Line Systemic Treatment Research Articles

P10 New rash in a child of skin of colour

Abstract A 7 year old Nigerian girl was referred by Haematology to the Paediatric Dermatology team with “suspected eczema”. She had known sickle cell disease, for which she was on hydroxycarbamide, Mum reported an 8 month history of a new rash with no systemic features. She had marked indurated plaques on face, forehead and forearms which were associated with scarring and hyperpigmentation. She had a number of investigation including negative urine dipstick. ANA was positive with elevated RO and RNP antibodies. Inflammatory markers were normal. Skin biopsy results were consistent with discoid lupus erythematosus. Stringent photo protection and sun blocking creams were advised. She was commenced on potent topical steroids and hydroxychloroquine which is first line systemic treatment. Within 4 weeks of commencing hydroxychloroquine there was significant flattening of the plaques. She was referred to Paediatric Rheumatology for assessment, given her high risk features. Clinical features of DLE in children are similar to adult DLE in presentation and chronic course. However it is rare in children with less than 2% of patients developing DLE before 10 years of age. DLE tends to be more common and severe in skin of colour. There are complications of scarring and pigmentation. It is important to be aware of the psychological impact on both parent and child’s quality of life. There is high risk of transition to SLE in children with DLE and hence screening bloods and early referral to Rheumatology should be considered.

Efficacy and tolerability of somatostatin analogues according to gender in patients with neuroendocrine tumors.

As the incidence of neuroendocrine tumors has been rising, gender differences in epidemiology and clinical behavior have emerged, and interest into a gender-driven management of these tumors has grown with the aim to improve survival and quality of life of these patients. Somatostatin Analogues represent the first line of systemic treatment of both functional and non-functional neuroendocrine tumors, through the expression of somatostatin receptors (SSTRs) in the tumor cells, and proved effective in controlling hormonal hypersecretion and inhibiting tumor growth, improving progression-free survival and overall survival of these patients. Aim of the present review is to investigate any differences by gender in efficacy and safety of SSTS-targeted therapies, that represent the mainstay treatment of neuroendocrine tumors, as they emerge from studies of varying design and intent. Although preclinical studies have provided evidence in favor of differences by gender in tumor expression of SSTR, as well as of the role of sex hormones and related receptors in modulating SSTRs expression and function, the clinical studies conducted so far have not shown substantial differences between males and females in either efficacy or toxicity of SSTR-targeted therapies, even if with sometimes inconsistent results. Moreover, in most studies gender was not a predictor of response to treatment. Studies specifically designed to address this issue are needed to develop gender-specific therapeutic algorithms, improving patients' prognosis and quality of life.

Management strategies for intracranial progression in ALK-positive non-small cell lung cancer: a real-world cohort study.

ALK-positive NSCLC patients exhibit a particularly high propensity for the development of brain metastases. Current guidelines suggest transit to next-line therapy (SysTx) or local radiotherapy (RadTx) including whole-brain radiotherapy and radiosurgery. However, the clinical impact of these two strategies remains unclear. We conducted a retrospective analysis focusing on patients with stage IV ALK-positive NSCLC who underwent first-line ALK TKI treatment. Patients with intracranial progression may receive two different treatment strategies: SysTx and RadTx. Our objective was to investigate the outcomes associated with these two distinct treatment pathways. A total 20 patients of ALK-positive NSCLC who received first-line ALK TKI therapy and subsequently developed intracranial progression were enrolled. About 55% of patients had brain metastasis initially. Nine patients (45%) were treated with crizotinib at first. Patients treated with crizotinib demonstrated a significantly shorter intracranial PFS1 (crizotinib: 8.27 months vs. others: 27.0 months, p = 0.006). Following intracranial progression, approximately 60% of patients transitioned to the next line of systemic treatment (SysTx), while the remaining 40% opted for local cranial radiotherapy (RadTx). Intriguingly, our analysis revealed no statistically significant difference in intracranial progression-free survival (PFS2) between these two distinct treatment strategies. (SysTx: 20.87 months vs. RadTx: 28.23 months, p = 0.461). The intracranial progression-free survival showed no difference between the two strategies suggesting that both local radiotherapy and systemic therapy may be valid options. Individualized strategy, molecular analysis, and multidisciplinary conferences may all play a pivotal role in decision-making.

Abstract B138: Pharmacodynamics-driven phase 2 trial of talazoparib in patients with advanced solid tumors and aberrations in genes involved in DNA damage response

