Second-Line Sequencing May Hinge on IHC Staining in Cervical Cancer

Ritu Salani, MD, MBA

Putting an emphasis on immunohistochemistry (IHC) staining is top of mind as fam-trastuzumab deruxtecan-nxki (Enhertu, T-DXd) sits alongside tisotumab vedotin-tftv (Tivdak) as options in the second-line cervical cancer setting. Unlike the tissue factor–directed antibody-drug conjugate (ADC), the HER2-targeted ADC does not hold an all-comer indication and is only applicable for a select few patients. Notably, following the 2024 approval of tisotumab vedotin for patients with recurrent or metastatic cervical cancer who experienced disease progression on or after chemotherapy, version 1.2025 of the NCCN Clinical Practice Guidelines in Oncology adjusted the preferred regimen recommendation for the agent from category 2A to category 1.1,2

“The landscape for gynecologic malignancies has been exploding, and it’s been very exciting [with] the advent of ADCs and [their] incorporation into standard therapies. What’s on the horizon is also [intriguing],” Ritu Salani, MD, MBA, a gynecologic oncologist and the director of the Division of Gynecologic Oncology at UCLA Health in Los Angeles, California, said in an interview with OncologyLive.

Salani and colleagues will shed light on the latest strategies, changes in the treatment of cervical cancer, and more at the 16th Annual International Symposium on Ovarian Cancer and Other Gynecologic Malignancies, which she is cochairing.3

“A challenge I’m looking forward to discussing with my colleagues is [therapeutic] sequencing in cancers, not just in cervical cancer but also in endometrial cancer, especially as immunotherapy has disrupted some of the earlier lines of therapy in a good way,” she noted. “We’ve seen improvements in survival, but we’re not curing all patients. Understanding which patients may benefit most from immunotherapy in the frontline vs second-line setting [and if] there [are] other combinations or agents that may be even more compelling to use in these settings are the most exciting areas.”

NCCN Updates Seem to Solidify Immunotherapy's Frontline Role

Although pembrolizumab (Keytruda) and atezolizumab (Tecentriq) are both listed in the NCCN guidelines as preferred regimens for use in combination with chemotherapy with or without bevacizumab (Avastin) in the first-line setting for cervical cancer, the pembrolizumab regimen is the only one holding an FDA approval.

“There have been 2 large studies that have looked at the role of checkpoint inhibitors in addition to chemotherapy for patients with metastatic or recurrent cervical cancer. Only the incorporation of pembrolizumab with chemotherapy with or without bevacizumab is FDA approved in the US—atezolizumab with bevacizumab and chemotherapy was also studied but is not on label in the US,” Salani explained. “But both studies [evaluating these regimens] showed a significant impact in both PFS and OS. Incorporation of [them for] select patients is critical, and it should be the standard.”

The combination of pembrolizumab plus chemotherapy with or without bevacizumab has been FDA approved since 2021, and the final OS analy- sis of the phase 3 trial that supported the approval, KEYNOTE-826 (NCT03635567), showed that patients with persistent, recurrent, or first-line metastatic cervical cancer (n = 617) had a meaningful improvement in OS with the combination vs chemotherapy with or without bevacizumab.4,5 The median OS was 26.4 months vs 16.8 months (HR, 0.63; 95% CI, 0.52-0.77), respectively.5 Additional data from the phase 3 BEATcc trial (NCT03556839) revealed that adding atezolizumab to bevacizumab and chemotherapy in the frontline yielded a high median OS.6 Interim analysis data from this trial showed that the median OS was 32.1 months (95% CI, 25.3-36.8) among those treated with the atezolizumab combination (n = 206) vs 22.8 months (95% CI, 20.3-28.0) with bevacizumab and chemotherapy alone (n = 204; HR, 0.68; 95% CI, 0.52-0.88; P = .0046).

