N+I is approved for the first-line (1L) treatment of adult patients with intermediate/poor-risk aRCC, with efficacy demonstrated in CheckMate 214. Real-world effectiveness (RWE) data are limited; we assessed clinical characteristics and outcomes for aRCC patients who received N+I in England. This retrospective, observational chart review examined patient demographics, clinical characteristics, treatment patterns, safety and outcomes (objective response [OR], progression-free survival [PFS], overall survival [OS]) of patients with aRCC treated with N+I at five sites in England. Eligible patients-initiated N+I at any line of therapy from 5-Apr-19 to 1-Apr-22 (including during COVID lockdown periods) and were followed until death or study end. 128 patients met eligibility criteria (mean age 60.7 yr, 71.1% male); 85.2% had clear cell histology; most had intermediate or poor IMDC classification at index (49.2% and 39.1%, respectively). Median follow-up (min-max) was 13.6 (0.8-37.9) mo. 95.3% (n=122) received 1L N+I. Median time on treatment from 1L initiation was 2.8 (0.03-34.4) mo and 54.1% (n=66) advanced to 2L therapy, mostly (n=56, 77.8%) to cabozantinib. Overall, 82% discontinued 1L therapy; most frequently for disease progression (n=23; 50.5%) or AEs (n=40; 38.1%). In patients receiving 1L N+I, OR was 29.7%, with a complete response rate of 1.1%; median PFS from 1L initiation was 7.6 mo; 1-yr PFS was 40.3% and 1-yr OS was 71.4%. This study provided RWE on the characteristics and outcomes of patients with aRCC who received N+I. OR, PFS and OS were slightly inferior to those observed in CheckMate 214 but comprised a real-world population with a higher proportion of poor risk patients, those with CNS metastases, non-clear cell histology and treatment during the COVID pandemic.

Historically, poorer outcomes are expected with BM in mRCC. With improved local therapies (LT) and advances in systemic therapies (ST) in recent years, we conducted a UK multicentre retrospective review of BM outcomes in mRCC. 15 UK centres conducted retrospective individual mRCC pts data review, who commenced first line ST (1L) between 01/01/2018 and 30/06/2021. BM, IMDC scores, ST, LT and outcomes were collected and analysed using Kaplan Meier Analysis. 1173 mRCC pts were analysed for BM status. At data cutoff, 105 pts had <6months (m) follow up from metastatic diagnosis (FUm), 405 pts <12m FUm, and 676 pts <24m FUm. 556 of 1173 pts had brain imaging (BI) at any time (47.4%), of which 305 pts were asymptomatic at time of BI. 154 pts (13.1%) had a diagnosis of BM at any time, of which 123 pts were symptomatic at BM diagnosis (79.9%). 20 BM pts had neurosurgery (13.0%), of which 10 had surgery alone as LT. 39 BM pts underwent Stereotactic Radiosurgery (SRS), 9 BM pts received Whole Brain Radiotherapy (WBRT), and 1 BM pt had SRS+WBRT sequentially. 105 BM pts had no LT (68.2%). All 154 BM pts received 1L. 80 pts were diagnosed before 1L. 75 pts received ST before BM diagnosis (20 pts received 2 prior ST lines and 6 pts received 3 prior ST lines before BM). 44 pts received no further ST after BM, 79 pts received only 1 ST line after BM, 24 pts received 2 ST lines after BM, 7 pts received 3 ST lines after BM, and no pts received 4 or more ST lines after BM. Median OS after BM is 21.0m. 245 pts had BI at any time prior to completing 3m on 1L (20.9%), with 225 pts having BI +/-3m of 1L. 26 of 225 pts had BM (11.6%).Table: 1457PBreakdown of incidence and OS by IMDCIMDCAll ptsNo BMBM%OS(m)%OS(m)%OS(m)Favourable20.533.822.530.713.065.8Intermediate48.326.749.025.359.131.7Poor24.020.925.120.324.724.1Missing7.1n/a3.4n/a3.2n/a Open table in a new tab In this analysis, the outcomes for BM mRCC pts in the modern era of immunotherapies and combination ST, are comparable to pts without BM. Use of refined modern LT and better ST in BM pts may explain the better than historical outcomes in this patient population, and supports incorporating routine BI in mRCC staging.