Abstract Background: Talazoparib is a poly (ADP-ribose) polymerase inhibitor (PARPi) with increased trapping of PARP-DNA complexes compared to other PARPi in clinical development. Talazoparib has single-agent synthetic lethality in BRCA1/2- and PTEN-deficient cell lines, has potent antitumor activity in animal models of tumors harboring mutations in DNA repair pathways, and has FDA-approved indications in advanced BRCA-mutated and HER2-negative breast cancer and in homologous recombination repair gene-mutated metastatic castration-resistant prostate cancer in combination with enzalutamide. This pilot study evaluated the pharmacodynamic (PD) effects of talazoparib on DNA damage response (DDR) markers in tumor biopsy tissue in both patients (pts) who are PARPi-naïve and pts who have received prior PARPi other than talazoparib to investigate for potential differential PARPi PD responses in DNA replication stress. Methods: We are conducting a multicenter phase 2 trial in adult pts with eligible deleterious germline or somatic mutations in BRCA1/2 or genes involved in DDR including ATM, ARID1A, IDH1, BAP1, ATR, CHK2, and PALB2. Pts were enrolled and assessed in two cohorts: 1) pts who were PARPi-naïve, and 2) pts who were treated with and had documented progression on a PARPi other than talazoparib. Talazoparib is administered orally at a dose of 1000 µg/day (D) in 28 D cycles (C). The primary objective is determining the replication stress PD effect of talazoparib as evaluated by activation of Rad51 combined with a lack of γH2AX activation. Paired tumor biopsies (baseline and C2D1) will be analyzed for DDR markers (γH2AX, pNBS1, and Rad51) by IFA. Responses and adverse events (AEs) are defined by RECIST 1.1 and CTCAE v5.0, respectively. Results: The PARPi-naïve cohort had 15 pts enrolled with a median age of 58 years (range 38-76) and median prior lines of systemic therapy of 2 (range 1-5). The PARPi-treated cohort had 8 pts enrolled with a median age of 72 years (range 35-85) and median prior lines of systemic treatment of 5.5 (range 1-10). A total of 11 sets of pre-treatment and post-treatment tumor biopsies have been received to date and analyses of DDR markers are ongoing. Of 11 pts in the PARPi-naïve cohort evaluable for response, 6 pts had stable disease (SD) as best response with 2 pts (nasal cavity cancer with ARID1A alteration, bile duct cancer with IDH1 alteration) who received talazoparib for ≥ 6 C. Of 7 pts in the PARPi-treated cohort evaluable for response, 4 pts had SD as best response. Treatment-related AEs of ≥ grade 2 with ≥ 5% incidence included anemia (n=10, 43.5%), leukopenia (n=7, 30.4%), lymphopenia (n=6, 26.1%), thrombocytopenia (n=6, 26.1%), and neutropenia (n=4, 17.4%). Conclusions: Study enrollment and analyses of PD DDR markers in paired tumor biopsies are both ongoing with data to be presented at the conference. No responses have been observed to date, which may be due to prior therapies, tumor histologies, mutational selection or dose delivered with further characterization anticipated via PD DDR marker data. Citation Format: Brian Ko, Geraldine H O'Sullivan Coyne, Abdul Rafeh Naqash, Thomas J George, David DeRemer, Larry Rubinstein, Jennifer Zlott, Deborah Wilsker, Donna Ketchum, Stephanie Runkle, Katherine V Ferry-Galow, Ralph E Parchment, Naoko Takebe, Sarah Shin, Andrea R Voth, Jiuping Ji, S. Percy Ivy, James H Doroshow, Alice P Chen. Pharmacodynamics-driven phase 2 trial of talazoparib in patients with advanced solid tumors and aberrations in genes involved in DNA damage response [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr B138.

Variation of Plasma Damage-Associated Molecular Patterns in Patients with Advanced Solid Tumors after Standard of Care Systemic Treatment

Background Immunogenic cell death (ICD) is known for releasing damage-associated molecular patterns (DAMPs) from tumor cells. We aimed to find ICD signals by assessing the variation of plasmatic DAMPs (HMGB1, S100A8) before-after standard of care (SoC) systemic treatment in patients with advanced solid tumors. Methods Patients scheduled to start a new line of systemic treatment were included. Plasmatic concentrations of HMGB1 and S100A8 were measured (ng/mL) before and after three months of treatment. Results Fifty-two patients were included. Forty-four patients (85%) had metastases, and 8 (15%) were treated for stage III tumors. The most frequent tumor sites were colorectal (35%) and lung (25%). Forty-two patients (81%) received this treatment in the first-line setting. Thirty-six patients (69%) were treated chemotherapy (CT) alone, ten (19%) CT plus targeted therapy, two (3.8%) carboplatin-pemetrexed-pembrolizumab, three (5.8%) pembrolizumab alone and one (1.9%) cetuximab alone. Median plasmatic concentration of S100A8 was significantly higher before than after treatment in the whole population (3.78 vs. 2.91 ng/mL; p = 0.011) and more markedly in the subgroups of patients who experienced RECIST-assessed tumor response (5.70 vs. 2.63 ng/mL; p = 0.002). Median plasmatic concentration of HMGB1was not significantly different before and after treatment (10.23 vs. 11.85 ng/mL; p = 0.382) and did not differ depending on tumor response. Median PFS was not significantly different between patients whose plasma HMBG1 concentration decreased or increased (8.0 vs. 10.6 months; p = 0.29) after treatment. Median PFS was significantly longer in those patients in whom the plasma concentration of S100A8 decreased after treatment (12 vs. 4.7 months; p < 0.001). Median OS was not significantly different between patients whose plasma HMBG1 concentration decreased or increased (13.1 vs. 14.7 months; p = 0.46) after treatment. Median OS was significantly longer in those patients in whom the plasma concentration of S100A8 decreased after treatment (16.7 vs. 9.0 months; p < 0.001). Conclusions Signals of ICD were not observed. S100A8 behaves as an inflammatory marker with decreased concentration after treatment, mostly in RECIST-responders. PFS and OS were significantly prolonged in those patients who experienced a decrease of S100A8 compared with those patients who experienced increase of plasma S100A8 at three months.

