Desensitization Protocol for Cemiplimab-Related Infusion Reaction in Cutaneous Squamous Cell Carcinoma: A Case Report and Literature Review.

BACKGROUND: The landscape of systemic therapies for advanced non-melanoma skin cancers has been revolutionized by the advent of immunotherapy. Cemiplimab is the only immune checkpoint inhibitor (ICI) approved by the European Medicine Agency for recurrent/metastatic cutaneous squamous cell carcinoma (cSCC). Its excellent efficacy outcomes are achieved due to its good tolerability profile. The drug-related hypersensitivity reaction (HSR) is a well-known issue in oncology, but it is rarely reported in respect to immune checkpoint inhibitors. Cemiplimab is among the agents with the best infusion tolerability profiles. Clinical practice guidelines in this field are lacking. RESULTS: We report on the successful management of a severe infusion reaction induced by Cemiplimab in a patient with cSCC based on a desensitization protocol, which led to adequate treatment delivery and prolonged clinical benefit. A review of the available literature on HSR rates and its management with ICIs, and on drug desensitization (DD) protocols and their efficacy, was conducted to highlight the limited knowledge on this topic and its importance. CONCLUSION: Our experience highlights the need for a DD protocol in order to improve the treatment of HSRs, particularly when elicited by an immunotherapy agent, preventing treatment discontinuation and preserving its efficacy.

Safety of CDK4/6 inhibitors and concomitant radiation therapy in patients affected by metastatic breast cancer.

PURPOSE: Cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) currently represent the standard of care for the initial treatment of patients with metastatic hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2-) breast cancer. The aim of our study is to evaluate the safety of the use of concomitant radiation therapy (RT) in a consecutive series of HR+/HER2- patients treated in two academic institutions with CDK4/6i in the metastatic setting. METHODS AND MATERIALS: From September 2017 to February 2020, we retrospectively collected and analysed data on a sequential series of patients treated with CDK4/6i, receiving RT or not, at two European institutions. Primary outcome of the study was the association between RT and any adverse events (AEs) ≥ G3. Secondary outcomes were the association between RT and any AEs (any grade), CDK4/6i dose reduction rate, and CDK4/6i treatment discontinuation rate. RESULTS: We analysed a total of 132 consecutive women; RT was prescribed in 57 (43.2%) patients (70 irradiated lesions). The median age of the series was 52.1 years (range 32.3-78.2). Concomitant RT administration was not significantly related to higher AEs ≥ G3 (p = 0.19) and any grade AEs (p = 1.0); there was no association with RT and CDK4/6i dose reduction (p = 0.49) and discontinuation rates (p = 0.14). At a median follow-up of 18.8 months, the progression-free survival (PFS) rate was 35% and the overall survival (OS) rate was 38.7% in the whole group. The use of concomitant RT did not affect both PFS (p = 0.71) and OS rates (p = 0.55). CONCLUSIONS: Our data are encouraging regarding the safety of this combination, showing that concurrent RT did not increase severe toxicity and did not have an impact on systemic treatment conduction.

Prospective assessment of AR splice variant and multi-biomarker expression on circulating tumor cells of mCRPC patients undergoing androgen receptor targeted agents: interim analysis of PRIMERA trial (NCT04188275).

Circulating tumor cells detection and ARV7 expression are associated with worse clinical outcomes in metastatic Castration-Resistant Prostate Cancer (mCRPC) undergoing Androgen Receptor Targeted Agents. ARFL, PSMA and PSA may help to refine prognostic models. In our institution, a prospective observational trial testing CTC detection in mCPRC undergoing I line ARTA therapy terminated the planned enrollment in 2020. Here, we present a pre-planned interim analysis with 18 months of median follow-up. RT-qPCR was used to determine the CTC expression of PSA, PSMA, AR and ARV7 before starting ARTA. PSA-drop, Progression-Free and Overall Survival (PFS and OS) and their correlation with CTC detection were reported. Forty-four patients were included. CTC were detected in 43.2% of patients, of whom 8.94% expressed PSA, 15.78% showed ARV7, 63.15% and 73.68% displayed ARFL and PSMA, respectively. Biochemical response was significantly improved in CTC + vs CTC- patients, with median PSA-drop of 18.5 vs 2.5 ng/ml (p = 0.03). After a median follow-up of 18 months, 50% of patients progressed. PFS was significantly longer in CTC- patients (NR vs 16 months). Eight (18.2%) patients died, a non-significant trend in terms of OS was detected in favor of CTC- patients (NR vs 29 months, p = 0.05). AR, PSA and PSMA expression in CTC + had no significant impact on PSA-drop, PFS or OS. PRIMERA-trial confirmed the CTC detection predictive importance in mCRPC patients.

