VB10.16, a first-in-class, off-the-shelf therapeutic cancer vaccine, yielded promising initial responses in patients with HPV16-positive advanced cervical cancer who were heavily pretreated and who were also receiving atezolizumab (Tecentriq), according to interim results from the phase 2 VB C-02 trial (NCT04405349) that were announced by Nykoke Therapeutics.

At a median follow-up of 6 months in 39 patients, data showed VB10.16 plus atezolizumab elicited an overall response rate (ORR) of 21%, including a complete response (CR) in 2 patients and a partial response (PR) in 6 patients. The disease control rate (DCR) was 64%.

“These interim results support Nykode’s unique approach of targeting antigen-presenting cells (APCs), designed to produce a robust and long-lasting CD8 killer T-cell response against cancer cells. We look forward to reporting updated efficacy data readouts from the phase 2 trial during the first half of 2023 as we continue to advance our cervical cancer program,” Michael Engsig, chief executive officer of Nykode Therapeutics, stated in a press release.

The single-arm, multicenter, open-label VB C-02 trial enrolled female patients who were at least 18 years of age with advanced or recurrent nonresectable HPV16-positive cervical cancer, including squamous cell carcinoma, adenosquamous carcinoma, or adenocarcinoma. Patients were required to have failed or be ineligible for systemic chemotherapy, radiotherapy, or other standard-of-care treatment.

Other eligibility criteria included a biopsy to assess PD-L1 status at screening; measurable disease per RECIST v1.1 criteria; recovery from the effects of surgery, radiation therapy, or chemoradiotherapy; an ECOG performance status of 0 or 1 at screening; and a life expectancy of at least 6 months per the best judgement of the investigator.

The primary end points of the study were incidence and severity of adverse effects (AEs), and ORR per RECIST v1.1 criteria. Secondary end points include duration of response, progression-free survival (PFS), overall survival, and the evaluation of immunogenicity of VB10.16 in combination with atezolizumab by analyzing HPV16 E6/E7-specific cellular immune responses.

Additional data from the interim results showed VB10.16 and atezolizumab elicited responses irrespective of PD-L1 status. In patients with PD-L1–positive disease, the ORR was 27% with a DCR of 77% compared with an ORR of 17% with a DCR of 58% in patients with PD-L1–negative disease. Patients with non-inflamed tumors had a DCR of 71%.

Per the press release, immunological analyses of the peripheral T-cell responses showed an increased HPV16-specific IFNγ T-cell immune response following vaccination in most subjects. These responses were associated with clinical efficacy, and the clearance of circulating HPV16 DNA was significantly correlated with clinical response and PFS, pointing to circulating tumor DNA as an early marker of response to treatment in cervical cancer.

After previously reporting positive interim safety data from the trial, this interim data found VB10.16 was generally safe and well tolerated. Notably, 10% of patients experienced grade 3 or higher treatment-related AEs, indicating no increased toxicity compared with atezolizumab monotherapy.

“The patients who were treated with VB10.16 in combination with atezolizumab in the C-02 trial were heavily pretreated and are prone to progress quickly. It is very encouraging to see that a majority of patients experienced a clinical benefit and that many patients had durable responses. The combination of VB10.16 and atezolizumab was also well tolerated by patients,” principal trial investigator Peter Hillemanns, MD, PhD, director of the Departments of Gynecology, Obstetrics and Breast Cancer at Hannover University Hospital in Germany, stated in a press release.

The VB C-02 trial is fully enrolled to date, with 52 patients across Europe.

Nykode Therapeutics announces positive interim results from its phase 2 trial with VB10.16 in combination with immune checkpoint inhibitor atezolizumab in advanced cervical cancer. News release. Nykode Therapeutics. May 9, 2022. Accessed May 10, 2022. 

Investigating the combination of VB10.16 and atezolizumab in patients with HPV 16-positive cervical cancer. ClinicalTrials.gov. Updated February 23, 2022. Accessed May 10, 2022. 

https://clinicaltrials.gov/ct2/show/NCT04405349

This article was originally published on OncLive as “VB10.16 Plus Atezolizumab Elicits Responses in HPV16-Positive Cervical Cancer”

Articles

Atezolizumab in conjunction with VB10.16, the first off-the-shelf therapeutic cancer vaccine, elicited encouraging responses in pretreated patients with HPV16-positive advanced cervical cancer.

Off-the-Shelf Cervical Cancer Vaccine Shows Promising Initial Results in HPV16+ Patients

mutated, platinum-sensitive, recurrent ovarian cancer who needed to reduce or interrupt treatment with olaparib during their first 12 weeks of treatment did not experience worse survival outcomes compared with those who received the recommended dose, according to ancillary findings from the SOLO2 study (NCT01874353). These data suggest that patients who need to alter their treatment with the PARP inhibitor because of adverse events (AEs) will not be negatively affected.

The findings, which were published in the 

, demonstrated that median overall survival (OS) rates were consistent across different dosages.

Relative dose intensity (RDI) represented the administered dosage compared with the recommended standard dose during the first 12 weeks of treatment, which is 30 mg twice a day. Investigators categorized participants as RDA greater than 98%, RDI 90% to 98%, and RDI less than 90%. After 12 weeks of olaparib, the mean 12-week RDI was 91.4%.