“Since those studies have been conducted, we had the advent of immunotherapy being incorporated into chemoradiation for patients [whom] you may consider to have high-risk locally advanced cervical cancer,” Salani said. “Therefore, some patients may already be experienced with check- point inhibitors by the time their cancer recurs. Understanding the role of checkpoint inhibitor therapy after checkpoint inhibitor therapy remains a needs gap for us because we have not encountered that yet. Whether we should use immunotherapy again, if it should be a different combination, or if we should avoid it is still something that’s unclear at this time.”

Diving Into the Second-Line Shift

Following encouraging data showing that tisotumab vedotin yielded significantly improved efficacy vs chemotherapy in patients with recurrent or metastatic cervical cancer who received 1 or 2 prior systemic regimens, the ADC has become a standard of care.2 In the phase 3 innovaTV 301 trial (NCT04697628), patients who received tisotumab vedotin (n = 253) achieved a median overall survival (OS) of 11.5 months (95% CI, 9.8-14.9) vs 9.5 months (95% CI, 7.9-10.7) in the chemotherapy arm (n = 249; HR, 0.70; 95% CI, 0.54-0.89; P = .004) at a median follow-up of 10.8 months (95% CI, 10.3-11.6).7 The 12-month OS rates were 48.7% (95% CI, 41.0%-55.8%) vs 35.3% (95% CI, 28.0%-42.7%), respectively.

Patients also had a 33% lower risk of disease progression or death in the tisotumab vedotin arm vs the chemotherapy arm as the median progression-free survival (PFS) was 4.2 months (95% CI, 4.0-4.4) compared with 2.9 months (95% CI, 2.6-3.1), respectively (HR, 0.67; 95% CI, 0.54-0.82; P < .001). Furthermore, the confirmed objective response rate (ORR) was 17.8% (95% CI, 13.3%-23.1%) among patients treated with the ADC vs 5.2% (95% CI, 2.8%-8.8%) among those treated with chemotherapy (OR, 4.0; 95% CI, 2.1-7.6). As assessed by the investigator, the median duration of response (DOR) was 5.3 months (95% CI, 4.2-8.3) in the tisotumab vedotin arm compared with 5.7 months (95% CI, 2.8-not reached) in the chemotherapy arm. The most common grade 3 or higher adverse effects (AEs) experienced in the tisotumab vedotin arm vs the chemotherapy arm in innovaTV 301 were anemia (8.4% vs 27.6%, respectively), urinary tract infection (4.4% vs 7.1%), and neutropenia (3.6% vs 13.4%). Patients also experienced serious AEs during treatment (32.8% vs 39.3%), and fatal AEs occurred in 4 and 5 patients, respectively.

“Currently, tisotumab vedotin is the second- line therapy after patients have experienced recurrence on first-line platinum-based therapy with or without immunotherapy, and most patients will have received immunotherapy,” Salani said. “HER2 is an exciting target, [and] it’s not highly prevalent in cervical cancer, so if you find it, it is a good target—we’re talking about [IHC] 2+ or 3+ expression. Both tisotumab vedotin and T-DXd could be used in a patient, and how you sequence them may be based on access, patient understanding, and the expression rates because very few patients will be candidates for HER2-[targeted therapies] with cervical cancer.”

Data on T-DXd that supported the April 2024 pan-tumor accelerated approval of the ADC for adult patients with unresectable or metastatic HER2-positive (IHC 3+) solid tumors who have received prior systemic treatment showed that patients with cervical cancer (n = 10) achieved an ORR of 70.0% (95% CI, 34.8%-93.3%).8,9 This was the highest ORR recorded among the follow- ing groups of patients examined with colorectal (46.9%), bladder (37.0%), biliary tract (45.5%), non–small cell (52.9%), endometrial (56.3%), ovarian (66.7%), salivary gland (66.7%), and pancreatic (0.0%) cancers (Figure). Notably, the DOR range was 7.2+ to 25.0+ months in patients with cervical cancer, and the recommended T-DXd dose for this indication is 5.4 mg/kg given every 3 weeks.9

Figure. Response Rates With T-DXd Supporting the Tumor-Agnostic FDA Approval6

“Sequencing continues to be an interesting challenge, and understanding which therapies may have the best response, but also the longest duration, is key. It makes good sense to use T-DXd in patients with HER2 3+ expression because we’re seeing provocative response rates and impressive durations of response [in this population and] it’s not typical to see that. [However,] tisotumab vedotin has an all-comers indication,” Salani noted.

