Patients with platinum-resistant epithelial ovarian cancer experienced elevated responses to pembrolizumab (Keytruda) following the addition of a short-term, flat dose of bevacizumab (Avastin) to the anti–PD-1 therapy, according to results from the phase 1 PEMBOV trial (NCT03596281) that were presented during the 2021 SITC Annual Meeting.

Results from the study showed that among the 19 patients enrolled, the combination yielded an overall response rate (ORR) of 26%; this was comprised of 1 complete response (CR; 5%) and 4 partial responses (PRs; 21%). Additionally, the disease control rate (DCR) with the doublet was 79%.

For patients with platinum-resistant ovarian cancer, there is an unmet medical need for more efficacious treatment options.

Previously, the phase 3 AURELIA trial (NCT00976911) examined the combination of chemotherapy and bevacizumab in platinum-resistant patients who were bevacizumab naïve and had received a maximum of 2 prior treatment regimens. Results showed that the median progression-free survival (PFS) was 3.4 months in those treated with chemotherapy vs 6.7 months in those who received the combination. Moreover, the ORRs reported in each group were 11.8% and 27.3%, respectively.

Bevacizumab monotherapy has been shown to induce a median PFS of 4.4 months and an ORR of 15.9% in this patient population.

 Anti–PD-1/PD-L1 monotherapies have been shown to elicit ORRs ranging from 3.7% to 15.0%, and a median PFS ranging from 1.9 months to 3.5 months. The addition of chemotherapy to these agents appears to slightly improve outcomes, with ORRs ranging from 13.3% to 23.0%, and a median PFS ranging from 3.7 months to 8.1 months.

Prior phase 2 trials have also examined the combination of anti­–PD-L1 therapy and PARP inhibitors, a regimen that has been shown to elicit an ORR of 14.0% and a median PFS of 3.9 months,

 as well as anti­–PD-L1 therapy, PARP inhibition, and bevacizumab, a triplet which yielded an ORR of 28.0% and a median PFS of 4.1 months.

Additionally, phase 1b/2 trials have previously examined pembrolizumab in combination with bevacizumab and chemotherapy. When pembrolizumab and bevacizumab were paired with pegylated liposomal doxorubicin (PLD), the regimen yielded an ORR of 32.0%.

 When the 2 agents were combined with cyclophosphamide, the regimen induced an ORR of 43.3% and a median PFS of 7.6 months.

Prior phase 2 clinical trials have investigated the combination of an anti–PD-1 blockade plus an anti–CTLA-4 blockade. Results from these trials have showed that this approach can produce an ORR of 31.4% and a median PFS of 3.9 months.

The PEMBOV study enrolled patients with platinum-resistant epithelial ovarian cancer. There was no limit to the number of previous treatments patients could have received, and prior treatment with bevacizumab was permitted.

The study was comprised of 2 cohorts. Patients in cohort A received pembrolizumab plus PLD, and those in cohort B were given pembrolizumab plus bevacizumab. Here, investigators reported data from cohort B of the study.

Patients enrolled to cohort B received 200 mg of pembrolizumab once every 3 weeks until disease progression, unacceptable toxicity, or withdrawal of consent, and 400 mg of bevacizumab every 3 weeks for 6 cycles.

The primary end point of the study was best overall response (BOR) per RECIST v1.1 criteria, and duration of response (DOR). Secondary end points included safety and tolerability, and key exploratory objectives were to examine PD-L1 status and the pharmacokinetics of bevacizumab.

Among the 19 patients enrolled, the median age was 70 years (range, 38-76), and most had an ECOG performance status of 0 (52.6%) with the ovary as their primary tumor location (79%). Additionally, most patients had serous high-grade disease (95%) and had received prior antiangiogenic therapy (68%). Sixteen percent of patients had a 

 mutation, and 47% had received prior treatment with PARP inhibitors. Moreover, 95% of patients had received 2 or more prior chemotherapy regimens.

The median follow-up time was 7.6 months (95% CI, 6.7-19.5), with a minimum of 2.9 months and a maximum of 29.0 months. Time to progression (TTP) was not reached for 26.0% of patients (n = 5/19), and 42.0% of patients (n= 8/18) had a TTP that was 24 weeks or more.

For patients who had a PD-L1 combined positive score (CPS) of 10% or higher (n = 4), the ORR with the regimen was 50%; this was comprised of 2 PRs, and 1 patient had stable disease. Among those with a PD-L1 CPS of 1% or higher (n = 10), the ORR was 30%, which was comprised of 3 PRs and 4 patients achieved stable disease. For patients with a PD-L1 CPS of 1% or lower (n = 8), the ORR was 25%, and this was comprised of 1 CR, 1 PR, and 6 patients with stable disease.

In terms of safety, grade 3/4 treatment-related adverse effects (TRAEs) were reported in 20% of patients. The most common grade 3/4 TRAEs were cerebral ischemia (5%), sepsis (5%), bowel proliferation (5%), and proteinuria (5%).

No new safety signals were observed on the study, and correlative studies are ongoing.

Michels J, Frenel J-S, Genestie C, et al. Pembrolizumab and bevacizumab in platinum resistant epithelial ovarian cancer patients. Presented at: 2021 SITC Annual Meeting; November 10-14, 2021; Washington DC. Abstract 355.

Pujade-Lauraine E, Hilpert F, Weber B, et al. Bevacizumab combined with chemotherapy for platinum-resistant recurrent ovarian cancer: the AURELIA open-label randomized phase III trial. 

. 2014;32(13):1302-1308. doi:10.1200/JCO.2013.51.4489

Cannistra SA, Matulonis UA, Penson RT, et al. Phase II study of bevacizumab in patients with platinum-resistant ovarian cancer or peritoneal serous cancer. 

. 2007;25(33):5180-6. doi:10.1200/JCO.2007.12.0782

Hamanishi J, Mandai M, Ikeda T, et al. Safety and antitumor activity of anti-PD-1 antibody, nivolumab, in patients with platinum-resistant ovarian cancer. 

. 2015;33(34):4015-4022. doi:10.1200/JCO.2015.62.3397

Disis ML, Taylor MH, Kelly K, et al. Efficacy and safety of avelumab for patients with recurrent or refractory ovarian cancer: phase 1b results from the JAVELIN solid tumor trial. 

