Developments With Immunotherapy, Maintenance Therapy, and Novel Strategies Push the Field of Women’s Cancers Forward

Melissa Geller, MD, MS

The treatment of women with breast and gynecologic cancers has improved with the emergence of checkpoint inhibitors, maintenance therapy, novel agents, and alternative formulations of standard options, paving the way for more research to further improve survival for these populations, according to a panel of experts from the Masonic Cancer Center of the University of Minnesota that presented during an OncLive^® Institutional Perspectives in Cancer webinar on gynecologic cancers.

Notably, Melissa Geller, MD, MS, chair of the event, gynecologic oncologist, Masonic Cancer Clinic, professor and division director of Gynecologic Oncology in the Department of Obstetrics, Gynecology, and Women’s Health (OBGYN) at the University of Minnesota, discussed the nuances of selecting second-line maintenance therapy for patients with platinum-sensitive recurrent ovarian cancer.

Geller was joined by fellow faculty from the Masonic Cancer Clinic:

• Andrea O’Shea, MD, gynecologic oncologist, Masonic Cancer Clinic, assistant professor, Department of OBGYN, University of Minnesota
• Britt Erickson, MD, gynecologic oncologist, Masonic Cancer Clinic, assistant professor, Department of OBGYN, University of Minnesota
• Heather Beckwith, MD, medical oncologist, University of Minnesota Medical Center, assistant professor of medicine, Division of Hematology, Oncology, and Transplantation, University of Minnesota
• Anne Blaes, MD, hematologist/oncologist, associate professor of medicine, interim division director, Division of Hematology, Oncology, and Transplantation, University of Minnesota, director, Cancer Survivorship Services and Translational Research, co-leader SPECS, section lead, Medical Oncology, Masonic Cancer Center

During the meeting, the panelists discussed key clinical trials that have changed the landscapes of HER2-positive breast cancer and triple-negative breast cancer (TNBC), the role of first- and second-line maintenance therapy in ovarian cancer, and key updates in cervical and endometrial cancers.

HER2+ Breast Cancer Paradigm Continues to Grow

Blaes: Several studies, including HER2CLIMB [NCT02614794], KATHERINE [NCT01772472], FeDeriCa [NCT03493854], and PHranceSCa [NCT03674112] have changed the treatment paradigm for patients with HER2-positive breast cancer. The HER2CLIMB trial demonstrated a 5.5-month overall survival [OS] benefit with tucatinib [Tukysa], which was maintained after an additional 15.6 months of follow-up. Moreover, the OS benefit was maintained across all prespecified subgroups. Tucatinib in combination with trastuzumab [Herceptin] and capecitabine [Xeloda] was well tolerated and few patients required treatment discontinuations.

In the curative-intent, HER2-positive setting, paclitaxel plus trastuzumab remains the standard of care for patients with stage I disease as it has demonstrated excellent outcomes. For patients with larger tumors greater than 2 cm or lymph node–positive disease, the goal of curative-intent therapy is to achieve a pathologic complete response [pCR]. Patients who don’t achieve a pCR with neoadjuvant chemotherapy may receive ado-trastuzumab emtansine [T-DM1; Kadcyla] in the adjuvant setting for 14 cycles. Patients who do achieve a pCR with neoadjuvant chemotherapy may continue adjuvant trastuzumab with or without pertuzumab [Perjeta] to complete 1 year of treatment.

Finally, the FDA granted approval to the fixed-dose combination of trastuzumab, pertuzumab, and hyaluronidase-zzxf [Phesgo] for subcutaneous administration in combination with intravenous chemotherapy for the treatment of patients with early or metastatic HER2-positive breast cancer. The subcutaneous regimen reduces the time a patient must spend in an infusion center, so it has quickly become the preferred regimen among patients. However, in the era of biosimilars, a question of how and where the subcutaneous formulation will be utilized remains unanswered.

Checkpoint Inhibitors Transform the Treatment of TNBC

Beckwith: The addition of pembrolizumab [Keytruda] to chemotherapy improved progression-free survival [PFS] when used as first-line treatment for patients with metastatic TNBC and event-free survival when used as neoadjuvant treatment for patients with early-stage TNBC.

The utility of immune checkpoint inhibitors must be weighed against the risks of adverse autoimmune effects, some of which can be lifelong.

As such, further research evaluating biomarkers of response to checkpoint inhibitors, new combination regimens with checkpoint inhibitors, and alternative dosing strategies are likely to improve the efficacy of checkpoint inhibitors.

Front-Line Maintenance Therapy in Ovarian Cancer

Erickson: We are now faced with a lot of exciting options for women with newly diagnosed ovarian cancer. Our hope, ultimately, is to improve the survival of these women. Right now, we do have promising data that adding PARP inhibitors in the up-front maintenance setting, at least for now, provides a significant improvement in PFS. We will see if that translates into an OS advantage, but we now have multiple phase 3 up-front clinical trials that do show a PFS benefit with the addition of PARP inhibitor maintenance following chemotherapy.

