-up of 39.1 months, with median OS and PFS of 28.6 and 10.5 months versus 16.5 and 8.2 months in the pembrolizumab + chemotherapy arm versus the placebo + chemotherapy arm, respectively (HR, 0.60; 95% CI, 0.49–0.74; P<.0001).52 The NCCN panel continues to recommend pembrolizumab for patients whose tumors express PD-L1 (CPS ≥1) as determined by an FDA-approved assay or a validated test performed in a CLIA-certified laboratory. The panel revised the language for the assays used in the determination of specific biomarkers by including tests that are either approved by the FDA or are validated tests performed in CLIA-certified laboratories (CERV-F 1A of 3, page 1228).
Second-Line/Subsequent Systemic Therapy Options for Recurrent or Metastatic Cervical Cancer
The treatment options for patients who experience disease progression after first-line therapies have mostly been of limited effect, with low response rates to second-line and subsequent chemotherapies and a median PFS of approximately 3 to 6 months.53,54
Chemotherapy as Other Recommended, Second-Line/Subsequent Therapy
During the Version 1.2023 updates of the NCCN Guidelines, the panel reevaluated the list of single-agent chemotherapies included as second-line/subsequent therapy options in the “Other Recommended Regimens” category by revoting on each of these agents for their efficacy and use based on panel members’ clinical experience and judgement. The panel agreed to include the following options as second-line/subsequent treatment: bevacizumab, paclitaxel, albumin-bound paclitaxel, docetaxel, fluorouracil, gemcitabine, pemetrexed, topotecan, vinorelbine, and irinotecan. All agents were added as category 2A options, except irinotecan. Single-agents ifosfamide and mitomycin were no longer recommended by the panel as options for second-line/subsequent therapies in Version 1.2023. Furthermore, irinotecan, which was previously a category 2B option, was changed to category 2A, other recommended option, in the recently updated Version 1.2024 (CERV-F 1 of 3, page 1227).
Immunotherapy as Preferred, Second-Line/Subsequent Therapy
Increasingly available data from several prospective studies have demonstrated the effectiveness of immunotherapies or specific biomarker-based therapies in the setting of disease progression and has significantly transformed the management of cervical cancer. In addition, many biomarker-specific therapies have demonstrated meaningful clinical efficacy and durability regardless of the underlying tumor type leading to an increase in tumor-agnostic regulatory approvals.
Pembrolizumab as a Preferred, Second-Line/Subsequent Therapy
Pembrolizumab is an FDA-approved therapy for patients with recurrent or metastatic cervical cancer with disease progression on or after chemotherapy for PD-L1–positive tumors (CPS ≥1). It is also approved for unresectable or metastatic microsatellite instability–high/mismatch repair–deficient (MSI-H/dMMR) or tumor mutational burden–high (TMB-H) solid tumors that have progressed following prior treatment and who have no satisfactory alternative treatment options. In the NCCN Guidelines, pembrolizumab monotherapy is the preferred, second-line therapy option for recurrent/metastatic MSI-H/dMMR or TMB-H or PD-L1–positive tumors based on results from KEYNOTE-028 (phase Ib) and KEYNOTE-158 (phase II) trials.55–57
Tisotumab Vedotin-tftv as a Preferred, Second-Line/Subsequent Therapy
Tisotumab vedotin-tftv is an antibody–drug conjugate directed against tissue factor that is aberrantly expressed across multiple solid tumors and is associated with poor clinical outcomes and an increase in metastatic potential. Studies have indicated that tissue factor is highly prevalent in cervical cancer and might have a role in disease progression and poor patient outcome in the clinic.58 The phase I/II, innovaTV 201 trial enrolled 147 patients with pretreated advanced or metastatic solid tumors, including 34 patients with advanced cervical cancer, in the dose expansion phase of the study to evaluate the safety and durability of tisotumab vedotin-tftv.59,60 The ORR was 15.6% (95% CI, 10.2%–22.5%) with a median duration of response (DoR) of 5.7 months (95% CI, 3.0–9.5 months), and the median PFS was 3 months (range, 2.8–4.1 months). Among the patients with cervical cancer, an overall response was achieved by 9 of 34 (ORR, 26.5%; 95% CI, 12.9%–44.4%). The study protocol was further amended to include additional patients in the cervical cancer expansion cohort. Among a total of 55 