. 2019;5(3):393-401. doi:10.1001/jamaoncol.2018.6258

Matulonis UA, Shapira-Frommer R, Santin AD, et al. Antitumor activity and safety of pembrolizumab in patients with advanced recurrent ovarian cancer: results from the phase II KEYNOTE-100 study. 

. 2019;30(7):1080-1087. doi:10.1093/annonc/mdz135

Pujade-Lauraine E, Fujiwarab K, Ledermannc JA, et al. Avelumab alone or in combination with pegylated liposomal doxorubicin versus pegylated liposomal doxorubicin alone in platinum-resistant or refractory epithelial ovarian cancer: Primary and biomarker analysis of the phase III JAVELIN Ovarian 200 trial. Presented at: 50th Annual Meeting of the Society of Gynecologic Oncology; March 16-19, 2019. Honolulu, HI.

Lee EK, Xiong N, Cheng S-C, et al. Combined pembrolizumab and pegylated liposomal doxorubicin in platinum resistant ovarian cancer: a phase 2 clinical trial. 

. 2020;159(1):72-78. doi:10.1016/j.ygyno.2020.07.028

Lampert EJ, Zimmer A, Padget M, et al. Combination of PARP inhibitor olaparib, and PD-L1 inhibitor durvalumab, in recurrent ovarian cancer: a proof-of-concept phase II study. 

. 2020;26(16):4268-4279. doi:10.1158/1078-0432.CCR-20-0056

Freyer G, Floquet A, Tredan O, et al. 733P Bevacizumab (bev), olaparib (ola) and durvalumab (durva) in patients with recurrent advanced ovarian cancer (AOC): the GINECO BOLD study. 

. 2021;32(5):S734-S735. Doi:10.1016/j.annonc.2021.08.1176

Michels J, Ghiringhelli F, Frenel J-S, et al. Pembrolizumab in combination with bevacizumab and pegylated liposomal doxorubicin in patients with platinum-resistant epithelial ovarian cancer. 

. 2021;39(15):5522. Doi:10.1200/JCO.2021.39.15_suppl.5522

Zsiros E, Lynam S, Attwood K, et al. Efficacy and safety of pembrolizumab in combination with bevacizumab and oral metronomic cyclophosphamide in the treatment of recurrent ovarian cancer: a phase 2 nonrandomized clinical trial

. 2021;7(1):78-85. Doi:10.1001/jamaoncol.2020.5945

Zamarin D, Burger RA, Sill MW, et al. Randomized phase II trial of nivolumab versus nivolumab and ipilimumab for recurrent or persistent ovarian cancer: an NRG oncology study. 

. 2020;38(16):1814-1823. Doi:10.1200/JCO.19.02059

Pembrolizumab in combination with bevacizumab and pegylated liposomal doxorubicin in patients with ovarian cancer (PEMBOV). ClinicalTrials.gov. Updated July 22, 2021. Accessed November 17, 2021. 

https://clinicaltrials.gov/ct2/show/NCT03596281

This article was originally published on OncLive as “Addition of Bevacizumab to Pembrolizumab Improves Responses in Epithelial Ovarian Cancer.”

Articles

The addition of bevacizumab was found to boost responses in patients with epithelial ovarian cancer receiving pembrolizumab. 

Adding Bevacizumab to Pembrolizumab Enhances Response Rates in Epithelial Ovarian Cancer

Patients with platinum-resistant ovarian cancer responded favorably to the investigative agent SL-172154 (SIRPα-Fc-CD40L) in a phase 1 dose-escalation trial. Findings from the study, which were presented during the 2021 SITC Annual Meeting, revealed that the agent was well tolerated and that there were no observed dose-limiting toxicities (DLTs).

Results showed that among 14 patients who were evaluable for efficacy and had undergone a post-baseline scan, the hexameric bifunctional fusion protein resulted in a best response of stable disease in 4 patients. Nine patients experienced disease progression. Moreover, 1 patient was determined to be not evaluable, as they were considered to have stable disease, but they did not meet the protocol-specified minimum interval for disease stability.

“SL-172154 was well tolerated with no DLTs or evidence of anemia, thrombocytopenia, liver dysfunction, cytokine release syndrome, or pneumonitis,” Nehal Lakhani, MD, PhD, lead study author and director of clinical research at START Midwest, and colleagues, wrote in the poster. “Preliminary pharmacokinetic [PK] parameters for SL-172154 suggest target-mediated drug disposition via receptor binding. High receptor occupancy was observed for [the agent] on CD47-positive leukocytes at the doses studied, with minimal binding to red blood cells [RBCs].”

SL-172154 was developed using an Agonist Redirected Checkpoint platform, which connects the extracellular domain of a type 1 membrane protein to the domain of a type 2 membrane protein through a central Fc domain derived from an IgG4 antibody. The bifunctional proteins are designed to block the tumor cells from transmitting an immune inhibitory signal, as they concurrently deliver an immune stimulatory signal to immune cells in the tumor microenvironment.

SL-172154 is comprised of SIRPα, which has a binding affinity to CD47 of 0.628 nM, linked to CD40L, which has a binding affinity to CD40 of 4.74 nM, through an Fc linker protein. The agent was developed to bridge innate and adaptive immunity by strengthening tumor cell phagocytosis and antigen cross-presentation to CD8 T cells.

In preclinical studies, the agent resulted in higher rates of tumor rejection and long-term immunity than CD47-blocking antibodies, CD40 agonist antibodies, or a combination comprised of these 2 modalities.

In the first-in-human phase 1 trial, investigators set out to evaluate single-agent SL-172154 in patients with locally advanced or metastatic ovarian cancer, primary peritoneal cancer, or fallopian tube cancer who were refractory to existing therapies or ineligible to receive further platinum-based treatment.

To be eligible for enrollment, patients needed to be at least 18 years of age, have an ECOG performance status of 0 or 1, and measurable disease per RECIST v1.1 criteria. Patients who were positive for homologous recombination deficiency must have previously received a PARP inhibitor with or without bevacizumab (Avastin).

If patients had primary platinum-refractory disease, or received previous treatment with an anti-CD47, anti-SIRPα targeting agent, or a CD40 agonist, they were excluded. Patients with a documented history of autoimmune disease or active pneumonitis, or who required concurrent use of systemic corticosteroids or other immunosuppressive medications, were also excluded.

The planned dose-escalation for the trial was in half-log increments. The agent was given at the following doses: level 1 was 0.1 mg/kg (n = 3), level 2 was 0.3 mg/kg (n = 3), level 3 was 1.0 mg/kg (n = 3), level 4 was 3.0 mg/kg (n = 3), and level 5 was 10.0 mg/kg.