Furthermore, the median OS, following 12 weeks of olaparib, was 49.7 months in the greater than 98% group, 49.5% in the 90% to 98% group, and 54.1 months in the less than 90% group (

 = .84). The median PFS was 14.2 months, 49.5 months, and 54.1 months, respectively (

Moreover, patients were at an increased risk of requiring a dosage less than 90% of the recommended dose if they exhibited a baseline performance status of 1 (odds ratio [OR], 2.54; 95% CI, 1.11-5.82), any nausea (OR, 3.17; 95% CI, 0.9-11.23), or had a body weight of 70 kg or lower (OR, 1.86; 95% CI, 0.92-3.76).

The international, multicenter, double-blind, randomized, placebo-controlled, phase 3 SOLO2 trial enrolled patients with platinum-sensitive, relapsed ovarian cancer patients whose disease harbored a 

 mutation and who had been pretreated with at least 2 lines of previous chemotherapy. Patients were randomized to receive either maintenance olaparib (300 mg in two 150 mg tablets twice daily) or placebo. The trial revealed that olaparib yielded significantly longer PFS than placebo (19.1 vs 5.5 months, respectively), meeting its primary endpoint (HR, 0.30; 95% CI, 0.22-0.41; 

Because maintenance therapy is a long-term therapy, it is often associated with necessary alterations to mitigate potential AEs, the authors noted. Investigators analyzed data from SOLO2 to determine the impact of treatment interruptions or reductions on survival outcomes as well as to reveal which characteristics were linked with treatment alteration.

Throughout the SOLO2 study, AEs caused 50% of patients to interrupt treatment, 28% of patients to reduce their dosage, and 17% of patients to discontinue treatment. There were 110 patients in the RDI greater than 98% category, 29 patients in the RDI 90% to 98% category, and 45 patients in the RDI less than 90% category.

The association between RDI categories with progression-free survival (PFS) and overall survival (OS) were examined using a 12-week landmark Cox regression analysis. Logistic regression analysis was used to correlate baseline factors with RDI at 12 weeks.

No impact on survival from dose reduction and interruption for the management of olaparib associated adverse events. ESMO. News release. March 8, 2022. Accessed April 4, 2022. https://bit.ly/3NMOiWr

 The impact of olaparib dose reduction and treatment interruption on treatment outcome in the SOLO2/ENGOT-ov21 platinum-sensitive recurrent ovarian cancer. 

 2022;S0923-7534(22)00338-6. doi:10.1016/j.annonc.2022.02.222.

Pujade-Lauraine E, Ledermann JA, Selle F, et al. Olaparib tablets as maintenance therapy in patients with platinum-sensitive, relapsed ovarian cancer and a BRCA1/2 mutation (SOLO2/ENGOT-Ov21): a double-blind, randomized, placebo-controlled, phase 3 trial [published correction appears in 

. 2017;18(9):1274-1284. doi:10.1016/S1470-2045(17)30469-2

New research suggests that olaparib treatment interruption or dosage reduction is not linked with inferior survival outcomes in patients with BRCA1/2–mutated, platinum-sensitive, recurrent ovarian cancer.  

Olaparib Dosage Can Be Reduced Without Affecting Survival in Ovarian Cancer 

® spoke with Heidi Donovan, PhD, RN, professor of nursing and medicine, and co-director of the National Center on Family Support, at the University of Pittsburgh. Donovan recently co-led a study evaluating the utility of an online symptom management tool for women with recurrent ovarian cancer.

found that women who used the intervention experienced higher satisfaction with their symptom management.

“[In my opinion] some principles of our intervention are critical and actually overdue in clinical practice for ovarian cancer and other cancers,” she noted, emphasizing the importance of systematic symptom assessment in clinical settings, and enhancing women’s confidence in their ability to manage their symptoms, as well as their confidence communicating these symptoms to their healthcare providers.

“[By systematic] I mean [asking] the same questions repeatedly, over time, in order to pick up on changes that that are affecting patients and on symptoms that are affecting their quality of life, and their ability to function on a day-to-day basis,” she said. “The second principle was really enhancing women's confidence… A lot of what we did in this intervention was try to motivate women to recognize how much [of an] effect their symptoms were [causing] and build their confidence in their ability or their knowledge of things that they could try to get better management.”

Donovan HS, Sereika SM, Wenzel LB, et al. Effects of the WRITE symptoms interventions on symptoms and quality of life among patients with recurrent ovarian cancers: an NRG Oncology/GOG Study (GOG-0259). Published online ahead of print February 7, 2022. 

Podcasts

In this episode of “The Vitals,” Heidi Donovan, PhD, RN, discusses novel symptom management intervention for women with recurrent ovarian cancer.

Bringing a New Approach to Symptom Management in Ovarian Cancer

Patients with solid tumors experienced promising initial responses with the CAR T-cell therapy BNT211. Furthermore, the treatment yielded tolerable safety results, according to data from a phase 1 trial (NCT04503278) that were presented at the 2022 AACR Annual Meeting.

The trial of BNT211, consisting of a Claudin-6 (CLDN6)-targeting CAR T-cell product plus the CAR T-cell cell-amplifying RNA vaccine (CARVac), had an overall response rate (ORR) of 43% and an acceptable safety profile in 14 patients with relapsed/refractory testicular cancer, ovarian cancer, or other solid tumors.