The addition of atezolizumab to carboplatin/etoposide (A-CE) for patients with extensive stage SCLC (ES-SCLC) has been recently established as standard first-line treatment on the basis of the IMPOWER-133 trial. Unfortunately, efficacy and safety data of this combination in the real-world setting is lacking. We retrospectively evaluated consecutive patients with ES-SCLC treated with A-CE between January 2020 and September 2021 in eight centres in the UK. Clinical and pathological data was collected and analysed. A total of 192 patients were included. Baseline clinical characteristics are summarized in the table. One hundred forty seven (77,8%) patients received four cycles of A-CE; median number of doses of atezolizumab was 7 (range 1-20). Fifty-two (27%) patients also received prophylactic cranial irradiation and sixty-one (31,7%) consolidation thoracic radiotherapy. Seventy-six (39,6%) patients received at least one subsequent treatment. At a median follow-up of 15 months, median progression-free survival (PFS) and overall survival (OS) were 5,31 and 8,85 months, respectively. Overall response rate was 69,7%. The OS rates at 12 months and 18 months were 38,25% and 20,36%, respectively. Treatment-related adverse events led to discontinuation of treatment in 32 patients (16,7%).Table: 1541PMedian age – years (range)66 (35-83)Sex – no. (%)MaleFemale83 (43,2)109 (56,8)Smoking status NeverCurrentFormerUnknown9 (4,7)50 (26,0)116 (60,4)17 (8,8)ECOG performance status score – no. (%)012330 (17)140 (73)21 (11)1 (0,5)Stage (TNM 8th edition) – no. (%)IIIIV14 (7,3)178 (93)Concomitant autoimmune disease – no. (%) Brain metastasis – no. (%)12 (6) 29 (15) Open table in a new tab Data from our series show comparable PFS but inferior OS than those reported in the trial. Known negative prognostic factors were more common in our cohort of patients at baseline and may have determined a shorter OS. Real-world data in this setting could help to optimise clinical management of these patients.

BMs are associated with higher morbidity and mortality in mRCC patients. With the evolution of systemic therapies (ST), we conducted a UK multicentre retrospective review of outcomes in mRCC pts with BM. 1246 mRCC pts data from 15 UK centres, who commenced first line ST between 01/01/18 and 30/06/21 were reviewed. Data on BM, IMDC scores, ST, local therapies (LT) were collected. Progression free survival (PFS) & Overall survival (OS) were calculated as time between start of 1st ST and subsequent ST/ date of progression & date of death/last follow-up, respectively. PFS & OS were analysed using Kaplan Meier Analyses (log rank test). 353 (28%) pts had BM (62 bone only; 291 bone & visceral mets) with a median age of 65 (range: 27-90). 102 pts had LT (resection-25, stereotactic radiotherapy (RT)-4, palliative RT-72, vertebroplasty-1). 20 patients presented with cord compression. The IMDC risk groupings were favourable 48, intermediate 195, and poor 109. Pts just receiving 1, 2, 3 or more lines of ST were 171, 125, & 55, respectively. PFS was similar for the different ST (tyrosine kinase inhibitors (TKI), immunotherapy (IO), IO/TKI) either in 1st, 2nd or 3rd line therapies, or between patients with bone only or bone & visceral metastases (all risk groups). In intermediate & poor risk groups there was a trend in favour of PFS advantage with single agent TKI or IO/TKI compared to IO/IO (Table). The median OS of all BM pts was 21. The OS was significantly longer in the favourable IMDC group (favourable-34.4m vs. intermediate-24m vs. poor-8.7m; p<0.0001), pts with prior nephrectomy (32.7 vs. 16.4m; p<0.0001) and pts with bone only metastases (29.9 vs.19.7m; p<0.05).Table: 1463PMedian PFS: Intermediate & poor risk ptsCabozantinibOther TKIIpi/NivoIO/TKINivoBone only metastases (n=51)First-line17.114.64.614.7Second-lineNot reached9.1--2.1Bone + visceral metastases (n=254)First-line8.95.67.18.8Second-line7.16.1--3.6 Open table in a new tab Our analyses indicate that TKIs remain a standard of care in mRCC pts with BM and OS is consistent with published literature. The PFS in intermediate and poor risk mRCC pts with BM favours TKI based ST compared to IO/IO treatment.