Looking to the future, Salani added, “There are some exciting trials in the cervical cancer space that should be on everybody’s radar, particularly with TROP2 ADCs, which are being looked at in the second line for patients after receipt of platinum-based chemotherapy with immunotherapy whether it’s with radiation or with chemotherapy. Continuing to look at opportunities to improve the landscape is critical.”

One study showed that TROP2 was expressed in 98.5% of cervical cancer samples (n = 66/67), demonstrating the potential promise for targeting TROP2 in cervical cancer.10 TROP2-directed ADCs under investigation in this setting include sacituzumab govitecan-hziy (Trodelvy), which is being evaluated in those with recurrent or persistent disease in a phase 2 trial (NCT05838521).11

References

1. FDA approves tisotumab vedotin-tftv for recurrent or metastatic cervical cancer. FDA. April 29, 2024. Accessed February 4, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-tisotumab-vedotin-tftv-recurrent-or-metastatic-cervical-cancer
2. NCCN. Clinical Practice Guidelines in Oncology. Cervical cancer, version 2.2025. Accessed February 4, 2025. https://www.nccn.org/professionals/physician_gls/pdf/cervical.pdf
3. 16th Annual International Symposium on Ovarian Cancer and Other Gynecologic Malignancies. Physicians’ Education Resource, LLC. Accessed February 4, 2025. https://www.gotoper.com/courses/international-symposium-on-ovarian-cancer-and-other-gynecologic-malignancies
4. FDA approves pembrolizumab combination for the first-line treatment of cervical cancer. FDA. October 13, 2021. Accessed February 4, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-pembrolizumab-combination-first-line-treatment-cervical-cancer#:~:text=On%20October%2013,2021,%20the,by%20an%20FDA-approved%20test
5. Monk BJ, Colombo N, Tewari KS, et al; KEYNOTE-826 Investigators. First-line pembrolizumab + chemotherapy versus placebo + chemotherapy for persistent, recurrent, or metastatic cervical cancer: final overall survival results of KEYNOTE-826. J Clin Oncol. 2023;41(36):5505-5511. doi:10.1200/JCO.23.00914
6. Oaknin A, Gladieff L, Martínez-García J, et al; ENGOT-Cx10–GEICO 68-C–JGOG1084–GOG-3030 Investigators. Atezolizumab plus bevacizumab and chemotherapy for metastatic, persistent, or recurrent cervical cancer (BEATcc): a randomised, open-label, phase 3 trial. Lancet. 2024;403(10421):31-43. doi:10.1016/S0140-6736(23)02405-4
7. Vergote I, González-Martín A, Fujiwara K, et al; innovaTV 301/ENGOT-cx12/GOG-3057 Collaborators. Tisotumab vedotin as second- or third-line therapy for recurrent cervical cancer. N Engl J Med. 2024;391(1):44-55. doi:10.1056/NEJMoa2313811
8. FDA grants accelerated approval to fam-trastuzumab deruxtecan-nxki for unresectable or metastatic HER2-positive solid tumors. FDA. April 5, 2024. Accessed February 4, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-fam-trastuzumab-deruxtecan-nxki-unresectable-or-metastatic-her2
9. Enhertu. Prescribing information. Daiichi Sankyo, Inc; 2025. Accessed February 4, 2025. https://daiichisankyo.us/prescribing-information-portlet/getPIContent?productName=Enhertu&inline=true
10. Mallmann MR, Tamir S, Alfter K, Ratiu D, Quaas A, Domroese CM. Expression of potential antibody-drug conjugate targets in cervical cancer. Cancers (Basel). 2024;16(9):1787. doi:10.3390/cancers16091787
11. A study of sacituzumab govitecan (IMMU-132) in patients with recurrent or persistent cervical cancer. ClinicalTrials.gov. Updated December 17, 2024. Accessed February 4, 2025. https://clinicaltrials.gov/study/NCT05838521