“We found robust engraftment of CAR T cells in all patients, which translated into a very encouraging clinical benefit with an ORR of 43% and a disease control rate of 86%. CARVac really supports the T-cell engraftment and also mediates expansion,” John Haanen, MD, PhD, director of the Center for Cellular Therapy at the Netherlands Cancer Institute and professor of translational immunotherapy of cancer at Leiden University, said during his presentation.

CAR T-cell therapy has demonstrated limited success in patients with solid tumors. CLDN6 was identified as a tumor-specific antigen expressed in solid tumors but silenced in adult healthy tissue during organogenesis, leading to the development of a second-generation CAR T-cell product with high affinity and specificity for CLDN6. In addition, CARVac encoded with CLDN6 has previously been demonstrated to promote expression and persistence of CLDN6 CAR T cells.

In part 1 of the study, patients received 1 course of lymphodepletion (LD) followed by dose escalation of CAR T cells to assess dose-limiting toxicities (DLTs) and determine a recommended phase 2 dose. In the second part, patients received a dose escalation of CAR T cells and CARVac starting on day 4. There were 2 dose levels in each part. Doses were increased every 3 weeks and CARVac was administered every 6 weeks.

As of March 10, 2022, 3 cohorts with a total of 16 patients were treated, and 1 more cohort is ongoing. The patient population included 8 patients with testicular cancer, 4 with ovarian cancer, and 4 with other solid tumor types.

Robust CAR T-cell engraftment was seen in all patients across dose levels and in both parts. At an assessment 6 weeks following infusion, 14 of 16 patients were evaluable. There were 6 partial responses (PR), 5 with stable disease (SD) with shrinkage of target lesions, and 1 with SD alone. At 12 weeks, patients with a PR showed a deepening of response including 1 complete response (CR), though investigators observed disease progression in 5 patients who had previously had SD or PR.

“These early responses unfortunately don’t appear to be as durable as we would have hoped because only 1 patient in the analysis set had a response past 18 weeks and that was the CR,” Vincent K. Lam, MD, assistant professor of oncology and director of the Esophageal Cancer Research Program at Johns Hopkins University, said during the conference presentation. “We do note, though, that there’s another patient with ongoing PR at about 6 weeks and we await further follow-up.”

The patient with CR had failed 6 previous lines of treatment for testicular cancer. His remission included a lowered level of alpha-fetoprotein that has lasted for 6 months. This patient’s CAR T cells persisted for 150 days and had a dominant phenotype of effector memory cells re-expressing CD45RA, while other patients had a phenotype of effector memory cells negative for CCR7 and CD45RA.

Two cases of DLTs were observed, 1 in each arm. In the monotherapy arm, prolonged cytopenia was observed after LD in a patient with testicular cancer who had recently received high-dose chemotherapy and autologous stem cell transplant, leading to the creation of a cohort who would receive reduced or no LD. Hemophagocytic lymphohistiocytosis occurred in a patient with ovarian cancer in the CARVac arm before CARVac was started. Both toxicities were managed successfully.

Grade 3 or higher adverse events were mainly caused by LD or were asymptomatic enzyme elevations. Manageable grade 1 or 2 cytokine release syndrome occurred in 8 patients, 7 of whom were in the CARVac arm and 70% of whom were treated with the higher dose level. These patients showed an increase in interleukin-6 and elevated lipase but were confirmed to not have pancreatitis.

According to Lam, “CARVac appears safe in combination with CLDN6 CAR T, but CAR T persistence does not appear to be consistently enhanced yet.” He suggested that more optimal timing, dose, and duration of CARVac could maximize its effectiveness in mediating CAR T cell persistence.

Though these data are preliminary, and the study population is small, it suggests a future role for CAR T cells in solid tumors including testicular and ovarian cancer as well as CLDN6’s potential as a targetable biomarker.

“The infusion of CLDN6 CAR T, alone or in combination with CARVac, is safe and holds promise for patients with CLDN6-positive cancers,” Haanen stated in a press release.

“CLDN6 was never targeted before with cellular therapy, but in our study, this approach is already showing efficacy that may be better than the data from other CAR T trials in solid tumors.”

Haanen JB, Mackensen A, Koenecke C, et al. CT002 - BNT211: A Phase I trial to evaluate safety and efficacy of CLDN6 CAR-T cells and CARVac-mediated in vivo expansion in patients with CLDN6-positive advanced solid tumors. Presented at: American Association for Cancer Research Annual Meeting; April 8-13, 2022; New Orleans, LA. Abstract CT002.

Reinhard K, Rengstl B, Oehm P, et al. An RNA vaccine drives expansion and efficacy of claudin-CAR-T cells against solid tumors. 

. 2020;367(6476):446-453. doi:10.1126/science.aay5967

New CAR T-cell Therapy for Solid Tumors Was Safe and Showed Early Efficacy. American Association for Cancer Research. Published April 10, 2022. Accessed April 11, 2022. https://bit.ly/3KrcZFY

Findings from a phase 1 trial evaluating CAR T-cell therapy in patients with solid tumors showed promising clinical benefit with the treatment strategy.  