patients enrolled in the cervical cancer cohort, a confirmed overall response was achieved in 22% (95% CI, 12%–35%), with a median DoR of 6.0 months (95% CI, 1.0–9.7 months) and median PFS of 4.1 months (range, 1.7–6.7 months). This study was followed by the innovaTV 204 trial, a phase II single-arm study that evaluated the efficacy of tisotumab vedotin-tftv in 102 patients with recurrent or metastatic cervical cancer who experienced disease progression on previous systemic therapy.61 At the median follow-up of 10 months, the confirmed ORR was 24% (95% CI, 16%–33%) which included 7% CR and 17% PR, and the median DoR was 8.3 months (95% CI, 4.2 months–not reached). Following the results from innovaTV 201 and innovaTV 204 trials that showed clinically meaningful and durable activity of tisotumab vedotin-tftv against pretreated recurrent/metastatic cervical cancer, the FDA approved it as a therapy for adult patients with recurrent or metastatic cervical cancer who experienced disease progression on or after chemotherapy.62 In the ongoing phase III, randomized, innovaTV 301 trial, the efficacy and safety of tisotumab vedotin-tftv are being evaluated in 502 patients with pretreated advanced/metastatic cervical cancer, compared with an investigator’s choice of chemotherapy (topotecan, vinorelbine, gemcitabine, irinotecan, or pemetrexed) (ClinicalTrials.gov identifier: NCT04697628). The interim analysis of the study has shown significant improvement in OS compared with chemotherapy.63 The NCCN Guidelines recommend tisotumab vedotin-tftv as a preferred therapy option for the treatment of recurrent/metastatic cervical cancer with disease progression on or after chemotherapy regardless of biomarker status. It was included under “Other Recommended Regimens” in previous versions of the guidelines and was moved to “Preferred Options” in Version 1.2023 (CERV-F 1 of 3, page 1227).
Cemiplimab as a Preferred, Second-Line/Subsequent Therapy
Cemiplimab is a PD-1–blocking monoclonal activity shown to have antitumor activity against cervical cancer. The phase III, randomized, EMPOWER-Cervical 1 clinical trial evaluated the efficacy of cemiplimab or investigator’s choice of chemotherapy (topotecan, vinorelbine, gemcitabine, irinotecan, or pemetrexed) in patients with recurrent or metastatic cervical cancer whose disease had progressed on prior therapy.64 The trial enrolled 608 patients who had previously received ≥1 lines of systemic therapy for recurrence, and randomized them to receive either cemiplimab or chemotherapy. The median OS and PFS were significantly longer in the cemiplimab arm versus the control arm (12.0 vs 8.5 months; HR, 0.69; 95% CI, 0.56–0.84; P<.001, and 2.8 vs 2.9 months; HR, 0.75; 95% CI, 0.63–0.89; P<.001, respectively).65 A total of 16.4% of the patients in the cemiplimab arm achieved an objective response (95% CI, 12.5%–21.1%) compared with 6.3% (95% CI, 3.8%–9.6%) in the chemotherapy arm. Among patients with SCC cervical cancer, the median OS was 11.1 in the cemiplimab versus 8.8 months in the chemotherapy arm (HR, 0.73; 95% CI, 0.58–0.91), and was 13.3 versus 7.0 months (HR, 0.56; 95% CI, 0.36–0.85), respectively, for those with AC/ASC cervical cancer, indicating that there is an OS benefit irrespective of histology. In a subanalysis of the study,66 samples from 254 patients were evaluated for PD-L1 expression to test the efficacy of cemiplimab in tumors with PD-L1 expression of ≥1%. The median OS of cemiplimab-treated PD-L1–expressed tumors (CPS ≥1) versus chemotherapy was 13.9 vs 9.3 months (HR, 0.70; 95% CI, 0.48–1.01), whereas the OS benefit for tumors with low PD-L1 expression (CPS <1) was comparable in the 2 arms; however, the authors of the study noted that due to smaller size of the subgroup population, reliable assessment of the benefits could not be made. In a 1-year follow-up analysis of this study, cemiplimab efficacy in PD-L1–positive (CPS ≥1) tumors was further tested by evaluating samples from 371 patients. Median OS in patients with PD-L1–positive (CPS ≥1) tumors was 12.1 versus 7.7 months (HR, 0.61; 95% CI, 0.45–0.83) in the cemiplimab versus chemotherapy arms, respectively, whereas in patients with PD-L1 CPS <1 tumors, OS was 10.8 versus 7.0 months (HR, 0.65; 95% CI, 0.43–0.98), respectively, indicating that cemiplimab has continued to show meaningful clinical benefits in both populations.66 In Version 1.2024 of the NCCN Guidelines, cemiplimab was added as a preferred, second-line/subsequent therapy option (CERV-F 1 of 3, page 1227).