Those receiving schedule 1 escalated from dose level 1 to 2, and those receiving schedule 2 escalated from dose level 2 to dose level 5. Those on schedule 1 received the agent on day 1, 8, and 15 and then every 2 weeks of each 28-day treatment cycle. Those on schedule 2 received the drug on day 1, 8, 15, and 22 once weekly of each 28-day cycle.

At least 3 patients were enrolled to sequential dose levels and evaluated for DLTs in the first treatment cycle. Patients received intravenous (IL) SL-172154 on schedule 1 or 2. Treatment was administered until progressive disease, intolerable toxicity, or withdrawn consent. Patients are currently being enrolled to receive the agent at dose level 5.

The primary objective of the research was to assess for safety and identify the maximum tolerated dose of SL-172154. Secondary objectives included identifying the recommended phase 2 dose, characterizing the PK and immunogenicity of the agent, and evaluating antitumor activity per RECIST v1.1 criteria for solid tumors. Exploratory objectives comprised assessment of receptor occupancy of SIRPα and CD40 on peripheral blood mononuclear cells and investigation of pharmacodynamic (PD) effects in the blood and tumor tissue.

At a data cutoff of September 15, 2021, a total of 15 patients were enrolled; these patients had received a median of 5 prior lines of systemic therapy (range, 2-7) and were given IV SL-172154 across 4 dose levels on 2 schedules. Six patients received treatment on schedule 1, and 9 received treatment on schedule 2.

The median age of participants was 67 years (range, 33-79). Sixty percent of patients had ovarian cancer, 27% had primary peritoneal cancer, and 13% had fallopian tube cancer. Moreover, 60% had FIGO stage IV disease, and the remainder had stage III disease. Most patients (73%) had high-grade disease. Regarding histology, 73% had serous carcinoma, 13% had adenocarcinoma, and 13% had serous adenocarcinoma. Thirteen patients had an ECOG performance status of 1 at baseline.

Additional PK data from the trial showed that Cmax and AUCinf increased disproportionately as the dose of the agent increased. Clearance decreases were also observed with increasing doses. Moreover, the PK appeared to be biphasic at 1.0 mg/kg and 3.0 mg/kg, according to the study authors. However, the elimination phase of the curve was not fully characterized at the doses evaluated.

SL-172154 was also found to stimulate reproducible increases in serum cytokines after repeated dosing, and the agent also stimulated dose-dependent and reproducible increases in serum IL-12. Moreover, the agent was also noted to preferentially bind CD47 on leukocytes, but not RBCs. The drug stimulated dose-dependent B-cell margination and activation.

Regarding safety, all 15 patients experienced any-grade adverse effects (AEs). Toxicities included fatigue (60%), infusion-related reactions (IRRs; 53%), nausea (33%), diarrhea (27%), decreased appetite (20%), dehydration (20%), pruritus (20%), abdominal distention (13%), back pain (13%), chills (13%), constipation (13%), dyspnea (13%), hypomagnesemia (13%), injection site reactions (13%), and vomiting (13%).

Three grade 3 AEs were reported and included sepsis, embolism, and IRR, although these toxicities were not determined to be associated with the study drug. No grade 4 or 5 toxicities were observed.

Ninety-three percent of patients experienced treatment-related AEs (TRAEs), which comprised IRR (53%), fatigue (47%), nausea (27%), decreased appetite (20%), chills (13%), diarrhea (13%), and dyspnea (13%). No grade 3 or higher TRAEs were experienced.

Fifty-three percent of patients experienced IRRs; this included 3 patients who received the agent at a dose of 0.3 mg/kg, 2 who received it at a dose of 1.0 mg/kg, and 3 who received it at a dose of 3.0 mg/kg. One of these effects was grade 3 in severity and was determined to be secondary to iron infusion. Fourteen IRRs were grade 2 and 2 were grade 1. These effects were noted to be manageable with pre-medications and did not prevent the completion of dosing or result in discontinuation.

Notably, no DLTs were reported with SL-172154 on either schedule, with doses ranging from 0.1 mg/kg to 3.0 mg/kg.

Eighty-seven percent of patients discontinued treatment with the agent; 12 of the 13 patients discontinued because of radiological or clinical progression and 1 patient chose to stop treatment.

“SL-172154 has been well-tolerated at doses which saturate both CD40 and CD47, with evidence of on-target PD activity which has not yet plateaued, warranting further dose escalation,” the study authors concluded.

Lakhani NJ, Richardson D, Kristedja T, et al. Phase 1 dose escalation study of the agonist redirected checkpoint, SL-172154 (SIRPα-Fc-CD40L) in subjects with platinum-resistant ovarian cancer. Presented at: 2021 SITC Annual Meeting; November 10-14, 2021; Washington DC. Abstract 429.

This article was originally published on OncLive as “SL-172154 Shows Favorable Tolerability in Platinum-Resistant Ovarian Cancer”

In a phase 1 dose-escalation trial, treatment with the investigative agent was well tolerated with no dose-limiting toxicities.

SL-17154 Appears Promising, Tolerable in Treatment of Platinum-Resistant Ovarian Cancer

A long-term follow-up analysis of a phase 1b/2 study found that patients with previously treated, advanced endometrial cancer experienced durable responses with a manageable safety profile after receiving the combination of lenvatinib (Lenvima) plus pembrolizumab (Keytruda). Vicky Makker, MD, preented the updated findings from the trial (NCT02501096) during the 2021 Society for Immunotherapy of Cancer (SITC) Annual Meeting.

“With extended follow-up, this updated analysis continued to show durable responses, as well as [survival] benefits in patients with challenging to treat, advanced endometrial cancer who received lenvatinib plus pembrolizumab,” said Makker, MD, a medical oncologist at Memorial Sloan Kettering Cancer Center in New York, New York. “The safety profile [for the combination] was generally consistent with that of the individual monotherapies.”

At the August 18, 2020, data cutoff, the total population of the analysis included 108 patients. The objective response rate (ORR) was 39.8% (95% CI, 30.5%-49.7%), including 9 (8.3%) complete responses (CRs). The median progression-free survival (PFS) was 7.4 months (95% CI, 5.2-8.7) and the median overall survival (OS) was 17.7 months (95% CI, 15.5-25.8). The median duration of response (DOR) was 22.9 months (95% CI, 10.2-not evaluable [NE]).