Impact of EDP-M on survival of patients with metastatic adrenocortical carcinoma: A population-based study

IntroductionHistorically, stage IV adrenocortical carcinoma (mACC) has a poor prognosis with a median overall survival (OS) of only 5 months. Based on the FIRM-ACT trial published in 2012, guidelines now advise first line systemic treatment with etoposide, cisplatin, doxorubicin and mitotane (EDP-M). The effect of EDP-M on patient survival in clinical practice in the Netherlands is unknown. MethodsThe data of all patients with mACC (2005–2020) were obtained from the Netherlands comprehensive cancer organization (IKNL). The effect of EDP-M on patient survival was assessed using Kaplan-Meier analysis and multivariate Cox regression analysis including clinical, therapy and tumor characteristics. ResultsIn total 167 patients with mACC were included. For patients diagnosed from 2014 onwards, EDP-M (in 22 patients (22%)) lead to a numerically but not statistically significant improved OS compared to those not receiving EDP-M (11.8 vs 5.6 months, p = 0.525). For systemic treatments, patients treated with mitotane only had the best 5-year OS (11.4%, p = 0.006) regardless of year of diagnosis. In multivariate Cox regression analysis EPD-M was not associated with OS; palliative adrenalectomy (HR: 0.26, p = <.001) and local treatment of metastases (HR: 0.35, p = 0.001) were associated with a better OS and a primary tumor Ki-67 index > 20% (HR: 2.67, p = 0.003) with a worse OS from 2014 onwards. Patients diagnosed before 2014 had a significantly poorer OS compared to from 2014 onwards (5-yr: 4.5 vs 8.4%, OS: 6.8 vs 8.3 months, p = 0.032). ConclusionOS for mACC in the Netherlands has improved in the last decade. Receiving EDP-M did not significantly improve OS for patients with mACC. The use of multimodality treatment including palliative adrenalectomy, mitotane and local treatment of (oligo-)metastases in appropriately selected patients has improved the OS for mACC patients since 2014.

Indolent Lymphoma Care Delivery and Outcomes during the COVID-19 Pandemic in Ontario, Canada

Background At the outset of the coronavirus infectious disease 2019 (COVID-19) pandemic, hematological malignancy was recognized as a risk factor for severe COVID-19 disease, particularly patients with lymphoma, presenting a unique challenge for optimal management of indolent non-Hodgkin lymphoma (iNHL). To this end, professional societies including ASH favoured less immunosuppressive treatment regimens and omission of rituximab maintenance therapy. However, the implications of these recommendations on the care delivery and outcomes of patients with iNHL are unclear. Accordingly, we examined treatment selection, healthcare utilization, and COVID-19 outcomes of patients with iNHL receiving front line systemic treatment during pre-pandemic vs. pandemic period. Methods We performed a retrospective cohort study using administrative databases in Ontario, Canada, comparing outcomes in patients with iNHL who initiated first-line (1L) treatment with rituximab (R) monotherapy, or with bendamustine (B) or cyclophosphamide, vincristine, prednisone (CVP) from Jan 1, 2015 - Dec 31, 2018 (pre-pandemic cohort) and from Sept 1, 2019 - Aug 1, 2020 (pandemic cohort), with end of follow-up Mar, 31 2022. The primary outcome was comparison of treatment pattern before and during the COVID-19 pandemic which includes the following: 1L regimen received (R-CVP vs. B-R vs. R monotherapy), number of cycles received, dose delays, use of rituximab maintenance, and time-to-completion of full rituximab maintenance course (funded in Ontario every 3 months for 8 doses). Secondary outcomes were death, toxicities, healthcare utilization (emergency department [ED] visit, hospitalization, and ICU admission), and COVID-19 outcomes (SARS-CoV-2 PCR-confirmed infection, ED visit, hospitalization, and death). Adjusted odds ratios (aOR) and hazard ratios (aHR) with 95% confidence intervals (CI) from logistic regression and cause-specific proportional hazards models, respectively, were used to estimate associations between covariates (age, sex, comorbidity burden as measured by Aggregated Disease groups) and outcomes. Results We identified 4,143 patients (1,079 pandemic, 3,064 pre-pandemic), median age 69 (interquartile range 60-76) years, 44% female. In both pre- and pandemic periods, B-R was the most frequent prescribed regimen, with no difference in number of cycles given or in treatment delays (Table). During the pandemic, fewer patients received rituximab maintenance (69.6% vs 75.9%; aOR 0.72, 95% CI 0.60-0.88, p=0.0012). Older age was associated with lower odds of rituximab maintenance initiation (age 75+ vs. age &amp;lt; 60 aOR 0.44, 95% CI 0.35-0.56, p&amp;lt;0.0001). Moreover, patients who initiated maintenance during the pandemic period were less likely to complete the full maintenance course (48.7% vs 56.3%) (aHR 0.81, 95% confidence interval [CI] 0.71-0.92, p=0.0010) (Table) (Figure). Patients treated during the pandemic had less healthcare utilization (ED visit aHR 0.77, 95% CI 0.68, 0.88, p&amp;lt;0.0001; hospitalization aHR 0.81, 95% CI 0.70-0.94, p=0.0067) and treatment-related complications (infection aHR 0.69, 95% CI 0.57-0.82, p&amp;lt;0.0001; febrile neutropenia aHR 0.66, 95% CI 0.47-0.94, p=0.020), with no difference in death (aHR 0.79, 95% CI 0.58-1.08, p=0.14, Table). For COVID-19 outcomes, there were 131 SARS-CoV-2 infections from the beginning of the pandemic until December 31, 2021; with follow-up until March 31, 2022, there were 30 ED visits, 56 hospital admissions, and 23 ICU admissions, and 45 deaths related to COVID-19. Rituximab use (first dose to 1-year post-last dose) was associated with higher risk of COVID-19 infection (aHR 1.56, 95% CI 1.09-2.24, p=0.015) and COVID-19 complications (ED visit aHR 4.28, 95% CI 1.79-10.26, p=0.001; hospitalization/death 1.81, 95% CI 1.11-2.93, p=0.016). Primary vaccination series was associated with lower risk of infection and severe outcomes (infection aHR 0.52, 95% CI 0.28-0.97, p=0.04; hospitalization/death aHR 0.36, 95% CI 0.14-0.94, p=0.036; death aHR 0.26, 95% CI 0.07-0.89, p=0.033). Conclusion During the pandemic, B-R remained the preferred regimen for iNHL treatment, while rituximab maintenance use was less. Despite similar 1L regimen use, healthcare utilization and infectious complications were less in the pandemic cohort. Rituximab use was associated with nearly 2-fold risk of COVID-19 hospitalization/death.