Investigators Inch Closer to Unlocking CAR T-Cell Therapy Potential in Solid Tumors

Courtney Arn, APRN-CNP, a nurse practitioner in the Division of Gynecologic Oncology, The Ohio State University Wexner Medical Center and The James Comprehensive Cancer Center, discusses the recent FDA approval of pembrolizumab (Keytruda) for patients with microsatellite instability–high (MSI-H)/mismatch repair deficient (dMMR) advanced endometrial carcinoma.

On March 21, 2022, the FDA approved pembrolizumab monotherapy to treat patients with MSI-H or dMMR advanced endometrial carcinoma. This approval provides patients with an effective treatment option with manageable toxicity, according to Arn.

The decision is based off findings from cohorts D and K of the KEYNOTE-158 trial (NCT02628067). Findings showed that the objective response rate (ORR) was 46% (95% CI, 35%-56%) among patients who received pembrolizumab. Furthermore, at a median follow-up of 16.0 months (range, 0.5-62.1), the complete response (CR) rate among this population was 12% and the partial response rate was 33%.

Among patients who responded to treatment, 68% reported responses lasting 12 months or longer, and 44% reported responses lasting 24 months or longer. No median duration of response (DOR) was reached (range, 2.9-55.7 months).

In terms of safety, the drug has demonstrated promising toxicity levels, according to Arn. It is also a straightforward drug to administer to patients, she added.

“[There is a] very low risk of [developing] a hypersensitivity reaction to pembrolizumab, but there is a possibility of having a hypersensitivity infusion–related reaction,” said Arn. “These are a little bit different than with typical chemotherapy; they sometimes can become hypotensive, tachycardic, or have a fever. This hypersensitivity is usually managed with IV fluids, antipyretic, or antihistamines to help stop the reaction.”

“If it is a mild reaction, they can restart the infusion,” she continued. “However, it might be in a patient's best interest to give pre-medications or give the infusion over a slower rate if they do have an infusion-related reaction.”

Videos

Courtney Arn, APRN-CNP, a nurse practitioner comments on the recent approval of pembrolizumab for patients with MSI-H/dMMR advanced endometrial carcinoma.

Nurse Takeaways: Latest Pembrolizumab Indication in Endometrial Cancer

First-line maintenance treatment with rucaparib (Rubraca) significantly improved progression-free survival (PFS) among patients with advanced ovarian cancer who had prior platinum-base chemotherapy, meeting the primary end point of the ATHENA-MONO study (NCT03522246).

Among the 538 patients randomized to receive rucaparib, the median PFS was 20.2 months with rucaparib compared with 9.2 months with placebo (HR, 0.52; 95% CI, 0.40-0.68; 

 <.0001) in the intent-to-treat population, according to an investigator review.

Similarly, in a homologous recombination deficiency [HRD]-positive population, the median PFS was 28.7 months with rucaparib compared with 11.3 months with placebo (HR, 0.47; 95% CI, 0.31-0.72; 

= .0004). Furthermore, in the HRD-negative population, the PARP inhibitor yielded a median PFS of 12.1 months vs 9.1 months with placebo (HR, 0.65; 95% CI, 0.45-0.95; 

Positive results were also observed in the exploratory 

mutant subgroup. In this population, the median PFS was not reached (NR) vs 14.7 months for those who received placebo (HR, 0.40; 95% CI, 0.21-0.75; 

.0041). These results were consistent among those with germline 

“I believe the significant improvement in PFS demonstrated in the ATHENA-MONO trial underscores the importance of first-line maintenance therapy and the benefit that rucaparib can provide to women with advanced ovarian cancer irrespective of HRD status,” Rebecca S. Kristeleit, MD, PhD, of Guy’s and St Thomas’ NHS Foundation Trust in London and lead ENGOT/NCRI National Cancer Research Institute investigator of the ATHENA trial, said in a news release.

“Ovarian cancer remains a leading cause of cancer-related death among women, which highlights the continued need for new treatment options and strategies for women with newly diagnosed disease. The ATHENA-MONO study demonstrates the role of rucaparib monotherapy in the first-line maintenance treatment setting for advanced ovarian cancer.”

The double-blind, placebo-controlled, phase 3 ATHENA trial sought to evaluate rucaparib as a first-line ovarian maintenance treatment in patients with high-grade ovarian, fallopian tube, or primary peritoneal cancer.2 In the ATHENA-MONO arm of the study, which pits the PARP inhibitor as a monotherapy against placebo, 538 women were enrolled. The ATHENA-COMBO arm, which is set to compare rucaparib/nivolumab with single-agent rucaparib, is expected to have results by 2023.

The trial did not yield any new safety signals in regard to previously reported adverse events (AEs). The most common 3/4 treatment-emergent AEs (TEAEs) included anemia/decreased hemoglobin (28.7%), neutropenia (14.6%), alanine aminotransferase and raised aspartate aminotransferase increase (10.6%), and thrombocytopenia (7.1%). Overall, 11.8% of patients receiving rucaparib needed to discontinue treatment because of TEAEs compared with 5.5% of patients receiving placebo.

In the experimental arm, 0.2% of patients experienced treatment-emergent myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML). No patients on the placebo arm experienced this TEAE.

