Real-life efficacy and safety of cemiplimab in advanced cervical cancer from a nominal use program in Italy: The MITO 44 study.

BACKGROUND: cemiplimab is an immunoglobulin G4 monoclonal antibody targeting the programmed cell death-1 receptor. A nominal use program is available in Italy in advanced cervical cancer (CC) patients treated with platinum based chemotherapy based on the results of EMPOWER-Cervical 1/GOG-3016/ENGOTcx9 trial. This real-world, retrospective cohort, multicenter study aimed at describing clinical outcomes of patients with advanced CC treated with cemiplimab in Italy. METHODS: The primary objective of the study was to assess the feasibility and the replicability of the initial results in a real world setting of cemiplimab nominal use. The primary endpoint of our analysis was progression free survival (PFS). Secondary endpoints included overall response rate (ORR), overall survival (OS) and safety data. RESULTS: From March 2022 to December 2023, 135 patients were treated in 12 Multicenter Italian Trials in Ovarian cancer and gynecologic malignancies (MITO) Centers. Forty-two percent of patients had one or more comorbidities, hypertension being the most common (23.4%). Median PFS was 4.0 months (range 3.0-6.0) and median OS was 12.0 months (12.0- NR) with no differences according to PD-L1 status. Complete response (CR) or no evidence of disease (NED) were observed in 8.6%; partial response (PR) in 21.1%, stable disease (SD) in 14.8% and progression was recorded in 44.5% of patients. Most common drug related adverse events (AEs) were anemia (39.1%) and fatigue (27.8%). Immune related AEs occurred in 18.0%. CONCLUSIONS: This study confirms the feasibility and the replicability of the cemiplimab nominal use in advanced CC, in a real-world practice in Italy.

The Revolution of Immunotherapy in Gynecological Cancers: The Lazarus Effect in Endometrial Cancer.

Patients with solid tumors and mismatch repair deficiency (dMMR) or microsatellite instability-high (MSI-H) are eligible for immunotherapy. Recently, different reports described patients with poor performance status (PS), unrelated to comorbidities, which showed a rapid improvement of their clinical conditions under immunotherapy, which evoked a Lazarus response. Very few data on the efficacy and safety of immunotherapy in patients with gynecological malignancies and poor PS are available. Based on the GARNET trial, Dostarlimab, a monoclonal antibody anti-programmed death receptor-1 (PD-1), has been approved in advanced or recurrent mismatch repair deficient endometrial cancer (EC) which progressed after platinum-based therapy. For the first time, in gynecological oncology, an immune checkpoint inhibitor drastically changed the clinical practice. We collected a multicenter case series of six patients with advanced endometrial carcinoma and PS ECOG 3-4 treated with Dostarlimab, showing exceptionally quick responses and significant improvement of PS to configure a Lazarus response.

Consensus statements and treatment algorithm to guide clinicians in the selection of maintenance therapy for patients with newly diagnosed, advanced ovarian carcinoma: Results of a Delphi study.

INTRODUCTION: Standard treatment of newly diagnosed, advanced ovarian carcinoma (OC) consists of cytoreductive surgery followed by platinum-based chemotherapy with or without bevacizumab. Maintenance therapy with PARP inhibitors and olaparib-bevacizumab has recently shown to significantly improve progression-free survival in the first-line setting. Some practical aspects of maintenance therapy, however, are still poorly defined. AIM OF THE STUDY: To provide guidance to clinicians in the selection of maintenance therapy for newly diagnosed, advanced ovarian carcinoma. METHODS: A board of six gynecologic oncologists with expertise in the treatment of OC in Italy convened to address issues related to the new options for maintenance treatment. Based on scientific evidences, the board produced practice-oriented statements. Consensus was reached via a modified Delphi study that involved a panel of 22 experts from across Italy. RESULTS: Twenty-seven evidence- and consensus-based statements are presented, covering the following areas of interest: use of biomarkers (BRCA mutations and presence of homologous recombination deficiency); timing and outcomes of surgery; selection of patients eligible for bevacizumab; definition of response to treatment; toxicity and contraindications; evidence of synergy of bevacizumab plus PARP inhibitor. Two treatment algorithms are also included, for selecting maintenance therapy based on timing and outcomes of surgery, response to platinum-based chemotherapy and biomarker status. A score for the assessment of response to chemotherapy is proposed, but its validation is ongoing. CONCLUSIONS: We provide here consensus statements and treatment algorithms to guide clinicians in the selection of appropriate and personalized maintenance therapy in the first-line setting of advanced OC management.