Impact of high dose radiotherapy for breast tumor in locoregionally uncontrolled stage IV breast cancer: a need for a risk-stratified approach

AimPatients with locoregionally uncontrolled breast tumors are frequently referred for breast palliative radiotherapy (PRT) to mitigate symptoms. We analyzed the outcomes following breast PRT to optimize PRT according to risk groups.MethodsWe reviewed 133 patients who underwent breast PRT. A median total dose of 45 Gy was prescribed with an equivalent dose in 2 Gy fractions (EQD2, α/β = 3.5) of 53 Gy. The Cox proportional hazards model was used to analyze the prognostic factors of local control (LC).ResultsMost (90.2%) had polymetastatic disease (> 5 lesions), and 48.9% had bone metastasis. With a median follow-up of 17.2 months, the 2-year LC and overall survival (OS) rates were 49.4%, and 48.3%, respectively. Multivariable analyses demonstrated progressive or mixed responses outside the breast and > 2 lines of previous therapy as adverse features for clinical outcomes. Group 1 (0 risk factors) showed favorable 2-year LC and OS of 63.9%, and 72.8%, respectively, whereas group 3 (2 risk factors) showed the worst outcomes of 0%, and 6.8%, respectively. Breast PRT with EQD2 ≥ 63 Gy showed a significant benefit in LC for group 1 and marginal benefit (p = 0.055) for group 2, but no improvement for group 3 (p = 0.300).ConclusionBreast PRT showed favorable LC outcomes in patients with stable disease outside the breast and treated with ≤ 2 lines of systemic treatment. Our findings warrant future clinical trials investigating the role of higher than palliative dose and early intervention of PRT in stage IV patients.

Progression-Directed Therapy in Oligoprogressive Castration-Refractory Prostate Cancer: Results of the Prospective Single-Arm Phase II MEDCARE Trial

Next-line systemic treatment (NEST) for progressive metastatic castration-refractory prostate cancer (mCRPC) is associated with significant costs and non-negligible toxicity. For oligoprogressive (OP) disease, defined as the appearance of up to 3 progressive and/or new lesions and/or local recurrence on conventional imaging, progression-directed therapy (PDT) may prolong the efficacy of ongoing systemic therapy and delay initiation of NEST. To investigate whether PDT could postpone NEST in patients with OP mCRPC in the prospective, single-arm, monocentric MEDCARE trial. We enrolled patients with OP mCRPC while on ongoing treatment with androgen deprivation therapy (ADT), with or without an androgen receptor-targeted agent (ARTA). Progression was detected with conventional imaging (bone scan and CT of MRI). A history of docetaxel treatment was allowed. All progressive lesions had to be treatable with PDT, either (stereotactic body) radiation therapy ((SB)RT) or metastasectomy. Repeated PDT was allowed at the time of further oligoprogression. The primary endpoint was NEST-free survival. Secondary outcomes of the trial included clinical progression-free survival (cPFS), prostate cancer specific survival (PCSS), overall survival (OS) as well as acute and late toxicity. Between January 2020 and January 2021, 20 patients were included. Median age was 74 years. Median PSA level and PSA doubling at the time of inclusion were 4 ng/ml (IQR 2-11) and 4 months (IQR 3-5), respectively. Median follow-up was 28 months (IQR 5-33). A total of 31 lesions were treated with SBRT to 22.5-30 Gy in 3-5 fractions of 7.5-10 Gy. 11, 7 and 2 patients had one, two and three concurrent lesions respectively. At the time of inclusion, sixteen patients had bone metastases, two patients had only lymph node metastases, one patient a liver metastasis and one patient had local recurrence. If the primary tumor had not yet been treated, local radiotherapy to the prostate was given (n = 5). Five patients received repeated PDT for oligoprogression. Ongoing therapy at time of inclusion was ADT (n = 8) alone or ADT + ARTA (n = 12). The number of different systemic treatment lines received before inclusion was one, two and three for 5, 13 and 2 patients respectively. The median NEST-free survival was 17 months (95% CI: 9-25). The median cPFS was 6 months (95% CI: 5-7). The median PCSS was not reached while the median OS was 29 months (95% CI, 28-30). At last follow-up, 9 patients had died, of whom 6 due to progressive prostate cancer and 3 due to rapid progression of a second primary tumor (small cell lung cancer, leiomyosarcoma and acute myeloid leukemia). PDT was well tolerated with no acute nor late grade ≥3 toxicity. In OP mCRPC patients, PDT postpones the need for NEST for almost 1.5 years without inducing severe toxicity.

The percutaneous management of pulmonary metastases.