Study protocol and preliminary results from a mono-centric cohort within a trial testing stereotactic body radiotherapy and abiraterone (ARTO-NCT03449719).

BACKGROUND: ARTO trial was designed to evaluate the difference in terms of outcomes between patients affected by oligo metastatic castrate resistant prostate cancer (mCRPC) treated with Abiraterone acetate and randomized to receive or not SBRT on all sites of disease. Here, we present a preliminary analysis conducted on patients enrolled at promoting institution. OBJECTIVE: To present a preliminary overview about population features, clinical outcomes, adverse events, quality of life and explorative translational research. DESIGN, SETTING, AND PARTICIPANTS: ARTO (NCT03449719) is a phase II trial including patients affected by oligo mCRPC, randomized to receive standard of care (GnRH agonist or antagonist plus abiraterone acetate 1000 mg and oral prednisone 10 mg daily) with or without SBRT on all metastatic sites of disease. All subjects have < 3 bone or nodal metastases. All patients are treated in I line mCRPC setting, no previous lines of treatment for mCRPC are allowed. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Data about a mono-centric cohort of 42 patients enrolled are presented in the current analysis, with focus on baseline population features, PSA drop at 3 months, biochemical response, and quality of life outcomes. Descriptive statistics regarding translational research are also presented. RESULTS AND LIMITATION: Significant difference in terms of PSA drop at three months was not detected (p = 0.68). Biochemical response (PSA reduction > 50%) was reported in 73.7 versus 76.5% of patients in control vs SBRT arm, respectively (p = 0.84). All patients are alive. Progression occurred in 1 versus 0 patients in the control versus SBRT arm, respectively. After 3 months, an average decrease of 13 points in terms of Global Health Score was reported for the overall population. However, complete recovery was noticed at 6 months. Circulating tumor cells detection rate was 40%. CONCLUSIONS: SBRT + Abiraterone treatment was safe and well tolerated, non-significant trend in terms of PSA drop and biochemical response at 3 months was detected in SBRT arm. Interestingly, CTCs detection in this selected cohort of oligo-mCRPC was lower if compared to historical data of unselected mCRPC patients.

A narrative review of postoperative adjuvant radiotherapy for non-small cell lung cancer.

Objective: To summarize the principal studies investigating the role of postoperative radiation therapy (PORT) for non-small cell lung cancer (NSCLC) and to discuss the recent major breakthroughs deriving from the Lung ART trial, in order to provide a real-world scenario of the management of resected NSCLC patients. Background: Surgery followed by platinum-based chemotherapy remains the mainstay of adjuvant treatments for completely resected stage II and IIIA NSCLC. Less consistent is the employment of PORT, as no significant benefit was clearly identified from the previous published meta-analysis. Furthermore, the recent results of Lung ART trial questioned for the first time the efficacy of PORT for pathological N2 (pN2) NSCLC patients. Hence, the need to define if PORT still has a role for resected NSCLC and which subgroup of patients could benefit most from this treatment. Methods: A literature search of PubMed was performed to identify publications, including prospective and retrospective clinical studies, meta-analysis and systematic review of PORT for NSCLC. No limit concerning years of publication or publication status were applied. Only papers using the English language were selected. The ESMO 2020 and ESMO 2021 online resources were used to analyze the Lung ART trial results. The authors provide a narrative summary of the findings and implications of these studies and how they improve the clinical practice. Conclusions: PORT was considered the standard of care for patients with completely resected pN2 NSCLC based on the results of an old meta-analysis that did not demonstrate a detrimental effect. The more recent randomized phase III Lung ART trial concluded that PORT could not anymore be recommended for pN2 NSCLC as a significant benefit in terms of 3 years disease-free survival (DFS) was not reached and an increased rate of radiotherapy related toxicity was observed. Retrospective studies suggest a possible role of PORT for incompletely resected NSCLC patients and those with an extranodal extension (ENE), but this issue needs to be reinforced from randomized prospective trials. The extensive publication of Lung ART trial is largely awaited to define if there is a role of PORT for resected NSCLC patients.

Durvalumab with cetuximab and radiotherapy for locally advanced squamous cell carcinoma of the head and neck: A phase 1/2 trial.