To be eligible for the open-label, single-arm trial, patients needed to have histologically confirmed and metastatic endometrial carcinoma measurable by immune-related RECIST. A maximum of 2 prior systemic therapies were permitted and patients needed to have an ECOG performance status of 1 or less. The study required patients have a minimum life expectancy of at least 12 weeks.

Investigators administered oral lenvatinib at a dose of 20 mg per day; 200 mg pembrolizumab was administered intravenously every 3 weeks. Pembrolizumab could be given for a maximum of 35 cycles and lenvatinib could continue beyond this point as long as benefit was observed. The primary end point of the trial was ORR at week 24. Key secondary end points included overall ORR, disease control rate (DCR), DOR, and progression-free survival (PFS).

The mean age of the total population was 65.1. Most patients (50.9%) had an endometroid carcinoma and 32.4% had a serous adenocarcinoma. The vast majority of the population (98.1%) had previously been treated for endometrial cancer with a platinum plus taxane combination and 49.1% of patients were PD-L1 positive.

The end points of the follow-up analysis included ORR, PFS, DOR, OS, and safety. The median follow-up duration was 34.7 months (95% CI, 30.9-41.2). The analysis population included 94 patients who were MMR proficient (pMMR) and 11 patients who were MMR deficient (dMMR).

In the pMMR cohort, the mean age was 65.4 and 48.9% of patients were PD-L1-positive. An even number (50%) of patients received 1 or 2 prior treatments for endometrial cancer. Common histological subtypes included endometrioid adenocarcinoma (48.9%), serous adenocarcinoma (35.1%), and clear cell adenocarcinoma (5.3%). Nearly all (98.1%) had been previously treated for endometrial cancer with a platinum plus taxane combination.

In the dMMR group, the mean age was 62.4 and most patients were PD-L1-positive (63.6%). All patients had been previously treated for endometrial cancer with a platinum plus taxane combination and 36.4% had undergone 2 prior treatment regimens. The most common histological subtype was endometrioid carcinoma (72.7%), of which 36.4% of patients were FIGO grade 2.

Among the patients who were pMMR, the ORR was 38.3% (95% CI, 28.5%-48.9%) and 8 patients achieved a CR. The median DOR was 25.0 months (95% CI, 8.5-NE) and the mean time to response was 3.2 months. The median PFS was 7.4 months (95% CI, 4.4-7.6) and the median OS was 17.2 months (95% CI, 15.0-28.5).

In the dMMR cohort, the ORR was 63.6% (95% CI, 30.8%-89.1%). The median DOR was 21.2 months (95% CI, 7.33-NE). Notably, the median OS was NE (95% CI, 7.4-NE) and the median PFS was 26.4 months (95% CI, 4.0-NE).

In terms of safety, 96.3% of the total population experienced any treatment-related treatment-emergent adverse events (TEAEs). Most patients (74.1%) experienced a TEAE that lead to study-drug interruption and 21.3% had a TEAE that lead to study-drug discontinuation. TEAEs of grade 3 or higher were reported in 71.3% of patients.

Common TEAEs of any grade included hypertension (60.2%), diarrhea, fatigue (both 53.7%), decreased appetite (50%), and hypothyroidism (46.3%). Grade 3 or higher TEAEs included hypertension (33.3%), fatigue (8.3%), and diarrhea (7.4%).

“Study 309/KEYNOTE-775 (NCT03517449), a confirmatory study of lenvatinib plus pembrolizumab vs treatment of physician’s choice in advanced endometrial cancer, further supports the lasting clinical benefits observed in this follow-up study,” concluded Makker.

On July 21, 2021, the FDA granted a full approval to lenvatinib plus pembrolizumab for the treatment of patients with advanced endometrial carcinoma that is not microsatellite instability-high or dMMR, who have disease progression after previous systemic therapy in any setting, and who are not candidates for curative surgery or radiation based on data from the KEYNOTE-775 trial.

Makker V, Aghajanian C, Cohn AL, et al. Lenvatinib and pembrolizumab in advanced endometrial carcinoma: long-term efficacy and safety update from a phase 1b/2 study. Presented at: 2021 Society for Immunotherapy of Cancer (SITC) Annual Meeting; November 10-14, 2021; Washington, DC. Abstract 354.

FDA grants regular approval to pembrolizumab and lenvatinib for advanced endometrial carcinoma. News release. FDA. July 22, 2021. Accessed September 6, 2021. https://bit.ly/3wRB9Sw

This article was originally published on OncLive as “Lenvatinib Plus Pembrolizumab Displays Strong Efficacy in Advanced Endometrial Cancer”

A presentation at the 2021 Society for Immunotherapy of Cancer (SITC) Annual Meeting shared updated findings on the efficacy of lenvatinib plus pembrolizumab in patients with advanced endometrial cancer. 

Lenvatinib/Pembrolizumab Combo Continues to Show Benefit in Advanced Endometrial Cancer

Endometrial cancer is a molecularly driven malignancy with 4 distinct subtypes. In a presentation during the 

 Chemotherapy Foundation Symposium Innovative Cancer Therapy for Tomorrow® (CFS®),Bhavana Pothuri, MD, MS, explained how recent regulatory approvals of checkpoint blockade has significantly progressed the management of this cancer type.

Moreover, Pothuri added that phase 3 trials of other immune-based combinations with chemotherapy, PARP inhibitors, and other novel agents are on the horizon to target some of these select subsets.

“The endometrial cancer treatment paradigm has changed significantly and will continue to evolve,” said Pothuri, a professor in the Department of Obstetrics and Gynecology and Medicine at NYU Grossman School of Medicine, and director of Gynecologic Oncology Clinical Trials at NYU Langone Health’s Laura & Isaac Perlmutter Cancer Center.

Pothuri dedicated her CFS® presentation to the late Franco M. Muggia, MD, a leader in the field of gynecologic oncology who died on September 8, 2021. Pothuri called Muggia her “dear friend and mentor,” and was most recently involved with him on endometrial cancer research.

Endometrial cancer is comprised of 4 distinct subtypes: 

-mutant, microsatellite instability–high (MSI-H)/mismatch repair deficient (dMMR), copy number (CN) low, and CN high/

-mutant disease tend to have the best prognosis compared with CN-low and MSI/dMMR disease (intermediate outcomes), and CN-high/

Up until 2017, the sole FDA-approved therapy in the endometrial cancer armamentarium was megestrol acetate. Now, clinical practice has benefitted from 3 new regimens that are available based on patients’ molecular profiles: pembrolizumab (Keytruda), dostarlimab-gxly (Jemperli), and pembrolizumab plus lenvatinib (Lenvima).