Local treatment of lung metastases has been in the front scene since late 90s when an international registry of thoracic surgery reported a median overall survival of 35 months in resected patients versus 15 months in non-resected patients. Today, other local therapies are available for patients with oligometastatic lung disease, including image guided thermal ablation, such as ablation, microwave ablation, and cryoablation. Image-guided ablation is increasingly offered, and now recommended in guidelines as option to surgery. Today, the size of the target tumour remains the main driver of success and selection of patients with limited tumour size allowing for local tumour control in the range of 90% in most recent and larger series targeting lung metastases up to 3.5 cm. Overall survival exceeding five-years in large series of thermal ablation for lung metastases from colorectal origin are align with outcome of same patients treated with surgical resection. Moreover, thermal ablation in such population allows for one-year chemotherapy holidays in all comers and over 18 months in lung only metastatic patients, allowing for improved patient quality of life and preserving further lines of systemic treatment when needed. Tolerance of thermal ablation is excellent and better than surgery with no lost in respiratory function, allowing for repeated treatment when needed. In the future, it is likely that practice of lung surgery for small oligometastatic lung disease will decrease, and that minimally invasive techniques will replace surgery in such indications. Randomized study will be difficult to obtain as demonstrated by discontinuation of many studies testing the hypothesis of surgery versus observation, or surgery versus SBRT.

Platinum-based chemotherapy for metastatic insulinoma harboring germline mutation in DNA damage repair pathway: a case report

Malignant insulinomas are rare neuroendocrine tumors that require management for both symptomatic control and tumor reduction. It is clinically challenging to optimize treatment strategies for refractory malignant insulinoma. We report a case of metastatic grade 3 insulinoma presented with recurrent hypoglycemia in a 23-year-old female with RAD51D p.Q192 germline mutation. During the disease course of 5 years, the tumor has continuously progressed despite locoregional therapy and multiple lines of systemic treatment. However, oxaliplatin-based chemotherapy achieved a partial response, which was maintained for 2 years. The hypoglycemic symptoms were controlled after the treatment response and did not recur. The platinum-based regimen could be a feasible therapeutic strategy for malignant insulinoma. The relationship between germline mutation in the DNA damage repair pathway and treatment response to platinum-based regimens in neuroendocrine tumors warrants further investigation.

Real world evidence reveals improved survival outcomes in biliary tract cancer through molecular matched targeted treatment

Biliary tract cancers are rare cancers with poor prognosis due to a lack of therapeutic options, especially after the failure of first-line systemic treatment. Targeted treatments for this clinical situation are promising and have entered clinical practice. We aimed to describe the overall survival of matched targeted treatment after first-line treatment in patients with biliary tract cancers in an Austrian real-world multicenter cohort. We performed a multicenter retrospective chart review of patients with biliary tract cancer between September 2015 and January 2022. Data, including comprehensive molecular characteristics—next generation sequencing (NGS) and immunohistochemistry (IHC), clinical history, surgical procedures, ablative treatments, patient history, and systemic chemotherapy, were extracted from the records of the participating institutions. Targeted treatment was matched according to the ESMO scale for the clinical actionability of molecular targets (ESCAT). We identified 159 patients with the available molecular characteristics. A total of 79 patients underwent second-line treatment. Of these, 36 patients received matched targeted treatment beyond the first-line and were compared with 43 patients treated with cytotoxic chemotherapy in terms of efficacy outcomes. For Tier I/II alterations, we observed a progression free survival ratio (PFStargeted/PFSpre-chemotherapy) of 1.86, p = 0.059. The overall survival for patients receiving at least two lines of systemic treatment significantly favored the targeted approach, with an overall survival of 22.3 months (95% CI 14.7–29.3) vs. 17.5 months (95% CI 1.7–19.8; p = 0.048). Our results underscore the value of targeted treatment approaches based on extended molecular characterization of biliary tract cancer to improve clinical outcomes.

OUTCOMES OF STEREOTACTIC RADIOSURGERY/RADIOTHERAPY (SRST) IN MALIGNANT MELANOMA WITH CRANIAL METASTASES - THE WESSEX EXPERIENCE

Abstract AIMS To assess overall survival in malignant melanoma with cranial metastases following stereotactic radio- surgery/radiotherapy (SRST). METHOD Patients with metastatic melanoma who received SRST for their cranial metastases at the Wessex Neuro- Oncology Unit were evaluated between January 2017 and January 2023. Subtype analysis based on BRAF mutation was also performed. Their overall survival (OS) was plotted using Kaplan-Meier graph. RESULTS 121 patients were identified. The mean age at referral was 62 years (range 30-90). 50 patients had a BRAF mutation while 71 were BRAF wild type. This is a heterogenous cohort of patients, ranging from cranial-only disease to widespread disease, receiving one to two lines of systemic treatment. The median OS in patients with malignant melanoma with cranial metastases following SRST is 15 months (similar in both BRAF mutant and BRAF wildtype subgroups). The 3-year survival rate is 22.8% (BRAF mutant – 27.3%, BRAF wildtype - 20.3%). There is a small group of patients (28%) that died within six months of SRST. CONCLUSIONS Limitations were the small number of patients, short follow up period and heterogeneity in terms of systemic therapy. Our experience reveals in malignant melanoma, the median OS is 15 months after SRST to their cranial metastases. We found that BRAF mutation is non-discriminatory when predicting response to SRST and not the sole factor in predicting OS. A small cohort did not benefit from SRST as they survived for 6 months or less. Further analysis of this subgroup is needed to improve patient selection and treatment personalisation.