Gender matters. Sex-related differences in immunotherapy outcome in patients with non-small cell lung cancer.

BACKGROUND: Emerging evidence identified sex as a variable that can regulate immune system functions and modulate response to immunotherapy in cancer patients. OBJECTIVE: This retrospective study analysed sex-related differences in immunotherapy outcome in a real-world population of non-small cell lung cancer (NSCLC) patients treated with immune checkpoint inhibitors (ICIs). METHODS: We retrospectively investigated clinical data of 99 patients with advanced NSCLC and treated with single agent nivolumab and pembrolizumab, at Medical Oncology Unit, Careggi University Hospital, Florence (Italy), between April 2014 to August 2019. Main clinical characteristics and clinical outcomes were analysed. RESULTS: Our study showed that efficacy of ICI treatment differed according to gender. A trend for better median progression free survival (mPFS) was reported in males (mPFS 5.0 months, 95% Confidence Interval [CI] 4.0-11.0) than females (mPFS 4.5 months, 95% CI 2.0-9.0) (p=0.133), while no significant difference for overall survival (OS) between the two sex groups was observed (p=0.622). In the nivolumab cohort we showed a statistically significant difference for a longer PFS in men compared to women (log-rank p=0.054), HR for PFS in females versus males was 1.81 (95% CI 0.97-3.37, p=0.062). Disease control rate (DCR) was achieved in 55.7% and 45.7% in men and women, respectively, while disease progression was registered in 44.3% of males and 54.3% of females (p=0.386). CONCLUSIONS: Gender is a variable that should be taken into account in the choice of immunotherapy. Future prospective randomized trials testing tailored sex-based immunotherapy strategies are required to validate our findings before integrating into clinical practice.

Immune checkpoint blockade with anti-programmed cell death 1 (PD-1) monoclonal antibody (mAb) cemiplimab: ongoing and future perspectives in rare genital cancers treatment.

Cemiplimab is a highly potent, hinge-stabilized human IgG4 monoclonal antibody (mAb) targeting programmed cell death 1 (PD-1) receptor approved for patients with locally advanced or metastatic cutaneous squamous cell carcinoma (SCC) who are not candidates for curative surgery or curative radiation. Recently, the phase 3 trial EMPOWER-Cervical 1 has investigated cemiplimab in patients with recurrent/metastatic cervical cancer. At interim analysis, overall survival (OS), progression free survival (PFS) and objective response rate (ORR) in overall and SCC populations favored cemiplimab over single agent chemotherapy. Cervical SCCs are the first for incidence among Human Papilloma Virus (HPV) related neoplasms and are highly correlated (about 95%) with the viral infection. Similarly, penile and vulvar SCC may develop on chronic HPV infections or on dermatological chronic conditions (ie, lichen). The molecular and viral similarities between external genital SCC and SCC originating from the cervical epithelium could be the rationale for using cemiplimab to treat locally advanced or metastatic penile and vulvar SCC as well. Some retrospective data have shown that cemiplimab may provide objective response and clinical benefit to some patients with penile or vulvar SCC and is overall safe to utilize in this population. Given the complexity of the immune activation and the considerable variability in tumor biology across patients and tumor types, the identification of biomarkers to warrant patient selection needs to be further explored. Ongoing clinical trials will hopefully shed light on the treatment paradigm of these rare tumors too, with special regard to the ideal combination and sequencing of immunotherapeutic strategies.

The anti-IgE monoclonal antibody omalizumab as adjuvant treatment in desensitization to carboplatin in patients with ovarian cancer.

•Ovarian cancer is the most lethal among gynecological cancers.•Carboplatin-based chemotherapy identifies as the main systemic treatment for ovarian cancer patients.•Almost one every three patients treated with carboplatin experiences hypersensitivity reactions.•Patients may experience breakthrough reactions during drug desensitization.•Omalizumab represents a promising new treatment to overcome carboplatin hypersensitivity.

Capecitabine in treating patients with advanced, persistent, or recurrent cervical cancer: an active and safe option?