Biomarker-Directed, Useful in Certain Circumstances, Second-Line/Subsequent Therapy
The NCCN Guidelines for Cervical Cancer have included a list of biomarkers with their associated targeted treatments as second-line/subsequent therapies under “Useful in Certain Circumstances” options. The pathology section of the guidelines provides recommendations for individual biomarkers that should be evaluated for targeted therapy.
Nivolumab for PD-L1–Positive Tumor
Nivolumab, a checkpoint inhibitor, has shown efficacy in patients with recurrent/metastatic cervical cancer who received at least one prior chemotherapy regimen. The CheckMate 358, phase I/II single-arm trial evaluated 19 patients with advanced, pretreated, PD-L1–positive (CPS ≥1) cervical tumors.67 The ORR was 26.3% (95% CI, 9.1%–51.2%) and the disease control rate (DCR) was 68.4% (95% CI, 43.4%–87.4%). The 12-month OS rate was 77.5% (95% CI, 50.5%–91.0%). The phase II NRG-GY002 trial showed low antitumor activity of nivolumab in 25 patients with pretreated persistent/recurrent cervical cancer; 36% of the patients had stable disease (90% CI, 20.2%−54.4%) as the best response with a median duration of 5.7 months, and the PFS and OS at 6 months were 16% and 78.4%, respectively.68,69 In Version 1.2023 of the NCCN Guidelines, the panel moved nivolumab from being a preferred, second-line or subsequent therapy option to the “Useful in certain Circumstances” category for PD-L1–positive tumors, and continues to recommend nivolumab in the same category in Version 1.2024.
Selpercatinib for RET Gene Fusion–Positive Tumors
RET gene fusions most commonly occur in thyroid and non–small cell lung cancers and are observed in <1% of patients with other solid tumors. In this small subset of patients, the prognosis of disease is poor in those who have experienced disease progression while on or after prior systemic therapy. The phase I/II LIBRETTO-001 multicenter, open-label trial evaluated the efficacy of selpercatinib in 806 patients with RET-mutant advanced solid tumors.70 This interim analysis of the trial in a tumor-agnostic population, the efficacy and safety of selpercatinib was investigated in 41 patients with RET fusion–positive solid tumors across 14 tumor types who have experienced disease progression on or after previous systemic therapies or who had no satisfactory therapeutic options. The ORR was 43.9% (95% CI, 28.5%–60.3%), with median DoR of 24.5 months (95% CI, 9.2 months–not evaluable). Selpercatinib received tumor-agnostic approval by the FDA for patients with solid tumors with a RET gene fusion who have experienced disease progression on or after prior systemic treatment or who have no satisfactory alternative treatment options. The NCCN panel recommends selpercatinib as a biomarker-directed second-line/subsequent therapy in the “Useful in Certain Circumstances” category for RET gene fusion–positive tumors, given its efficacy in tumor-agnostic population. The panel also specified in the “Principles of Pathology” section of the guidelines that RET gene fusion testing may be considered for patients with locally advanced or metastatic cervical cancer.