Recent Regulatory Advances in Endometrial Cancer Treatment

The PD-1 inhibitor pembrolizumab was explored in the open-label, nonrandomized, phase 2 KEYNOTE-158 trial (NCT02628067), which comprised previously treated patients with advanced MSI-H/dMMR tumors, including endometrial cancer. Patients received either pembrolizumab at 200 mg every 3 weeks, or at 10 mg/kg every 2 weeks.

Preliminary findings from all-comers showed that the objective response rate (ORR) was 39.6% (95% CI, 31.7%-47.9%), and responses lasting at least 6 months occurred in 78% of responders.

The FDA granted a tissue-agnostic approval in May 2017 to pembrolizumab based on the preliminary KEYNOTE-158 data, making it the first regulatory approval based on a biomarker regardless of tumor type.

Longer follow-up of the endometrial cancer cohort was presented at the 2021 ESMO Congress, which had a data cutoff date of October 5, 2020.4 In the efficacy-evaluable population of the endometrial group (cohorts D and K; n = 79), the ORR was 48% (95% CI, 37%-60%), which included a 14% complete response (CR) rate and a 34% partial response rate; 18% of patients had stable disease.

The median time to response was 2.3 months (range, 1.3-10.6). Additionally, the median duration of response (DOR) had not been reached, but 68% of patients were still in response at 3 years. The median progression-free survival (PFS) and overall survival (OS) was 13.1 months (95% CI, 4.3-34.4) and not reached (NR; 95% CI, 27.2-NR), respectively.

Safety with pembrolizumab was consistent with that of other checkpoint inhibitors. Treatment-related adverse events (TRAEs) occurring in at least 10% of patients included pruritus (24%), fatigue (21%), diarrhea (16%), arthralgia (14%), nausea (14%), hypothyroidism (13%), and rash (11%). Immune-related AEs (irAEs) at any grade occurred in 28% of patients, but 7% of patients experienced these as grade 3/4 events, including colitis (n = 1), severe skin reactions (n = 2), type 1 diabetes mellitus (n = 1), hepatitis (n = 1), and adrenal insufficiency (n = 1).

The multicenter, single-arm, multiple parallel-cohort, open-label, phase 1b GARNET trial (NCT02715284) evaluated single-agent dostarlimab, a PD-1 inhibitor, in expansion cohorts across multiple tumor types, including endometrial cancer. Patients were treated with dostarlimab at 500 mg of intravenous (IV) every 3 weeks for 4 cycles followed by 1000 mg IV every 6 weeks until disease progression.

The trial featured dose-finding (part 1), fixed-dose safety run-in (part 2A), and expansion cohorts (part 2B). In the expansion cohort, there were 5 groups: dMMR endometrial cancer, MMR proficient (pMMR) endometrial cancer, non–small cell lung cancer, nonendometrial dMMR/MSI-H cancer, and platinum-resistant ovarian cancer.

Dostarlimab elicited a 42.3% ORR in 71 patients with dMMR recurrent or advanced endometrial cancer, which included a 12.7% CR rate and a 29.6% PR rate.

 The DOR was at least 6 months for 93.3% of responders, and the median DOR was not reached at a median follow-up of 14.1 months (range, 2.6-22.4+).

At a median follow-up of 16.5 months, the ORR via investigator-assessed irRECIST criteria was 45.5% in patients with dMMR endometrial cancer (n = 110).

Based on the GARNET findings, the FDA granted an accelerated approval in April 2021 to dostarlimab for the treatment of patients with recurrent or advanced endometrial cancer that has progressed on or following prior treatment with a platinum-containing chemotherapy and whose cancers are dMMR, as determined by an FDA-approved test.

The safety profile with dostarlimab was also found to be manageable. Any-grade treatment-emergent AEs (TEAEs) occurred in 69.9% of patients; grade 3 or higher irTRAEs had an incidence of 1.6% or lower. Additionally, increased alanine aminotransferase led to discontinuation in 1.4% of patients, but no TRAEs led to death.

Microsatellite Stable/pMMR: Pembrolizumab/Lenvatinib

The combination of pembrolizumab and lenvatinib was tested in patients with advanced endometrial cancer who received prior platinum-based chemotherapy in the phase 3 Study-309/KEYNOTE-775 trial (NCT03517449).

At a median follow-up of 11.4 months and in those with microsatellite stable (MSS)/pMMR disease, the median OS was 17.4 months (95% CI, 14.2-19.9) with pembrolizumab/lenvatinib vs 12.0 months (95% CI, 10.8-13.3) with chemotherapy (HR, 0.68; 95% CI, 0.56-0.84; 

Results showed that the median PFS in patients with pMMR status was 6.6 months (95% CI, 5.6-7.4) and 3.8 months (95% CI, 3.6-5.0) with pembrolizumab/lenvatinib and chemotherapy, respectively (HR, 0.60; 95% CI, 0.50-0.72; 

 <.0001). Here, the ORR was 30.3% (95% CI, 25.5%-35.5%) with pembrolizumab/lenvatinib vs 15.1% (95% CI, 11.5%-19.3%) with physician’s choice; the median DOR was 9.2 months (range, 1.6-23.7) vs 5.7 months (range, 0.0-24.2), respectively.

In all-comers, the median OS was 18.3 months (95% CI, 15.2-20.5) and 11.4 months (95% CI, 10.5-12,9), respectively (HR, 0.62; 95% CI, 0.51-0.75; 

 <.0001). The median PFS was 7.2 months (95% CI, 5.7-7.6) with pembrolizumab/lenvatinib and 3.8 months (95% CI, 3.6-4.2) with chemotherapy (HR, 0.56; 95% CI, 0.47-0.66; 

 <.0001). The ORRs were 31.9% (95% CI, 27.4%-36.6%) and 14.7% (95% CI, 11.4%-18.4%) with pembrolizumab/lenvatinib and physician’s choice, respectively. Finally, the median DOR was 14.4 months (range, 1.6-24.2) and 5.7 months (range, 0.0-24.2).