Introduction: Advanced, persistent or recurrent cervical cancer in patients not amenable to curative surgery or radiotherapy predicts a dismal prognosis. Systemic chemotherapy based on paclitaxel/cisplatin ± bevacizumab is the current standard of care. However, once progression occurs, the possibility of alternative treatment options is very limited.Areas covered: The usefulness of capecitabine has been well-established against several cancer types, including head and neck, breast, and colorectal cancer. This review covers current literature evidence on the clinical efficacy and safety of capecitabine in cervical cancer treatment, either as monotherapy or combined with other agents or chemo-radiotherapy.Expert opinion: Recent clinical data, albeit scant, suggested a promising role for capecitabine both as monotherapy in patients with platinum-resistant cervical cancer and in combination with cisplatin in chemotherapy-naïve patients with metastatic or recurrent cervical cancer. In our opinion, capecitabine, especially in combination regimens, could represent a valid treatment option and further research is warranted to better understand its effectiveness in these challenging patients.

Early-onset malignant phyllodes breast tumor in a patient with germline pathogenic variants in NF1 and BRCA1 genes.

We present a 24-year-old female patient affected by neurofibromatosis type 1 (NF1) who developed a malignant phyllodes tumor of the breast. The molecular studies showed that the patient carried a heterozygous inactivating deleterious variant in BRCA1 inherited from the father associated with a germline de novo pathogenic alteration in NF1; the tumor presented a biallelic inactivation of both genes. Therefore, tumor analyses helped to establish that the germline NF1 and BRCA1 variants were in cis on the paternal chromosome. This last information is important to provide adequate genetic counselling regarding the risk of recurrence in the offspring, as well as opportunity for early intervention. In conclusion, we present the first case of a malignant phyllodes tumor of the breast in patient carrying pathogenic variants in NF1 and BRCA1. Further studies will be necessary to understand if the phyllodes histotype represents a very rare component of NF1-associated breast cancer.

First-Line Treatment with Olaparib for Early Stage BRCA-Positive Ovarian Cancer: May It Be Possible? Hypothesis Potentially Generating a Line of Research.

Olaparib is currently approved in maintenance treatment of advanced ovarian cancer after response to first-line chemotherapy for breast related cancer antigens (BRCA) mutated patients. The use of this agent is based on data from SOLO1 study that observed a decreased risk of disease progression or death and a median progression-free survival about 36 months longer in case of therapy with olaparib. However, this trial recruited only patients with advanced stage ovarian cancer. The aim of this review is to retrace the available data in order to clarify the potential efficacy and feasibility of olaparib administration in newly diagnosed epithelial ovarian cancer also in early stages.

Targeting cervical cancer: Is there a role for poly (ADP-ribose) polymerase inhibition?

Patients with metastatic and recurrent cervical cancer (CC) have a poor prognosis with limited palliative treatment options. Increasing understanding of the cellular aberrations inherent to cancer cells has allowed the development of therapies to target biological pathways, an important step toward the individualization of cancer therapy. The poly (ADP-ribose) polymerase (PARP) family of enzymes is important in several DNA repair pathways. Drugs that inhibit these PARP enzymes have been investigated in many types of cancer and their application in the treatment of gynecologic malignancies has rapidly evolved. Although the majority of data for PARPi in gynecologic malignancies has been specifically regarding ovarian cancer, their role in the treatment of uterine and CC is currently being investigated. This review will examine PARP inhibitors in CC, summarizes the critical clinical trials of PARP inhibitors that have been completed, provides an overview of the on-going trials, presents the confirmed conclusions and notes the issues that need to be addressed in future studies.

Parp inhibitors as maintenance treatment in platinum sensitive recurrent ovarian cancer: An updated meta-analysis of randomized clinical trials according to BRCA mutational status.

OBJECTIVE: This meta-analysis investigated the effectiveness of PARP inhibitors (PARPis) as maintenance treatment in platinum sensitive recurrent ovarian cancer (ROC), stratifying results based on BRCA mutational status into five different categories: whole population, germ-line BRCA mutated patients, somatic BRCA mutated patients, HRD patients and wild type population. METHODS: PubMed, Medline, Scopus, EMBASE and clinicaltrials.gov, as well as meeting proceedings were searched for eligible studies that described RCTs testing the efficacy of PARPis as maintenance treatment in platinum sensitive ROC. Data were extracted independently and analysed using RevMan statistical software version 5.3. Primary end-point was progression free survival (PFS). RESULTS: The analysis confirmed the positive effect of PARPis in patients with platinum sensitive ROC in case of germinal or somatic BRCA mutations. Specifically, HR for PFS was 0.26, 95% CI 0.21-0.31, p < 0.00001 for the mutation of BRCA gene and 0.24, 95%, CI 0.12-0.48, p < 0.0001 for the somatic alteration. In addition, in the HRD population, studies that analysed the efficacy of PARPis  reported a PFS improvement with HR 0.34, 95% CI 0.26-0.43, p < 0.00001. Finally, our analysis confirms the role of these drugs in prolonging PFS in the whole population with HR 0.36, 95% CI 0.32-0.42, p < 0.00001, although to a lesser extent, with a significant improvement even in wild type cancers with HR 0.49, 95%, CI 0.41-0.59, p < 0.00001). CONCLUSIONS: PARPis are effective regardless of BRCA mutational status. Future investigations are necessary to explore the use of different PARPis as monotherapy, comparing them among each other in terms of efficacy and toxicity, and exploring their potential re-use.