TRK Inhibitors for NTRK Gene Fusion–Positive Tumors
In addition to selpercatinib, other targeted therapy regimens included in the NCCN Guidelines as biomarker-directed second-line/subsequent therapies that have been approved in a tumor-agnostic population are the tropomyosin receptor kinase (TRK) inhibitors, larotrectinib and entrectinib. Larotrectinib targets the TRK proteins that are encoded by the genes NTRK1, NTRK2, and NTRK3. NTRK gene fusions are found in approximately 1% of all solid tumors. In a primary analysis, the efficacy and safety of larotrectinib was reported in 55 patients enrolled in 3 clinical studies who had locally advanced or metastatic tumors with NTRK gene fusions and had experienced disease progression on standard chemotherapy received previously.71 The 3 clinical studies included a phase I dose-finding study in adults, phase I/II dose-finding study in pediatric population, and a phase II single-arm basket trial. The ORR of larotrectinib in these 55 patients was 75% (95% CI, 61%–85%), with 13% CRs and 62% PRs; the median DoR and PFS had not been reached at the time. In a long-term follow-up analysis, of 153 patients, 121 had an objective response (79%; 95% CI, 72%–85%), with 16% having a CR, 63% having a PR, and 12% with stable disease.72 The median DoR was 35.2 months (22.8 months–not estimable) and the median PFS was 28.3 months. Similarly, entrectinib showed a durable and clinically meaningful response in 54 patients with advanced/metastatic NTRK gene fusion tumors enrolled in 3 phase I/II clinical trials, with a 57.4% ORR, 10.4-month median DoR, and 11.2-month median PFS.74 In a long-term efficacy and safety analysis in 121 patients at a median follow-up of 25.8 months, 61.2% had a CR or PR, with a median DoR of 20 months (95% CI, 13.0–38.2).74 Both larotrectinib and entrectinib are FDA-approved for NTRK gene fusion–positive solid tumors for patients who have experienced disease progression after treatment or have no satisfactory standard therapy. The NCCN Guidelines recommend larotrectinib and entrectinib as a second-line/subsequent, useful in certain circumstances option for NTRK gene fusion–positive tumors and have changed the category of evidence from category 2B to category 2A (CERV-F 1 of 3, page 1227).
Trastuzumab Deruxtecan for HER2-Positive Tumors
Another tumor-agnostic study evaluated the durability and clinically meaningful response of trastuzumab deruxtecan across multiple HER2-expressing (immunohistochemistry [IHC] 3+ or 2+) advanced solid tumor types in patients who have experienced disease progression on prior therapy or who have no satisfactory alternative treatment options. HER2 expression is observed in a wide range of solid tumors and is an established prognostic biomarker for breast, gastric, and colorectal cancers. Cervical cancer has shown a HER2 positivity rate of approximately 2% to 6% in the literature.75–77 The panel recommends HER2 IHC testing (with reflex to HER2 fluorescence in situ hybridization [FISH] for equivocal IHC) for advanced, metastatic, or recurrent cervical carcinoma in the “Principles of Pathology” section of the NCCN Guidelines (see CERV-A 1 of 7 in the full version of these guidelines at NCCN.org). Trastuzumab deruxtecan is an antibody–drug conjugate that contains the humanized anti-HER2 monoclonal antibody trastuzumab attached to the topoisomerase inhibitor deruxtecan.78 In an interim analysis of DESTINY-PanTumor02, a phase II trial that enrolled 267 patients with locally advanced, unresectable, or metastatic HER2-expressing (IHC 3+ or 2+) solid tumors (including 40 patients with cervical cancer), the ORR was 37.1% (n=99; 95% CI, 31.3–43.2); median DoR was 11.3 months (95% CI, 9.6–17.8); median PFS was 6.9 months (95% CI, 5.6–8.0); and median OS was 13.4 months (95% CI, 11.9–15.5).79 In patients with cervical cancer, the confirmed ORR was 50% (95% CI, 33.8–66.2; 5% CR, 45% PR); median DoR was 14.2 months (95% CI, 4.1–NR); median OS was 13.6 months (95% CI, 11.1–NR); and DCR at 12 weeks was 67.5%. Version 1.2024 of the NCCN Guidelines include fam-trastuzumab deruxtecan-nxki as a category 2A, useful in certain circumstances, second-line/subsequent therapy option for HER2-positive tumors (IHC 3+ or 2+) (CERV-F 1 of 3, page 1227).
Summary
These NCCN Guidelines Insights focus on revisions and updates related to the systemic therapy options for patients with locally advanced or advanced/metastatic or recurrent cervical cancer. For a complete list of the recent updates, see Version 1.2024 of the NCCN Guidelines for Cervical Cancer at www.nccn.org.
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NCCN CATEGORIES OF EVIDENCE AND CONSENSUS
Category 1: Based upon high-level evidence, there is uniform NCCN consensus that the intervention is appropriate.
Category 2A: Based upon lower-level evidence, there is uniform NCCN consensus that the intervention is appropriate.
Category 2B: Based upon lower-level evidence, there is NCCN consensus that the intervention is appropriate.
Category 3: Based upon any level of evidence, there is major NCCN disagreement that the intervention is appropriate.
All recommendations are category 2A unless otherwise noted.
Clinical trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.
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