“While PARP inhibitors have shown efficacy as first-line maintenance treatment for patients with advanced ovarian cancer, questions still remain about the patient population that may benefit from their use. The results of ATHENA-MONO address many of these unanswered questions and expands the opportunity for rucaparib in all patients regardless of biomarker status,” added Bradley J. Monk, MD, FACOG, FACS, at GOG Foundation, HonorHealth Research Institute, University of Arizona College of Medicine, Creighton University School of Medicine, Phoenix, AZ and global primary investigator of the ATHENA trial.

Additional analyses from the ATHENA-MONO will be presented at the 2022 ASCO Annual Meeting.

Clovis Oncology’s Rubraca (rucaparib) significantly improves progression-free survival in first-line maintenance treatment in women with ovarian cancer regardless of their biomarker status in phase 3 ATHENA-MONO trial. Clovis Oncology. March 31, 2022. Accessed March 31, 2022. 

Monk BJ, Coleman RL, Fujiwara K, et al. ATHENA (GOG-3020/ENGOT-ov45): a randomized, phase III trial to evaluate rucaparib as monotherapy (ATHENA-MONO) and rucaparib in combination with nivolumab (ATHENA-COMBO) as maintenance treatment following frontline platinum-based chemotherapy in ovarian cancer. 

. 2021;31(12):1589-1594. doi:10.1136/ijgc-2021-002933

The PARP inhibitor rucaparib significantly prolonged progression-free survival compared with placebo as a first-line maintenance treatment in previously treated patients with ovarian cancer. 

Rucaparib Improves PFS in Advanced Ovarian Cancer

The recent FDA approval of pembrolizumab (Keytruda) for patients with microsatellite instability–high (MSI-H) or mismatch repair–deficient (dMMR) advanced endometrial carcinoma provides this patient population with an effective treatment option with a manageable toxicity profile, according to Courtney Arn, APRN-CNP.

Arn, a nurse practitioner in the Division of Gynecologic Oncology, The Ohio State University Wexner Medical Center and The James Comprehensive Cancer Center, was heavily involved in the KEYNOTE-158 study (NCT02628067). The findings of this trial informed the regulatory decision.

Cohorts D and K of KEYNOTE-158 showed that patients with unresectable or metastatic MSI-H or dMMR endometrial carcinoma who received pembrolizumab experienced an objective response rate of 46% (95% CI, 35%-56%). At a median follow-up of 16.0 months (range, 0.5-62.1 months), the complete response rate among this population was 12% and the partial response rate was 33%.

Moreover, 68% of responders experienced a response equal to or longer than 12 months, and 44% of these patients experienced a response of at least 24 months. The median duration of response has not yet been reached.

Under the indication for pembrolizumab, patients must have experienced disease progression following prior systematic therapy in any setting and are ineligible for curative surgery or radiation in order to be eligible for the PD-1 inhibitor.

 Arn discussed the significance of this approval and key nursing considerations for pembrolizumab administration.

 How will the recently approved indication for pembrolizumab impact this patient population?

 The full approval of pembrolizumab for patients with MSI-high endometrial cancer has a very positive impact on this patient population. It provides them with an additional treatment option that is well tolerated with manageable toxicities and has a clinically meaningful response.

Could you highlight dosing and administration with the immunotherapy?

Pembrolizumab is given as an intravenous (IV) infusion. Its dosage is 200 milligrams IV every 3 weeks. It's a 30-minute infusion. The patients do not require any premedication prior to their infusion. Following the 30 minutes, they can go home.

[There is a] very low risk of [developing] a hypersensitivity reaction to pembrolizumab, but there is a possibility of having a hypersensitivity infusion–related reaction. These are a little bit different than with typical chemotherapy; they sometimes can become hypotensive, tachycardic, or have a fever. This hypersensitivity is usually managed with IV fluids, antipyretic, or antihistamines to help stop the reaction.

If it is a mild reaction, they can restart the infusion. However, it might be in a patient's best interest to give pre-medications or give the infusion over a slower rate if they do have an infusion-related reaction.

Throughout the study, did you observe a need for specific patient education with the checkpoint inhibitor?

Patient education is very important, as well as education for other health care providers. First, you want to educate the patient on the possibility of immune-associated adverse events: pneumonitis, colitis, hypothyroidism, etc.

However, not only do you want to educate the patient on the possible adverse reactions, and the signs and symptoms to be looking for, but we also want to [ensure] that the whole team is aware of these possibilities too. In the past, if patients called in with a cough, we might defer to a primary care provider.

[However,] it is really important that everyone taking care of the patient is aware of the possible immune-related toxicities and making sure we are there intervening promptly. It is also helpful to have a multidisciplinary team involved. Referring to endocrinology, pulmonology, and even dermatology has been a great help for [our team] to [address] some of these conditions that can happen with immunotherapy.

Overall, we saw similar toxicities for patients being treated in KEYNOTE-158 as we do with immunotherapy for other solid tumors. [It has] a very consistent profile, and most of the patients managed well.

Courtney Arn, APRN-CNP, a nurse practitioner who supported cohorts D and K of the KEYNOTE-158 study, discusses the recent approval of pembrolizumab for patients with MSI-H/dMMR advanced endometrial carcinoma.

FDA Follow-Up: Utilizing Pembrolizumab for MSI-H/dMMR Advanced Endometrial Carcinoma

Patients with advanced ovarian cancer, regardless of biomarker status, experienced encouraging responses after receiving niraparib (Zejula) in combination with bevacizumab (Avastin) as a second-line treatment following platinum-based chemotherapy, according to findings presented in an updated analysis of the phase 2 OVARIO study (NCT03326193) during the 2022 SGO Annual Meeting on Womens’ Cancer.