Fertility preservation in ovarian tumours.

A considerable number of patients with a cancer diagnosis are of childbearing age and have not satisfied their desire for a family. Despite ovarian cancer (OC) usually occurring in older patients, 3%-14% are diagnosed at a fertile age with the overall 5-year survival rate being 91.2% in women ≤44 years of age when it is found at 1A-B stage. In this scenario, testing the safety and the efficacy of fertility sparing strategies in OC patients is very important overall in terms of quality of life. Unfortunately, the lack of randomised trials to validate conservative approaches does not guarantee the safety of fertility preservation strategies. However, evidence-based data from descriptive series suggest that in selected cases, the preservation of the uterus and at least one part of the ovary does not lead to a high risk of relapse. This conservative surgery helps to maintain organ function, giving patients of childbearing age the possibility to preserve their fertility. We hereby analysed the main evidence from the international literature on this topic in order to highlight the selected criteria for conservative management of OC patients, including healthy BRCA mutations carriers.

Risk-reducing Salpingo-Oophorectomy in Women at Higher Risk of Ovarian and Breast Cancer: A Single Institution Prospective Series.

BACKGROUND/AIM: Occult cancers' reported rates vary from 2-12% and serous tubal intraepithelial carcinomas (STICs) have been identified in 3-12% of the prophylactically removed tubes of women carrying a BRCA mutation. The aim of this study was to evaluate the incidence of tubal minor epithelial atypia (STIL), STIC, and occult invasive cancer and to evaluate the cancer-specific mortality in a prospective series of women at higher risk of ovarian and breast cancer undergoing risk-reducing salpingo-oophorectomy (RRSO) n a tertiary cancer center. PATIENTS AND METHODS: A series of RRSO specimens (including endometrial biopsy) from women carrying a BRCA mutation, BRCA-unknown and BRCA-negative were collected between January 1998 and April 2016 at the Division of Gynecology at the European Institute of Oncology. Inclusion criteria were: asymptomatic women who had a negative gynecologic screening within 3 months prior to RRSO. Exclusion criteria were: women with ovarian/tubal cancer prior to RRSO. RESULTS: A total of 411 women underwent RRSO. Median age at RRSO was 47.0 years (range=32-70 years); 75.2% had a history of breast cancer. Fifteen women were diagnosed with an occult cancer (7 STIC, 4 invasive cancers, 2 breast cancers metastatic to the adnexa, 2 endometrial cancer) (3.6%). Sixteen showed a STIL (3.9%). When excluding cases with preoperative positive markers, the occult invasive cancer rate drops to 1.5%. CONCLUSION: Our study, covering an 18-year period, shows a substantial low risk of occult cancer among a high-risk population of women undergoing RRSO. Our data still support the indication for RRSO in higher-risk patients. An endometrial biopsy should also be routinely obtained as it raises the chances of detecting occult endometrial cancers that may be otherwise missed.

Fertility preservation in women with borderline ovarian tumours.