Second-Line Maintenance Therapy in Recurrent Ovarian Cancer

Geller: PARP inhibitor maintenance therapy is standard of care for patients with newly diagnosed ovarian cancer or patients with platinum-sensitive relapses who are naïve to previous PARP inhibitors. Although most patients achieve a long-term response with PARP inhibitors, the majority will ultimately progress.

Maintenance therapy options in the second-line setting include no maintenance, maintenance with PARP inhibitors, maintenance with bevacizumab [Avastin], or a clinical trial. However, no trials have directly compared angiogenesis inhibitors following response to platinum-based chemotherapy vs a PARP inhibitor. As such, caution should be taken when comparing randomized phase 3 trials reporting on these 2 strategies. For example, the NOVA [NCT01847274], ARIEL3 [NCT01968213], and SOLO-2 [NCT01874353] trials enrolled women who had responded to induction chemotherapy, whereas the OCEANS [NCT00434642] and GOG-213 [NCT00565851] trials included patients who responded, as well as those who did not respond, to platinum-based therapy. Time-to-event calculations, analyses of BRCA vs non-BRCA–associated cancers, and histologic subtypes enrolled also differed between studies evaluating bevacizumab.

It remains unknown whether patients who relapse after PARP inhibitor maintenance therapy will benefit from rechallenging with a PARP inhibitor following response to platinum-based chemotherapy. However, the results of the phase 3 OReO trial [NCT03106987] demonstrated that rechallenging with olaparib [Lynparza] maintenance following response to platinum-based chemotherapy in patients with heavily pretreated ovarian cancer provided a statistically significant improvement in PFS, although modest, irrespective of BRCA mutational status. In the non-BRCA–mutated population, patients appeared to benefit regardless of homologous recombination deficiency status.

Going forward, the phase 3 UP-NEXT trial is evaluating upifitamab rilsodotin as monotherapy maintenance vs placebo in patients with platinum-sensitive recurrent ovarian cancer. Patients have to have NaPi2b high biomarker selection, and the primary end point is PFS. Additionally, the field is focusing on how to overcome PARP inhibitor resistance, which may be primary or acquired. This may further the field toward individualized medicine.

Key Trials in Cervical and Endometrial Cancers

O’Shea: In cervical cancer, the results of the phase 2 innovaTV 204 trial [NCT03438396] showed that at a median follow-up of 10 months, the objective response rate [ORR] with tisotumab vedotin-tftv [Tivdak] was 24%, comprising a 7% complete response [CR] rate and 17% partial response [PR] rate. Additionally, 62% of patients had responses ongoing at more than 6 months. The median duration of response [DOR] was 8.3 months, the median PFS was 4.2 months, and the median OS was 12.1 months. This was in 101 patients with recurrent or extra-pelvic metastatic cervix cancer who progressed during or after chemotherapy with bevacizumab if they were eligible.

In the KEYNOTE-158 trial [NCT02628067] with pembrolizumab, 98 patients with previously treated advanced cervical cancer who progressed after at least 1 prior line of therapy had an ORR of 12.2%, comprising a CR rate of 3% and a PR rate of 9%.

Tisotumab vedotin comes with a boxed warning for ocular toxicity, which is a big adverse effect associated with the agent. More than half of patients on the innovaTV 204 trial developed ocular toxicity, but most were grade 1 or 2 events. Moreover, an extensive program for eye care must be utilized when using tisotumab vedotin.

Tisotumab vedotin was approved on September 20, 2021, for patients with recurrent or metastatic cervical cancer with disease progression on or after chemotherapy.

In uterine cancer, the phase 3 KEYNOTE-775 trial [NCT03517449] randomized patients with advanced or recurrent endometrial cancer following progression on platinum-based therapy to pembrolizumab plus lenvatinib [Lenvima] vs physician’s choice of chemotherapy. The results showed that in all-comers, or patients with mismatch repair proficient [pMMR] and deficient [dMMR] disease, the median PFS was 7.2 months with pembrolizumab/lenvatinib vs 3.8 months with chemotherapy. The OS was 18.3 months vs 11.4 months, respectively, and the ORR was 31.9% vs 14.7%, respectively.

In the pMMR cohort, the median PFS was 6.6 months with the combination vs 3.8 months with chemotherapy. The median OS was 17.4 months vs 12 months, respectively, and the ORR was 30.3% vs 15.1%, respectively.

Another study, ROCSAN [NCT03651206], is currently enrolling patients with ovary and uterine carcinosarcoma. Although no data are available yet, patients will be randomized 2:2:1 to niraparib [Zejula] monotherapy, niraparib plus dostarlimab-gxly [Jemperli], or standard chemotherapy. The primary end point is ORR at 4 months. The first interim results are expected in 2022.