A phase II study on the efficacy of regorafenib in treating patients with c-KIT-mutated metastatic malignant melanoma that progressed after previous treatment (KCSG-UN-14-13)

Backgroundc-KIT mutations are found in approximately 15% of patients with malignant melanoma in the Asian population. Regorafenib, an oral multikinase inhibitor, acts against both wild-type and mutant KIT. ObjectiveThis multi-institutional, phase II, single-arm study aimed to evaluate the efficacy of regorafenib against metastatic malignant melanoma harbouring c-KIT mutations. MethodsPatients with metastatic melanoma positive for c-KIT mutations, upon progression after at least one line of systemic treatment, were enroled. Patients received oral regorafenib 160 mg once daily for 3 weeks (4-week cycle). The primary endpoint was disease control rate (DCR), and secondary endpoints were safety, overall response rate (ORR), progression-free survival (PFS), and overall survival (OS). ResultsIn total, 23 patients were enrolled. c-KIT mutations were frequently reported in exon 11 (14/23, 60.9%), followed by exons 13, 17, and 9 in 5 (21.7%), 5 (21.7%), and 2 (8.7%) patients, respectively. DCR at 8 weeks was 73.9%, with 2 patients (8.7%) achieving complete response, 5 (21.7%) achieving partial response, and 10 (43.5%) showing stable disease. ORR was 30.4% (7/23). The median follow-up period was 15.7 months (95% confidence interval [CI], 9.6–21.3), and median OS and PFS were 21.5 months (95% CI, 15.1–27.9) and 7.1 months (95% CI, 5.0–9.2), respectively. Circulating tumour DNA analysis in selected patients showed high c-KIT correlation (85.7%) with tissue-based tumour mutational profiles. The most common adverse events (AEs) were skin reactions, including palmar-plantar erythrodysesthesia (52.2%), and grade 3 AEs were reported in 39.1% (9/23) of the patients. ConclusionRegorafenib in second- or later-line settings demonstrated significant activity in patients with metastatic melanoma harbouring c-KIT mutations.

Evolution of Patterns of Care and Outcomes in the Real-Life Setting for Patients with Metastatic GIST Treated in Three French Expert Centers over Three Decades.

Gastrointestinal stromal tumors (GIST) are rare mesenchymal tumors characterized by KIT or PDGFRA mutations. Over three decades, significant changes in drug discovery and loco-regional (LR) procedures have impacted treatment strategies. We assessed the evolution of treatment strategies for metastatic GIST patients treated in the three national coordinating centers of NetSarc, the French network of sarcoma referral centers endorsed by the National Institute of Cancers, from 1990 to 2018. The primary objective was to describe the clinical and biological profiles as well as the treatment modalities of patients with metastatic GIST in a real-life setting, including access to clinical trials and LR procedures in the metastatic setting. Secondary objectives were to assess (1) patients' outcome in terms of time to next treatment (TNT) for each line of systemic treatment, (2) patients' overall survival (OS), (3) evolution of patients' treatment modalities and OS according to treatment access: <2002 (pre-imatinib approval), 2002-2006 (pre-sunitinib approval), 2006-2014 (pre-regorafenib approval), post 2014, and (4) the impact of clinical trials and LR procedures on TNT and OS in the metastatic setting. 1038 patients with a diagnosis of GIST made in one of the three participating centers between 1990 and 2018 were included in the national prospective database. Among them, 492 patients presented metastasis, either synchronous or metachronous. The median number of therapy lines in the metastatic setting was 3 (range 0-15). More than half of the patients (55%) participated in a clinical trial during the course of their metastatic disease and half (51%) underwent additional LR procedures on metastatic sites. The median OS in the metastatic setting was 83.4 months (95%CI [72.7; 97.9]). The median TNT was 26.7 months (95%CI [23.4; 32.3]) in first-line, 10.2 months (95%CI [8.6; 11.8]) in second line, 6.7 months (95%CI [5.3; 8.5]) in third line, and 5.5 months (95%CI [4.3; 6.7]) in fourth line, respectively. There was no statistical difference in OS in the metastatic setting between the four therapeutic periods (log rank, p = 0.18). In multivariate analysis, age, AFIP Miettinen classification, mutational status, surgery of the primary tumor, participation in a clinical trial in the first line and LR procedure to metastatic sites were associated with longer TNT in the first line, whereas age, mitotic index, mutational status, surgery of the primary tumor and LR procedure to metastatic sites were associated with longer OS. This real-life study advocates for early reference of metastatic GIST patients to expert centers to orchestrate the best access to future innovative clinical trials together with LR strategies and further improve GIST patients' survival.

Immunotherapy for Advanced Hepatocellular Carcinoma-a Large Tertiary Center Experience

IntroductionCombination of immune-checkpoint inhibitor (ICI) and vascular endothelial growth factor (VEGF) antagonist has become the first line systemic treatment for advanced hepatocellular carcinoma (HCC). However, two-thirds of patients do not respond to ICI-based treatments and biomarkers for response remain elusive. MethodsPatients with advanced HCC who received Atezolizumab/Bevacizumab combination or Nivolumab during 2016-2022 were identified in our Liver Cancer Database. Retrospective review of their clinical data was performed to investigate parameters that could be predictive of immunotherapy response. Results96 patients received Atezolizumab/Bevacizumab (n=60) or Nivolumab (n=36). Median age at diagnosis was 67.1 years. 70 patients had received treatment and 26 patients were treatment naïve before starting immunotherapy. Mean pre-treatment AFP was 9780.7 (±32035) ng/mL. Confirmed objective response (complete or partial) was seen in 29% of the population (n=27). Disease remained stable in 12% (n=11) and progressed in 60% (n=56). On univariate analysis, pre-treatment AFP>400 ng/mL was associated with objective response (OR=4.5, 95% CI:1.7-11.9, p=0.0015), while white race (OR=0.35, 95% CI:0.13-0.92, p=0.030) and prior radiotherapy (OR=0.14, 95% CI:0.01-1.1, p=0.033) or systemic therapy with TKIs (OR=0.25, 95% CI:0.08-0.81, p=0.017) were associated with poor response. On multivariate analysis only AFP>400 ng/mL remained associated with response (OR=3.7, 95% CI:1.3-10.5, p=0.014). Overall survival (OS) at one and three years was 86% and 43% in responders, and 45% and 29% in non-responders, respectively. ConclusionIn our institutional experience, treatment naivety and pre-treatment AFP>400 ng/mL were associated with objective response. Prospective studies aimed at identifying factors associated with response to immunotherapy will aide patient selection.