Furthermore, the combination has demonstrated a safety profile consistent with that typically observed with each agent as a monotherapy, according to Melissa Hardesty, MD, MPH.

At the data cutoff point, in June 2021, the PARP inhibitor niraparib plus the VEGF inhibitor bevacizumab yielded a median progression-free survival (PFS) of 19.6 months (95% CI, 16.5-25.1). Moreover, the 18-month PFS rate was 62% (95% CI, 52%-71%) and the 24-month PFS rate was 53% (95% CI, 43%-63%). Overall, the median follow-up time was 28.7 months (interquartile range, 23.9-32.5).

“OVARIO enrolled a high-risk population,” said Hardesty, a gynecologic oncologist with Alaska Women’s Cancer Care in Anchorage. “More than half of the patients remained progression-free at 24 months. Clinical benefit [by PFS] was observed in the overall population, and across biomarker subgroups in a continuum.”

OVARIO enrolled patients with high-grade serous or endometrioid stage IIIB to IV epithelial ovarian, fallopian tube, or peritoneal cancer. Eligible patients achieved a complete response (CR), partial response (PR), or no evidence of disease (NED) result after treatment with front-line platinum-based chemotherapy plus bevacizumab.

Patients weighing less than 77 kg and/or with a platelet count below 150,000 per µL (n = 82) received niraparib 200 mg daily plus bevacizumab 15 mg/kg once every 3 weeks. All other patients (n = 23) were treated with niraparib 300 mg daily plus bevacizumab 15 mg/kg once every 3 weeks. All patients underwent tissue testing for HRD at enrollment.

The primary end point of the trial was PFS rate at 18 months. Secondary end points included median PFS, overall survival (OS), time to first therapy, and safety. PFS rate at 6 and 12 months were exploratory end points.

The median age of patients included in the trial was 60 (range, 37-82).Most patients had and ECOG performance status of 0 (63%), stage IIIC disease at diagnosis (68%), serous histology (95%). Investigators observed HRD positivity at a rate of 47%, and 63% of patients underwent prior treatment with neoadjuvant chemotherapy or IDS debulking surgery. A majority of patients had a CR or NED to their prior surgery or chemotherapy (58%) and 42% experienced a PR.

Results showed that the median time to first subsequent treatment was 17.5 months (95% CI, 14.5-20.7). Notably, median time to second progression was not evaluable (NE; 95% CI, 32.1-NE). OS data was immature at the time of the analysis, with an event rate of 23.8%.

Investigators noted a higher median PFS patients in HRD subgroup compared with the homologous recombination proficient (HRP) and homologous recombination not determined (HRnd) subgroups, 28.3 months (n = 49; 95% CI, 19.9-NE) versus 14.2 months (n = 38; 95% CI, 8.6-16.8) and 12.1 months (n = 18; 95% CI, 8-NE), respectively. Within the HRD subgroup, patients with 

alterations (n = 29) had a median PFS of NE (95% CI, 19.3-NE), while patients with 

wild-type mutations (n = 16) had a median PFS of 28.3 months (95% CI, 12.1-NE).

No new safety signals were observed with the combination; all patients experienced a treatment-related adverse event (TRAE) of any grade. Most patients (80%) had a TRAE of at least grade 3, with 77% of these determined to be related to niraparib and 51% attributed to bevacizumab. TRAEs leading to treatment interruption, dose reduction, or treatment discontinuation were reported in 88%, 74%, and 40% of patients, respectively.

The most common TRAEs of any grade included thrombocytopenia (70%), fatigue (57%), anemia, and nausea (both 52%). Commonly occurring TRAEs grade 3 or higher included thrombocytopenia (39%), anemia (34%), and hypertension (27%), among others.

Investigators also noted that treatment with niraparib plus bevacizumab resulted in no clinically meaningful impact on patient quality of life; the baseline score was 25.7 (standard deviation [SD], 3.79) with a mean change from baseline of -0.7 (SD, 0.35).

“There was no impact on quality of life as assessed by change in FOSI [Functional Assessment of Cancer Therapy-Ovarian Symptom Index] score,” Hardesty concluded.

Hardesty M, Krivak T, Wright GS, et al. OVARIO, a phase 2 study of niraparib + bevacizumab in advanced ovarian cancer following front-line platinum-based chemotherapy with bevacizumab: updated analysis. Presented at: SGO Annual Meeting on Women’s Cancer; March 18 -21, 2022; Phoenix, AZ. Abstract 40.

This article was published on OncLive as “Niraparib Plus Bevacizumab Shows Promise in High-Risk Ovarian Cancer Population”

The PARP inhibitor, niraparib, in conjunction with the VEGF inhibitor, bevacizumab, resulted in encouraging responses from patients with advanced ovarian cancer. 

Niraparib/Bevacizumab Combo Elicits Promising Responses in Advanced Ovarian Cancer, Regardless of Biomarker Status 

Patients with persistent, recurrent, or metastatic cervical cancer experienced favorable outcomes with pembrolizumab (Keytruda), with or without bevacizumab (Avastin), with manageable levels of toxicity, according to patient-reported outcome (PRO) data collected as part of the phase 3 KEYNOTE-826 trial (NCT03635567).