Sotorasib has recently been licensed in Europe and USA for locally advanced and metastatic KRAS G12C mutant non-small cell lung cancer (NSCLC), following platinum chemotherapy and/or immunotherapy, based on the CodeBreaK 100 phase I/II trial. Given the small sample size and that patients in clinical trials are rarely representative of those in routine practice, it is vital to compare clinical trial data with real world experience. Under the auspices of the British Thoracic Oncology Group, retrospective data was collected on patients prescribed sotorasib as per license, including those on compassionate access schemes. Data included patient demographics, diagnostic and prior treatment information, as well as outcomes of therapy. 89 patients were treated from 22 sites across the UK. Objective response rate was 34.8% with a median progression-free survival of 185 days. The most common adverse event was diarrhoea (34%). One patient had a grade 4 event: thrombocytopenia. Comparison of efficacy and toxicity to the CodeBreak 100 trial is shown in the table.Table: 1116PCodeBreaK 100Real World DataBaseline DataN. of Patient12689Female (%)6366.1Median Age (Yrs; Range)63.5 (37 – 80)66 (42 – 88)Performance Score 0-1 (%)10071.9Median (range) previous therapies2 (1 – 3)2 (1-5)Brain Metastases (%)20.613.4Sotorasib Efficacy DataDisease Control Rate (%)80.662.9Objective Response Rate (%)37.134.8Overall Survival (Days)380 (95% CI 304 – NA)262 (95% CI 210 - NA)Progression Free Survival (days)206 (95% CI 155 – 249)185 (95% CI 171 – NA)Grade 3 and above adverse events (%)20.69Dose Reductions (%)22.219.1 Open table in a new tab Although immature, real world data matches that of the CodeBreaK 100 study, confirming sotorasib as an effective treatment for relapsed KRAS G12C mutant NSCLC. Updated response and survival data will be presented.

Corrigendum to “167 - An audit of the management of mesothelioma in Southern England” [Lung Cancer 139 (Suppl. 1) (January 2020) S72–S73]Lung CancerVol. 145PreviewThe authors regret that one author’s name was written incorrectly, being S. Prince instead of S. Austin. It has been corrected in this corrigendum. Full-Text PDF

The authors regret that one author’s name was written incorrectly, being S. Prince instead of S. Austin. It has been corrected in this corrigendum. The authors would like to apologise for any inconvenience caused. An audit of the management of mesothelioma in Southern EnglandLung CancerVol. 139Preview Full-Text PDF