RE-IRRADIATION FOR RECURRENT HIGH-GRADE GLIOMA: AN ANALYSIS OF PROGNOSTIC FACTORS FOR SURVIVAL AND PREDICTORS OF RADIATION NECROSIS

Abstract Recurrent high-grade glioma (rHGG) is a heterogeneous population, and the ideal patient selection for reirradiation (re-RT) has yet to be established. This study aims to identify prognostic factors for rHGG patients treated with re-RT. METHODS: We retrospectively reviewed consecutive adults with rHGG who underwent re-RT from 2009-2020 from our institutional database. The primary objective was overall survival (OS). The secondary outcomes included prognostic factors for early death (&amp;lt;6 months after re-RT) and predictors of radiation necrosis (RN). RESULTS: For the 79 patients identified, the median OS after re-RT was 9.9 months (95% CI 8.3-11.6). On multivariate analyses (MVA), re-resection at progression (HR=0.56, p=0.027), interval from primary treatment to first progression ≥16.3 months (HR=0.61, p=0.034), interval from primary treatment to re-RT ≥23.9 months (HR=0.35, p&amp;lt;0.001), and re-RT PTV volume &amp;lt;112 cc (HR=0.27, p&amp;lt;0.001) were prognostic for improved OS. Patients who had unmethylated-MGMT tumours (OR=12.4, p=0.034), ≥3 prior systemic treatment lines (OR=29.1, p=0.22), interval to re-RT &amp;lt;23.9 months (OR=9.0, p=0.039), and re-RT PTV volume ≥112 cc (OR=17.8, p=0.003) were more likely to survive &amp;lt;6 months. The cumulative incidence of RN was 11.4% (95% CI 4.3-18.5) at 12 months. Concurrent bevacizumab use (HR&amp;lt;0.001, p&amp;lt;0.001) and cumulative equivalent dose in 2 Gy fractions (cEQD2, a/b=2) &amp;lt;99 Gy2 (HR&amp;lt;0.001, p&amp;lt;0.001) were independent protective factors against RN. CONCLUSIONS: We observe favorable OS rates following re-RT and identified prognostic factors, including methylation status, that can assist in patient selection and clinical trial design. Concurrent use of bevacizumab and cEQD2 &amp;lt;99 Gy2 mitigates the risk of RN.

Checkpoint Inhibitors in Combination With Stereotactic Body Radiotherapy in Patients With Advanced Solid Tumors

Although immune checkpoint inhibitors (ICIs) targeting programmed cell death 1 (PD-1) and PD-1 ligand 1 have improved the outcome for many cancer types, the majority of patients fails to respond to ICI monotherapy. Hypofractionated radiotherapy has the potential to improve the therapeutic ratio of ICIs. To assess the addition of radiotherapy to ICIs compared with ICI monotherapy in patients with advanced solid tumors. This open-label, multicenter, randomized phase 2 trial was conducted in 5 Belgian hospitals and enrolled participants between March 2018 and October 2020. Patients 18 years or older with locally advanced or metastatic melanoma, renal cell carcinoma, urothelial carcinoma, head and neck squamous cell carcinoma, or non-small cell lung carcinoma were eligible. A total of 99 patients were randomly assigned to either the control arm (n = 52) or the experimental arm (n = 47). Of those, 3 patients (1 in the control arm vs 2 in the experimental arm) withdrew consent and thus were not included in the analysis. Data analyses were performed between April 2022 and March 2023. Patients were randomized (1:1) to receive anti-PD-1/PD-1 ligand 1 ICIs alone as per standard of care (control arm) or combined with stereotactic body radiotherapy 3 × 8 gray to a maximum of 3 lesions prior to the second or third ICI cycle, depending on the frequency of administration (experimental arm). Randomization was stratified according to tumor histologic findings and disease burden (3 and fewer or more than 3 cancer lesions). The primary end point was progression-free survival (PFS) as per immune Response Evaluation Criteria in Solid Tumors. Key secondary end points included overall survival (OS), objective response rate, local control rate, and toxic effects. Efficacy was assessed in the intention-to-treat population, while safety was evaluated in the as-treated population. Among 96 patients included in the analysis (mean age, 66 years; 76 [79%] female), 72 (75%) had more than 3 tumor lesions and 65 (68%) had received at least 1 previous line of systemic treatment at time of inclusion. Seven patients allocated to the experimental arm did not complete the study-prescribed radiotherapy course due to early disease progression (n = 5) or intercurrent illness (n = 2). With a median (range) follow-up of 12.5 (0.7-46.2) months, median PFS was 2.8 months in the control arm compared with 4.4 months in the experimental arm (hazard ratio, 0.95; 95% CI, 0.58-1.53; P = .82). Between the control and experimental arms, no improvement in median OS was observed (11.0 vs 14.3 months; hazard ratio, 0.82; 95% CI, 0.48-1.41; P = .47), and objective response rate was not statistically significantly different (22% vs 27%; P = .56), despite a local control rate of 75% in irradiated patients. Acute treatment-related toxic effects of any grade and grade 3 or higher occurred in 79% and 18% of patients in the control arm vs 78% and 18% in the experimental arm, respectively. No grade 5 adverse events occurred. This phase 2 randomized clinical trial demonstrated that while safe, adding subablative stereotactic radiotherapy of a limited number of metastatic lesions to ICI monotherapy failed to show improvement in PFS or OS. ClinicalTrials.gov Identifier: NCT03511391.