Results of a subgroup analysis from KEYNOTE-775 demonstrated the improvement of pembrolizumab/lenvatinib over physician’s choice of therapy in patients with dMMR endometrial cancer. The median OS with pembrolizumab/lenvatinib-treated patients was NR (95% CI, NR-NR) compared with 8.6 months (95% CI, 5.5-12.9) for physician’s choice of therapy (HR, 0.37; 95% CI, 0.22-0.62; 

Here, the median PFS was 10.7 months (95% CI, 5.6–not reached [NR]) and 3.7 months (95% CI, 3.1-4.4), respectively (HR, 0.36; 95% CI, 0.23-0.57; 

 <.0001). The ORRs were 40.0% (95% CI, 28.0%-52.9%) and 12.3% (95% CI, 5.5%-22.8%), respectively.

The combination was given accelerated approval in September 2019, followed by a regular approval in July 2021, for use in patients with advanced endometrial carcinoma that is not MSI-H/dMMR, who have disease progression following prior systemic therapy in any setting and are ineligible for curative surgery or radiation.

Regarding safety, toxicities associated with pembrolizumab/lenvatinib were consistent with those observed with each therapy given individually. The most frequent all-grade and grade 3 or higher TEAEs included hypertension (64% and 38%, respectively), hypothyroidism (all-grade, 57%), diarrhea (54% and 8%, respectively), nausea (all-grade, 50%), and decreased appetite (45% and 8%, respectively).

Additional grade 3 or higher TEAEs with the combination included weight decrease (10%), anemia (6%), asthenia (6%), fatigue (5%), and proteinuria (5%). It should be noted that 5.7% of patients on pembrolizumab/lenvatinib died due to grade 5 gastrointestinal disorders (1.2%), cardiac disorders (0.5%), general disorders (1.5%), infections (0.7%), decreased appetite (0.2%), and neoplasms, nervous system, psychiatric, renal, reproductive, or respiratory disorders (0.2% each). This was compared with 4.9% of patients on the physician’s choice arm.

“There are overlapping toxicities to also keep in mind, with the diarrhea and the hypothyroidism. It’s important to sort out: Are those related to the immunotherapy or to the lenvatinib?” Pothuri asked.

Ongoing phase 3 trials are tackling more checkpoint inhibitors alone or in combination in endometrial cancer, including RUBY (NCT03981796) with dostarlimab with carboplatin/paclitaxel, RUBY Part 2 with dostarlimab plus niraparib (Zejula; NCT03981796), AtTEnd (NCT03603184) with atezolizumab (Tecentriq), NRGY018 (NCT03914612) with pembrolizumab plus carboplatin/paclitaxel, KEYNOTE-B21 (NCT04634877) with pembrolizumab plus adjuvant chemotherapy with or without radiotherapy, and LEAP-001 (NCT03884101) with pembrolizumab plus lenvatinib.

Although CN-low endometrial cancer represents a subgroup of patients that has long been treated with chemotherapy, Pothuri admits that this likely not the optimal approach for this subset.

An additional trial of interest is the phase 2 ENGOT-EN3/NSGO-PALEO study (NCT02730429), which enrolled patients with primary stage IV or relapsed measurable/evaluable endometrial cancer who have received at least 1 prior systemic therapy. Patients were randomized 1:1 to receive palbociclib (Ibrance) at 125 mg days 1 to 21 plus letrozole at 2.5 mg on days 1 to 28 vs placebo and letrozole at the same dosage schedule every 28 days until disease progression. The primary end point was investigator-assessed PFS.

Data showed that the median PFS was 8.3 months and 3.0 months for the palbociclib/letrozole and placebo/letrozole arms, respectively (HR, 0.56; 95% CI, 0.32-0.98; 

 Additionally, the disease control rate was 63.6% and 37.8%, respectively.

“This was a phase 2 study and needs further study to determine if there is a role of CDK4/6 and hormonal therapy,” Pothuri added.

Patients with CN-high endometrial cancer form a group that is classically comprised of 

 positive-tumors, Pothuri explained, adding that homologous recombination deficiency is frequent in this subset and may be actionable.

For example, in a phase 2 trial (NCT01367002), patients with HER2-neu uterine serous carcinoma were randomized to receive carboplatin/paclitaxel for 6 cycles with or without IV trastuzumab (Herceptin) until progression or unacceptable toxicity. Data showed that in all patients, the median PFS was 12.6 months with the addition of trastuzumab vs 8.0 months for carboplatin/paclitaxel alone (HR, 0.44; 90% CI, 0.26-0.76; 

 In those with primary stage III to IV disease, the median PFS was 17.9 months and 9.3 months, respectively (HR, 0.40; 90% CI, 0.20-0.80; one-sided 

 = .013). In recurrent disease, the median PFS was 9.2 months and 6.0 months, respectively (HR, 0.14; 90% CI, 0.04-0.53; 

An updated analysis showed an OS benefit in the stage III to IV subgroup, in which the median OS was not reached in the trastuzumab arm vs 25.4 months with chemotherapy alone (HR, 0.49; 90% CI, 0.25-0.97; 

“[There is] lots of great interest and it is really an exciting time to be in the endometrial cancer space,” Pothuri said. “The role of trastuzumab and other HER2/neu-directed therapies for CN-high biomarker-positive tumors also needs further investigation in phase 3 trials.”

Pothuri B. Biomarker driven management of endometrial cancer. Presented at: 39th Annual CFS®: November 3-5, 2021; New York, NY.

Levine DA,The Cancer Genome Atlas Research Network. Integrated genomic characterization of endometrial carcinoma. 

 2013;497(7447):67-73. doi:10.1038/nature12113

FDA grants accelerated approval to pembrolizumab for first tissue/site agnostic indication. FDA. May 23, 2017. Accessed November 4, 2021. https://bit.ly/3k62CMS

O’Malley DM, Bariani GM, Cassier PA, et al. Pembrolizumab (pembro) in patients (pts) with microsatellite instability-high (MSI-H) advanced endometrial cancer (EC): Updated results from KEYNOTE-158. 

. 2021;32(suppl_5):S725-S772. doi:10.1016/annonc/annonc703

Oaknin A, Tinker AV, Gilbert L, et al. Clinical activity and safety of the anti–programmed death 1 monoclonal antibody dostarlimab for patients with recurrent or advanced mismatch repair–deficient endometrial cancer: a nonrandomized phase 1 clinical trial. 

. 2020;6(11):1766-1772. doi:10.1001/jamaoncol.2020.4515

6. Oaknin A, Gilbert L, Tinker AV, et al. Interim analysis of the immune-related endpoints of the mismatch repair deficient (dMMR) and proficient (MMRp) endometrial cancer cohorts from the GARNET study. 