BACKGROUND AND PURPOSE: To report on the anti-tumor activity of a novel combination in high-risk locally advanced head and neck squamous cell carcinoma. MATERIALS AND METHODS: At a fixed dose of 1500 mg every 28 days, anti PD-L1 Durvalumab was given concomitantly to Radiotherapy and Cetuximab starting from the first week of combined treatment, followed by adjuvant Durvalumab to a maximum of 6 months after completion of radiation. The primary endpoint of the study was 2-year progression-free survival (PFS). A safety run-in was planned. Due to regulatory issues which prevented from opening multiple centers, COVID-19 pandemic and withdrawal of Durvalumab from supporting company, the study was prematurely terminated in April 2021. RESULTS: Between July 2019 and August 2020, 9 patients were enrolled in the study. All tumors had a PD-L1 Combined Positive Score > 1. Optimal drug exposure was observed, with mean relative dose intensity of 85.5% and 87.5% for Cetuximab and Durvalumab, respectively. No radiation breaks were necessary. A grade 4 mucositis lasting for 14 days corresponded to the only dose limiting toxicity we reported. At a median follow-up of 11.5 months (IQR 7.7-16.7) all surviving patients (6 out of 9) are disease-free, with 1 and 2-year PFS rates of 77.7% and 58.3%, respectively. A selective sparing of node levels in the elective volume was performed in all cases, yielding a cumulative mean dose of 37.6 Gy (SD 8.4). CONCLUSION: Albeit limited by the small sample size, our preliminary observation of anti-tumor activity and tolerability of Durvalumab in addition to Cetuximab and radiation may warrant further investigations.

Stereotactic Body Radiotherapy in Oligomestatic/Oligoprogressive Sarcoma: Safety and Effectiveness Beyond Intrinsic Radiosensitivity.

BACKGROUND: Metastatic soft tissue sarcoma (STS) patients may benefit from local ablative treatments due to modest efficacy of systemic chemotherapy. However, use of stereotactic body radiotherapy (SBRT) is controversial because of presumed radioresistance of STS. METHODS: Patients treated with SBRT for oligometastatic and oligoprogressive metastatic STS were retrospectively reviewed to assess results in terms of local control (LC), disease-free survival (DFS), and overall survival (OS). Incidence and grade of adverse events were reported. Statistical analysis was performed to identify variables correlated with outcome and toxicity. RESULTS: Forty patients were treated with SBRT to a median biologic effective dose (BED) of 105 (66-305) Gy5 to 77 metastases. Two-year LC, DFS, and OS were 67%, 23%, and 40%. Improved LC was shown in patients receiving a BED >150 Gy5 (hazard ratio [HR], 3.9; 95% confidence interval [CI], 1.6-9.7; P = 0.028). A delay >24 months between primary tumor diagnosis and onset of metastases was associated with improved DFS (HR, 0.46; 95% CI, 0.22-0.96; P = 0.01) and OS (HR, 0.48; 95% CI, 0.23-0.99; P = 0.03). No toxicity grade ≥3 was observed. CONCLUSIONS: Stereotactic body radiotherapy is effective in metastatic STS with a benign toxicity profile. A BED >150 Gy5 is required to maximize tumor control rates. Metastatic relapse >24 months after diagnosis is correlated to improved survival.

Cyclin-Dependent Kinase 4/6 Inhibitors Combined With Radiotherapy for Patients With Metastatic Breast Cancer.

BACKGROUND: The cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) represent the standard treatment for hormone receptor-positive, human epidermal growth factor receptor 2-negative metastatic breast cancer. Data about the balance between efficacy and toxicity of combined palliative radiotherapy (RT) and CDK4/6 inhibition are lacking. PATIENTS AND METHODS: We undertook a review of 46 patients with metastatic breast cancer on systemic treatment with CDK4/6i who underwent 62 metastases-directed RT. Clinical, laboratory, and RT treatment planning data were collected. Statistical analyses included Student t test, paired sample t test, and logistic regression modeling. RESULTS: Thirty patients (65.2%) received palbociclib, 15 (32.6%) received ribociclib, and one patient received abemaciclib (2.2%). Median total prescribed RT dose was 20 Gy (range, 8-63 Gy). Sites of RT were bone (n = 50; 80.7%), visceral (n = 7; 11.3%), or brain metastases (n = 3; 4.8%), as well as primary tumor of the breast (n = 2; 3.2%). Overall, the rates of grade 3 or higher adverse events (AEs) were 6.5%, 4.3%, 15.2%, and 23.9% before the start of RT, during RT, 2 and 6 weeks after RT completion, respectively. We found no correlation between dose distribution to organs at risk and the development of AEs. The local control rates for the entire cohort were 98% at 6 months and 90% at 12 months. Overall, pain relief (complete or partial) was experienced by 80% (24/30) of patients who initially reported pain at the treated metastatic site. CONCLUSION: We observed a modest increase in the rates of grade 3 or higher AEs after combined RT and CDK4/6i, with maintained efficacy of concomitant RT.