The PRO findings were presented as part of the 2022 SGO Annual Meeting on Women’s Cancer and demonstrated that these pembrolizumab yielded a -0.3 global geometric least square mean change from baseline (95% CI, -3.1 to 2.6) compared with -1.3 (95% CI, -4.2 to 1.7) with placebo (difference in least squares mean, 1.01; 95% CI, –2.7 to 4.7).

The global geometric least square change metrics were measured in accordance with the European Organisation for Research and Treatment of Cancer (EORTC): Quality of Life Questionnaire-Core 30 (QLQ-C30) for global health status (GHS)/quality of life (QOL) scores. Placebo was determined to have a numeric improvement over placebo in terms of QOL although its impact was not statistically significant.

“Overall findings from KEYNOTE-826 support pembrolizumab plus chemotherapy with or without bevacizumab as the new standard of care for women with persistent, recurrent, or metastatic cervical cancer whose tumors express PD-L1 [combined positive score] of 1 or more,” Bradley Monk, MD, FACOG, FACS, professor in the department of obstetrics and gynecology, University of Arizona College of Medicine, said in his presentation of the data.

Eligible patients were randomized 1:1 to receive 200 mg of intravenous pembrolizumab or placebo every 3 weeks for 35 cycles plus intravenous paclitaxel, cisplatin, or carboplatin for up to 6 cycles with or without 15 mg/kg of intravenous bevacizumab every 3 weeks.

Co-primary end points of the KEYNOTE-826 trial were progression-free survival (PFS) and overall survival (OS). Key secondary end points included overall response rate, duration of response, 12-month PFS rate, safety, and changes from baseline in QOL questionnaire scores. Changes in PROs was an exploratory end point of the research.

To be eligible for enrollment, patients needed a diagnosis of persistent, recurrent, or metastatic cervical cancer not amenable to curative treatment. In addition, they were required to have an ECOG performance score of 0 or 1, and could not have received prior chemotherapy.

The KEYNOTE-826 trial’s co-primary end points were previously reported, showing that pembrolizumab plus platinum-based chemotherapy with or without bevacizumab significantly improved PFS and OS over placebo while maintaining a tolerable safety profile.

“KEYNOTE-826 improved progression-free survival and overall survival, but it’s all about the patient experience,” Monk explained in his presentation of the data. “We have to contextual this clinical benefit to see if it satisfies the risk-benefit ratio in the clinic.”

To measure PROs, the investigative team used the EORTC: QLQ-C30, EuroQol 5-Dimension 5-Level visual analog scale questionnaire (EQ-5D-5L VAS), and the EORTC QLQ-CX24 Cervical Cancer questionnaire which were administered before every cycle of treatment through cycle 14, and then after every subsequent cycle, end of treatment, and at safety follow up visit.

All PRO end points were prespecified, with the change in EORTC QLQ-C30 global health status labeled as a key secondary end point. To ensure the data were reliable, 60% and 80% compliance rates were required in the pembrolizumab and placebo groups, respectively.

At 30 weeks, completion and compliance rates were sufficient among the pembrolizumab and placebo groups to create the study’s focal end point.

When looking at the EORTC QLQ-C30 scale, physical, role, cognitive, and social functioning were slightly worse in the pembrolizumab group compared with the placebo group. By the QLQ-CX24 scale, peripheral neuropathy was worse in the placebo group than the pembrolizumab group.

In the time to true deterioration (TTD) analysis, with deterioration defined as a 10-point decrease in PRO scores, the pembrolizumab arm performed numerically better than the placebo arm across most measures. For the GHS/QOL by EORTC QLQ-C30, median TTD in the pembrolizumab arm was not reached (NR; 95% CI, 13.4-NR) compared with 12.9 months (95% CI, 6.6-NR) in the placebo arm (HR, 0.84; 95% CI, 0.65-1.09; 

 = .1851). For EQ-5D-5L VAS, median TTD in the pembrolizumab arm was NR (95% CI, 17.2-NR) vs 7.7 months (95% CI, 6.0-NR) in the placebo arm (HR, 0.75; 95% CI, 0.58-0.97; 

For physical functioning by EORTC QLQ-C30, the proportion of patients with improved PROs was 42.1% compared with 26.8% in the placebo arm. For the EQ-5D-5L VAS, the proportion of patients with improved PROs was 42.8% and 36.4% in the pembrolizumab and placebo groups, respectively.

Monk BJ, Tewari KS, Hasegawa CK, et al. Patient-reported outcomes from the phase 3 randomized, double-blind, KEYNOTE-826 trial of pembrolizumab plus chemotherapy versus placebo plus chemotherapy for the first-line treatment of persistent, recurrent, or metastatic cervical cancer. Presented at: 2022 SGO Annual Meeting on Women’s Cancer; March 18-21, 2022; Phoenix, AZ.

Data collected with patient-reported outcomes show that pembrolizumab, with or without bevacizumab, is associated with a favorable toxicity profile in effectively treating women with persistent, recurrent, or metastatic cervical cancer.