. 2021;162(suppl 1):S12-S13. doi:10.1016/S0090-8258(21)00672-7

7. Makker V, Colombo N, Herráez AC, et al. A multicenter, open-label, randomized, phase 3 study to compare the efficacy and safety of lenvatinib in combination with pembrolizumab vs treatment of physician’s choice in patients with advanced endometrial cancer: Study 309/KEYNOTE-775. 

. 2021;162(suppl 1):S4. doi:10.1016/S0090-8258(21)00657-0

Mirza MR, BjørgeL, Marmé F, et al. A randomised double-blind placebo-controlled phase II trial of palbociclib combined with letrozole (L) in patients (pts) with oestrogen receptor-positive (ER+) advanced/recurrent endometrial cancer (EC): NSGO-PALEO / ENGOT-EN3 trial. 

. 2020;31(suppl_4):S1142-S1215. doi:10.1016/annonc/annonc325

Fader AN, Roque DM, Siegel E, et al. Randomized phase II trial of carboplatin-paclitaxel versus carboplatin-paclitaxel-trastuzumab in uterine serous carcinomas that overexpress human epidermal growth factor receptor 2/neu. 

. 2018;36(20):2044-2051. doi:10.1200/JCO.2017.76.5966

Fader AN, Roque DM, Siegel E, et al. Randomized phase II trial of carboplatin-paclitaxel compared with carboplatin-paclitaxel-trastuzumab in advanced (stage III-IV) or recurrent uterine serous carcinomas that overexpress her2/neu (NCT01367002): updated overall survival analysis. 

 2020;26(15):3928-3935. doi:10.1158/1078-0432.CCR-20-0953

This article was originally published on OncLive as “Checkpoint Blockade Moves Needle in Molecularly Driven Endometrial Cancer Paradigm”

An expert from NYU Langone outlines how checkpoint blockade approvals have helped advance endometrial cancer management. 

Checkpoint Blockade Drives Progress in Endometrial Cancer Treatment

Findings from a phase 2 trial suggest that patients with vulvar cancer and sentinel micrometastases may be able to avoid the morbidity of a lymphadenectomy by receiving inguinofemoral radiotherapy. Full study results the trial, 1 GROINSS-V-II ((NTR608/NL552) were recently published in the 

Of a total of 1535 patients registered to the trial, 21.0% (n = 322) had sentinel node metastasis. The stopping rule was activated in June 2010 because the isolated groin recurrence rate in 91 patients with sentinel node positivity went above the predefined threshold for the trial.

In 10 patients who had isolated groin recurrence, 9 had sentinel node metastases that were bigger than 2 mm and/or they had extracapsular spread. The trial protocol was amended so that those with macrometastases in the sentinel node, which was defined as bigger than 2 mm, received standard-of-care inguinofemoral lymphadenectomy (IFL). Those with sentinel node micrometastases, defined as smaller than 2 mm, continued to receive inguinofemoral radiotherapy.

Of the 160 patients with sentinel node micrometastases, 126 were given inguinofemoral radiotherapy and experienced a 2-year ipsilateral isolated groin recurrence rate of 1.6%. In the 162 patients with macrometastases in the sentinel nodes, the 2-year ipsilateral isolated groin recurrence rate was 22% in those who received radiotherapy and 6.9% in those given standard of care (

“GROINSS-V-II demonstrated that inguinofemoral radiotherapy in patients with sentinel node micrometastases results in a very low isolated groin recurrence rate, with acceptable treatment-related morbidity,” Maaike H. M. Oonk, PhD, of the Department of Obstetrics and Gynecology at The University Medical Center Groningen, The Netherlands, and colleagues, wrote. “For patients with sentinel node macrometastases, inguinofemoral radiotherapy with a total dose of 50 Gy is not a safe alternative for IFL in view of the higher risk of isolated groin recurrence.”

Over the past decade, several advances have been made in the treatment of patients with early-stage vulvar cancer. In those with unifocal tumors that are smaller than 4 cm and nonsuspicious groin nodes, a sentinel node biopsy has become standard of care rather than elective IFL. However, for those with sentinel node metastases, further treatment with IFL remains standard.

The GROINSS-V-I trial demonstrated that inguinofemoral lymphadenectomy can be safely omitted in patients who have negative sentinel nodes, leading to a significant decrease in morbidity. Patients with metastases in the sentinel node still need to undergo IFL to prevent groin recurrences, which are often fatal.

Investigators launched GROINSS-V-II to identify an equally effective, but less morbid, approach for patients with a metastatic sentinel node. To do this, they set out to determine whether inguinofemoral radiotherapy may represent a safe alternative to IFL in this population. They also wanted to examine the short- and long-term treatment-related morbidity for this strategy.

The prospective, multicenter, single-arm trial enrolled patients with early-stage vulvar cancer who were planned to undergo surgery. To be eligible for enrollment, patients needed to have unifocal microinvasive squamous cell carcinoma of the vulva that was less than 4 cm, and preoperative imaging of their groins could not reveal any suspicious nodes.

The primary end point of the research was the 24-month isolated groin recurrence rate.

Investigators utilized a radioactive tracer with performance of a lymphoscintigram and blue dye to perform sentinel node biopsies on study participants. When metastases were identified, the size and presence of extracapsular spread were noted. If the sentinel node could not be identified, an IFL was recommended. If the sentinel node was negative following ultrastaging, no further treatment was given. If tumor cells were detected, patients were regarded to have metastatic disease.

If metastatic disease in the sentinel node was identified, inguinofemoral radiotherapy was indicated. The decision of whether the treatment would be administered to 1 or both sides in those with unilateral sentinel node involvement was dependent on the participating center. Radiotherapy had to be given within 6 weeks after surgery, and it was given at a total dose of 50 Gy in 25 to 28 fractions of 1.8 Gy to 2.0 Gy, 5 fractions per week. The target dose of 50 Gy was selected because it was an effective dose for subclinical disease.

A total of 1708 patients were registered to the trial between December 2005 and October 2016. Among 1535 patients determined to meet the eligibility criteria for the trial, 79.0% (n = 1213) had a negative sentinel node and 21.0% (n = 322) had a metastatic sentinel node. Of the 322 patients with a metastatic sentinel node, 160 had micrometastases and 162 had macrometastases.