The Impact of Metastasectomy on Survival Outcomes of Renal Cell Carcinoma: A 10-Year Single Center Experience.

The role of surgical metastasectomy (MST) in solitary or oligometastasis from renal cell carcinoma (RCC) and its impact on survival outcomes remains poorly addressed. We evaluated the impact of MST on overall survival (OS) in patients with oligometastatic (m)RCC. The institutional renal cancer prospective database was examined for cases treated with partial or radical nephrectomy who developed metastatic disease during follow-up. Patients with evidence of clinical metastasis at first diagnosis were excluded. Patients considered unfit for MST received systemic treatment (ST); all others received MST. The impact of MST vs. the ST only cohort was assessed with the Kaplan-Meier method. Age, gender, bilaterality, histology, AJCC stage of primary tumor, surgical margins, local vs. distant metastasis and MST were included in univariable and multivariable regression analyses to assess the predictors of OS. Overall, at a median follow-up of 16 months after primary treatment, 168 patients with RCC developed asynchronous metastasis at the adrenal gland, lung, liver, spleen, peritoneal, renal fossa, bone, nodes, brain and thyroid gland. Nine patients unfit for any treatment were excluded. The site of metastasis was treated with surgical MST (77/159, 48.4%), with or without previous or subsequent ST, while 82/159 cases (51.2%) received ST only. The 2-year, 5-year and 10-year OS probabilities were 93.8%, 82.8% and 79.5%, respectively. After multivariable analysis, MST and the primary tumor AJCC stage were independent predictors of OS probabilities (p = 0.019 and p = 0.035, respectively). After Kaplan-Meier analysis, MST significantly improved OS probabilities versus patients receiving ST (p < 0.001). The main drawbacks of our research were the small sample size from a single-tertiary referral institution, as well as the absent or different ST lines in the cohort of patients receiving MST. When an NED status is achievable, surgical MST of mRCC significantly impacts OS, delaying and not precluding further subsequent ST.

ECOG-ACRIN LUNG-MAP S1900E substudy: A phase II study of sotorasib in participants (Pts) with previously treated stage IV or recurrent KRAS G12C mutant non-squamous (Non-sq) non-small cell lung cancer (NSCLC).

TPS9143 Background: KRAS mutant NSCLC is further defined molecularly by specific mutation subtypes and co-mutations in tumor suppressor genes. Two targeted therapeutics, sotorasib and adagrasib, are currently approved for the treatment of previously treated advanced KRAS G12C mutant NSCLC. Sotorasib has also demonstrated superiority to docetaxel in the randomized phase III CodeBreaK 200 study ( de Langen et al Lancet. 2023 Feb 7 Epub). The impact of co-mutations in tumor suppressors, including TP53 and STK11, on the efficacy of first generation KRAS G12C inhibitors has been inconclusive. The S1900E substudy aims to prospectively understand, using rigorous biomarker testing/definitions, the impact of co-mutations on the clinical activity of sotorasib in pts with KRAS G12C mutant NSCLC. Methods: S1900E is a phase 2 open-label study of sotorasib in biomarker-defined cohorts for pts who have KRAS G12C stage IV/recurrent non-sq NSCLC, received at least one line of systemic treatment, and are naïve to KRAS G12C inhibitors. Pts are assigned to S1900E under the Lung-MAP screening protocol (NCT03851445) using FoundationOne F1CDx next generation sequencing assay on tissue (Foundation Medicine, Cambridge, MA). S1900E cohorts include: #1) Presence of TP53 co-mutation AND Wild Type STK11, KEAP1, NFE2L2, CUL3; #2) Presence of STK11 co-mutation AND Wild Type TP53, KEAP1, NFE2L2, CUL3; 3) All pts not eligible for Cohorts 1 and 2 (e.g. dual co-mutations in STK11 and TP53; co-mutations in KEAP1, NFE2L2, CUL3, or others; or lack of any co-mutations). Pts with treated, clinically controlled, and asymptomatic brain metastases are eligible and with amendment 3 (Mar 20 2022), eligibility expanded to pts with asymptomatic untreated brain metastases. Sotorasib is dosed 960 mg oral daily. The primary objective is to evaluate the RECIST 1.1 response rate (ORR) per cohort. For cohorts 1 and 3, the target sample size is 40 eligible pts based on a design with 92% exact power to rule out a 14% ORR at the 1-sided 5% level, if the true ORR were 34%; ≥10 responses would rule out a 14% ORR. Cohort 2 has a target sample size of 25 eligible pts with 93% exact power to rule out a 14% ORR at the 1-sided 5% level, if the true ORR were 40%; ≥7 responses would rule out a 14% ORR. Secondary endpoints include PFS, OS, duration of response, and toxicity. Circulating tumor DNA is being collected at day 1 of cycle 1, 2, and 3 and at progression. Enrollment started April 2 2021 with conservative accrual targets met, currently with 72% enrolled (84/116) as of Feb 14 2023, including 37, 16, and 31 pts, in cohorts 1, 2, and 3, respectively. Clinical trial information: NCT04625647 .