Borderline ovarian tumours (BOT) may occur in young women and have an excellent survival rate. Therefore, there is the obligation to put emphasis on fertility preservation in affected women. On the other hand, it has also been underlined that the disease should be managed with caution because these tumours can relapse and, albeit rare, malignant transformation can also occur. Unfortunately, evidence on fertility preservation in women with BOT is scanty. In this opinion paper, we tried to draw some clinical indications based on the few available studies on the clinical management of BOT and their possible relation with controlled ovarian hyper-stimulation (COH). We ultimately came to the following conclusions: (1) Fertility counselling should become an integral part of the clinical management of women with BOT. Conservative management without pre-surgical counselling may expose women without reasonable chances of future conceptions to undue risks. (2) Despite some epidemiological concerns on the possible relation between COH and BOT, the conservative surgical treatment should be associated to oocyte cryopreservation considering the high risk of recurrence of the disease. (3) Letrozole during COH should be considered to temper the theoretical risk of increased recurrences. (4) Pregnancy should not be delayed in women at low-moderate risk of recurrences. Fertility preservation may be avoided in these women provided that they start active pregnancy seeking early. (5) Albeit experimental, oocytes retrieval from affected ovaries removed at the time of surgery can be considered. Conversely, ovarian cortex cryopreservation is not justified given the possible risks of malignant reseeding.

Metronomic oral vinorelbine as first-line treatment in elderly patients with advanced non-small cell lung cancer: results of a phase II trial (MOVE trial).

BACKGROUND: Metronomic oral vinorelbine could be a safe option for elderly patients with advanced non small cell lung cancer (NSCLC). Metronomic administration of chemotherapy leads to a cytostatic action shifting treatment target from cancer cell to tumor angiogenesis. METHODS: 43 chemotherapy naive elderly (≥ 70 yrs) PS 0-2 patients with stage IIIB-IV NSCLC were prospectively recruited. Median age was 80 yrs (M/F 36/7) with predominantly squamous histology. PS distribution was 0-1(16)/2(27) with a median of 3 serious co-morbid illnesses. Study treatment consisted of oral vinorelbine 50mg three times weekly (Monday-Wednesday-Friday) continuously until disease progression, unacceptable toxicity or patient refusal. Primary endpoints were overall response rate (ORR), clinical benefit (CB--disease response plus disease stabilization >12 weeks) and safety. Health-related QoL (HRQoL) was also assessed with FACT-L V4 scoring questionnaire. We conducted an exploratory time-course analysis of VEGF and thrombospondin-1 (TSP1) serum levels in a subgroup of patients. RESULTS: Patients received a median of 5 (range 1-21) cycles with a total of 272 cycles delivered. ORR was 18.6% with 7 partial and 1 complete responses; 17/43 experienced stable disease lasting more than 12 weeks leading to an overall CB of 58.1%. Median time to progression was 5 (range 2-21) and median overall survival 9 (range 3-29) months. Treatment was well tolerated with rare serious toxicity. Regardless of severity main toxicities observed were anemia in 44%, fatigue in 32.4%, and diarrhoea 10.5%. FACT-L v4 scores did not significantly vary during treatment. Baseline VEGF levels were lower and showed a rapid increase during treatment in non-responders pts only while TSP1 levels did not change. CONCLUSIONS: Metronomic oral vinorelbine is safe in elderly patients with advanced NSCLC with an interesting activity mainly consisting in long-term disease stabilization coupled with an optimal patient compliance (Eudra-CT 2010-018762-23, AIFA OSS on 26 February 2010).

Efficacy of trastuzumab in unselected patients with HER2-positive metastatic breast cancer: a retrospective analysis.

AIMS AND BACKGROUND: The addition of trastuzumab to chemotherapy for HER2-positive metastatic breast cancer has significantly improved progression-free survival and overall survival, although most patients develop resistance or have a primarily resistant disease. The aim of the study was to describe the efficacy and safety of a first-line treatment in unselected metastatic HER2-positive breast cancer patients, treated according to clinical practice. METHODS: From 2000 to 2009, we conducted a retrospective multi-institutional analysis of 182 consecutive patients with HER2-positive metastatic breast cancer who underwent first-line treatment with trastuzumab. The primary end points were progression-free survival and overall survival; the secondary end points were survival after progression in patients treated with second-line chemotherapy with or without trastuzumab and safety. A total of 172 patients were analyzed. RESULTS: Median progression-free survival and overall survival were 1.2 (95% CI, 1.1-1.4) and 4.4 years (95% CI, 3.6-5.4), respectively. For 100 patients who received second-line chemotherapy, median survival after progression was significantly longer in those who also received trastuzumab: 2.8 (95% CI, 2.1-4.0) versus 1.2 years (95% CI, 0.6-1.9). CONCLUSIONS: Although based on retrospective data, the study confirms the role of trastuzumab as first-line treatment in metastatic breast cancer outside of a controlled trial. Moreover, information obtained on the use of trastuzumab beyond disease progression supports its use in this setting.