Among those with micrometastases, 78.8% (n = 126) were given inguinofemoral radiotherapy. Fourteen of these patients received radiotherapy plus chemotherapy; 9 were given cisplatin, and 5 had cisplatin and fluorouracil. Ten percent of the 126 patients underwent IFL rather than radiotherapy and 11.3% did not receive any further treatment because of either patient refusal, severe comorbidity, or older age.

Among the 160 patients, 6 isolated groin recurrences had occurred at 2 years following primary surgery; the 2-year rate was 3.8% (95% CI, 0.8%-6.8%) in this population. In the 126 patients who were given the radiotherapy, only 2 isolated ipsilateral groin recurrences were observed, in addition to 1 in a contralateral sentinel node–negative groin. Another 2 of 6 groin recurrences were reported in those who did not receive further treatment with IFL or radiotherapy. Additionally, 1 groin recurrence was observed in the contralateral sentinel node–negative groin following unilateral IFL for a metastatic node.

Among the 18 patients who were not given any additional treatment, the ipsilateral isolated groin recurrence rate proved to be higher than what was reported in those who received radiotherapy; the 2-year rates were 11.8% (95% CI, 0.0%-27.2%) and 1.6% (95% CI, 0.0%-3.9%), respectively (

Among the 162 patients who had macrometastases, 31.5% received only radiotherapy to the groins and 13.7% received radiotherapy plus chemotherapy in the form of cisplatin. Moreover, 64.8% of these patients (n = 105) had a unilateral or bilateral IFL; 56.2% of these patients also received adjuvant radiotherapy. Six patients did not receive further treatment following the removal of the sentinel nodes.

Among those with macrometastases, 19 groin recurrences were reported. The 2-year groin recurrence rates in those who received radiotherapy vs those who underwent IFL were 22.0% (95% CI, 10.5%-33.5%) and 6.9% (95% CI, 2.0%-11.8%), respectively. One recurrence was observed in a patient with 2 sentinel node macrometastases who did not receive any adjuvant treatment. No recurrences were reported in the contralateral nonirradiated groin.

Among those who received IFL, the groin recurrence rate in those who received adjuvant radiotherapy was not found to differ from those who did not receive adjuvant radiotherapy (

 = .43). In the 7 patients who received radiation plus chemotherapy, no recurrences were reported. A trend toward better disease control was observed in those who received this combination (

Of the 1213 patients who had sentinel node negativity, 31 had isolated groin recurrences. For 2 patients, metastases were noted to have been present in retrospect. In 4 patients, not all nodes visualized on the lymphoscintigram were removed. No concrete explanations were found for the other cases.

In patients with negative sentinel nodes, the estimated risk of disease-specific death at 2 years was 2.1% (95% CI, 1.3%-2.9%). In those with micrometastases, this rate was 6.5% (95% CI, 2.6%-10.4%); this rate was highest in those with macrometastases, at 25.5% (95% CI, 18.6%-32.5%; 

 < .0001). At 2 years following primary treatment, OS rates in those with negative sentinel nodes, micrometastases, and macrometastases were 95.2% (95% CI, 94.0%-96.5%), 88.3% (95% CI, 83.2%-93.4%), and 69.3% (95% CI, 62.0%-76.6%), respectively (

Of the 56 patients who experienced recurrence, 31 died from their disease during study follow-up. The estimated risk of disease-specific death at 2 years in those with macrometastases proved to be comparable in those who received IFL with or without radiotherapy and those who only received radiotherapy, at 24.2% (95% CI, 15.7%-32.6%) and 24.4% (95% CI, 12.4%-36.4%), respectively (

 = .88). Moreover, 25.5% of patients who received radiotherapy only died of vulvar cancer vs 22.9% of those who underwent IFL.

Notably, a sentinel node biopsy and subsequent radiotherapy to the groins was linked with low-grade toxicity. Cases of nausea, vomiting, mucositis, or anal and urinary incontinence were only grade 1 or 2 in severity. Diarrhea most frequently occurred at 4 to 6 weeks (grade 1, 12.3%; grade 2, 2.3%; grade 3, 0.6%) or 6 months following radiotherapy (7.9%, 0.0%, and 0.7%, respectively).

Moreover, 21.3% of patients reported grade 1 toxicity associated with the skin in the irradiated groin; in 14.8% and 1.3% of patients, respectively, this effect was grade 2 or 3 in severity. However, at 6 months, the incidence of this toxicity was found to significantly decrease. Notably, no grade 4 or 5 effects were observed.

Among patients who experienced lymphedema more than once at 6 months or 12 months following treatment, this effect was less frequent following biopsy alone, at 5.1% and 4.1%, respectively, vs when biopsy was done and followed by radiotherapy, at 16.4% and 10.7%, respectively (

 < .0001). The highest incidence of this toxicity was observed in those who underwent IFL, at 32.0% in those who also received radiotherapy and 22.9% in those who did not (

“Inguinofemoral radiotherapy for vulvar cancer patients with sentinel node micrometastases appears to be a safe alternative for IFL. The toxicity of radiotherapy is acceptable, and treatment-related morbidity is less frequent compared with IFL,” study authors concluded. “For patients with sentinel node macrometastases, radiotherapy with a total dose of 50 Gy showed more isolated groin recurrences than IFL.”

Inguinofemoral radiotherapy may be a safe alternative for patients with vulvar cancer and sentinel node micrometastases who might otherwise face the morbidity of a lymphadenectomy.

Gynecologic Cancers

Adding Bevacizumab to Pembrolizumab Enhances Response Rates in Epithelial Ovarian Cancer

SL-17154 Appears Promising, Tolerable in Treatment of Platinum-Resistant Ovarian Cancer

Lenvatinib/Pembrolizumab Combo Continues to Show Benefit in Advanced Endometrial Cancer

Checkpoint Blockade Drives Progress in Endometrial Cancer Treatment

Inguinofemoral Radiotherapy May Be Potential Alternative To Lymphadenectomy In Select Vulvar Cancer

FDA Approves Pembrolizumab Combination to Treat First-Line Cervical Cancer

Strategies That Combine Immunotherapies With Bevacizumab, Other Agents May Expand Utility of Immunotherapy in Recurrent Ovarian Cancer

New Research Seeks to Target Ovarian Malignant Germ Cell Tumors Without Compromising Fertility

Analysis Shows HPV Vaccine Not Associated with Infertility in Women

Loop Electrical Excision Procedure Superior to Cryotherapy in Clearing High-Risk HPV Infections