Patient-Reported Outcomes Demonstrate Satisfaction With Pembrolizumab in Advanced Cervical Cancer

Patients with locally advanced, node-positive cervical cancer experienced promising progression-free survival (PFS) and few dose-limiting toxicities (DLTs) as well as favorable T-cell clonal expansion in their tumors and peripheral blood after receiving atezolizumab (Tecentriq), either as an immune primer or concurrently with extended field chemoradiation, according to data from the randomized phase 1 NRG-GY017 trial (NCT03738228) that were presented during the 2022 SGO Annual Meeting on Womens’ Cancer.

At a median follow-up of 20 months, results showed an increase in peripheral blood T-cell receptor (TCR) clonal expansion and expansion of tumor-associated T-cell clones between the start of treatment and day 21 of chemoradiation with a priming dose of atezolizumab (

 = .0001) and concurrent use of atezolizumab (

Additionally, patients who had higher pretreatment TCR diversity had a greater likelihood of complete pathologic response in on-treatment biopsy (

“NRG-GY017 with concurrent atezolizumab or priming atezolizumab with chemoradiation was safe and very well tolerated. We think that the T-cell clonality expansion observed in tumors and the peripheral blood was irrespective of sequencing, but it’s quite interesting, and we hope to do more studies looking at this and correlating this [approach] with PFS and overall survival,” lead study author Jyoti Mayadev, MD, professor and assistant vice chair in the Department of Radiation Medicine and Applied Sciences at UC San Diego School of Medicine, said in a presentation during the meeting.

There are approximately 350,000 global deaths linked to cervical cancer each year, meaning that this subtype continues to be a lethal disease. Furthermore, the prognoses for patients with node-positive disease are considered poor; up to 50% of patients experience recurrence following standard chemoradiation.

The FDA approved chemoimmunotherapy for patients with persistent, recurrent, or metastatic cervical cancer, however, investigators have yet to establish its utility and optimal sequence with radiation in the locally advanced setting.

Investigators consequently designed the NRG-GY017 trial to assess the agent’s efficacy in treating patients with stage IB to IVA disease with para-aortic nodal metastases or stage IIB-IVA disease harboring pelvic lymph nodes with or without para-aortic nodal metastases. Enrolled participants were randomized to receive either 1 dose of priming atezolizumab in addition to 2 doses with chemoradiation (arm A; n = 19) or 3 doses of atezolizumab along with concurrent chemoradiation (arm B; n = 17).

The primary objective was the evaluation of clonal expansion of TCR beta and tumor-associated TCR clones in the peripheral blood. Secondary objectives were safety and toxicity, with exploratory objectives of assessing the immune microenvironment and use of biopsy to identify predictive markers.

Tumor samples were collected before and during therapy, and peripheral blood was also collected. The immunoSEQ assay was used to evaluate TCR metrics.

DLTs were evaluated during and up to 30 days after chemoradiation.

Overall, 40 patients were randomized; 36 patients who were evaluated received chemoradiation and at least 1 dose of atezolizumab.

The median age of patients was 47.5 years. The majority of patients were not Hispanic or Latino (n = 27; 75%), were White (n = 27; 75%), and had a performance status of 0 (n = 26; 72.2%). Most patients had squamous cell carcinoma (n = 28; 77.8%) and FIGO stage IIB disease (n = 22; 61.1%).

Additional results showed the clones that expanded in peripheral blood also expanded in the tumor in response to therapy. Notably, clonal expansion occurred most often in response to radiation vs atezolizumab, and most of the expanded clones were newly detected.

Furthermore, among 11 evaluable patients each in arms A and B, the complete response (CR) and CR/partial response rates were 45% and 82%,o and 27% and 36%, respectively.

The median PFS was not reached in either arm, with 4 events in arm A and 6 events in arm B. The 1-year PFS rate was approximately 72%, Mayadev said.

At data cutoff, 75% of patients had completed the study treatment. A total of 30 patients were evaluable for DLTs. None of the 16 patients in arm A experienced DLTs, and 3 of the 14 patients in arm B experienced DLTs (8%); these were immune-related colitis, non–immune related colitis, and thrombocytopenia with cisplatin delay of more than 2 weeks. Notably, the patient with immune-related colitis had the DLT resolved with medication.

Overall, 3 patients in arm A and 10 patients in arm B reported a grade 3 or higher treatment-related adverse effect, only 1 of which was immune related.

“The translational aspects of this study will also let us report more on how the tumor microenvironment will affect prognosis [and] functionality, and we also hope to look at imaging and PET data that was collected by the sites and the patients for long-term outcomes,” concluded Mayadev.

Mayadev J, Zamarin D, Deng W, et al. Safety and immunogenicity of Anti PD-L1 (Atezolizumab) given as an immune primer or concurrently with extended field chemoradiotherapy for node positive locally advanced cervical cancer: an NRG Oncology trial. Presented at: 2022 SGO Annual Meeting on Women’s Cancer; March 18-21, 2022; Phoenix, Arizona.

NRG oncology trial indicates using atezolizumab with chemoradiation is safe and demonstrates signs of immune activation in women with cervical cancer. News release. NRG Oncology. March 18, 2022. Accessed March 19, 2022. https://bit.ly/3InmLan

Whether administered as an immune primer or concurrently with extended field chemoradiation, atezolizumab demonstrated efficacy in triggering T-cell clonal expansions and prolonging progression-free survival in patients with cervical cancer. 

Gynecologic Cancers