Abstract Background In the UK renal cancer has an incidence of around 12600 cases per year. Nivolumab is an anti-PD1 checkpoint inhibitor, which was approved in the UK for second or subsequent line treatment of advanced renal cancer in 2016. The aim of this study was to evaluate a regional experience of nivolumab use in this setting. Methods A retrospective analysis was undertaken of patients who commenced nivolumab as monotherapy for advanced renal cancer at three Cancer Centres in South Central England between February 2016 and April 2019. Information was collated from electronic patient records and e-prescribing systems. Information was gathered on patient demographics, Heng (IMDC) prognostic scores, previous treatments, treatment toxicity, use of steroids and radiotherapy during treatment, physician assessment of response and survival data. Results 109 eligible patients were identified. The average age was 59 with 72.5% of patients male. 67.9% (74/109) of patients had prior nephrectomy and 50.5% (55/109) had metastatic disease at diagnosis. 82.6% (90/109) had pure clear cell histology. 63.3% (69/109) received nivolumab as second-line treatment, 27.5% (30/109) as third-line treatment and 9.2% (10/109) as fourth-line and beyond. At the start of treatment 19.41% (19/103) had a ‘favourable’ risk Heng score, 61.2% (64/103) had an ‘intermediate’ risk and 18.3% (19/103) had a ‘poor’ risk. The number of Nivolumab cycles received ranged from 1-69, with a mean of 11 and median of 5. 45.9% of patients experienced toxicity of any grade, with 16.5% experiencing grade 3/4 toxicity. 24.8% (28/109) received radiotherapy and 40.4% (44/109) received steroids during nivolumab treatment. At response assessment 31.5% showed a response to nivolumab, 9.3% had stable disease and 59.3% had disease progression. From the start of nivolumab treatment median progression-free survival was 5.4 months, and the 12-month overall survival rate was 56.88%. 22.6% (24/109) are still receiving nivolumab. Conclusions This review has given us important real-world data on the safety and efficacy of nivolumab which reflects the findings of the pivotal phase 3 trials that led to it’s use. Further analysis will allow us to see the effect of different factors on these outcomes. Legal entity responsible for the study The authors. Funding Has not received any funding. Disclosure All authors have declared no conflicts of interest.

Efficacy of afatinib in EGFR mutant patients with comorbidities or those with suspected EGFR mutations unfit for chemotherapy is poorly explored. We evaluated afatinib in this population, with serial plasma ctDNA to investigate the role of molecular EGFR genotyping and monitoring. Phase-II trial enrolled NSCLC patients with comorbidities precluding chemotherapy, and either (i) EGFR-mutation, PS 0-3, or (ii) suspected EGFR-mutation (tissue unavailable/failed genotyping), never/former-light smoker, adenocarcinoma, and PS 0-2. Afatinib (40mg daily) given until progression/toxicity. Blood samples obtained at baseline and 12-weekly until discontinuation; plasma ctDNA performed using InVisionSeq™ (amplicon-based NGS). 39 patients recruited (14 UK centres). Median age 72 years; 27 PS 0-1/12 PS 2-3. 21 patients (54%) had known tissue EGFR-mutations. Additional 8 patients with unknown tissue status (8/17;47%), were ctDNA EGFR-mutant, making 74% EGFR-mutant in total (29/39). Combined tissue and ctDNA data identified 21 patients with common mutations (exon 19/L858R), 8 with rare mutations (exon 18/20), and 10 suspected only. Corresponding median PFS of these cohorts were 10.2/3.9/5.3 months, with 6-month PFS of 71/38/50% all exceeding the 30% target; median OS were 24.8/5.7/11.4 months (p<0.001). Therefore, all patient groups benefitted; known EGFR-mutants having best outcomes. In April 2018, 5/39 patients survived >36 months, including 4/39 progression-free (median follow-up 33 months, maximum 55). Patients with ctDNA mutation clearance during afatinib treatment had substantially improved outcomes compared to those without clearance (Figure). 40% (4/10) of mutant cases who discontinued after 3 cycles because of progressive disease developed an exon 20 EGFR-mutation. Patients unsuitable for chemotherapy with confirmed/suspected EGFR-mutations by tissue or ctDNA benefit from afatinib. Serial ctDNA is a potentially useful stratification and monitoring tool; amplicon-based ctDNA analysis can identify EGFR mutations when tissue is unavailable. Exon 20 mutations were observed at acquired resistance. ctDNA clearance during afatinib treatment is strongly associated with better PFS/OS.

Background: Osimertinib is a third-generation, CNS-active EGFR-TKI that potently and selectively inhibits both EGFR-TKI sensitising and EGFR T790M resistance mutations. We report results from the European subset of the ongoing global ASTRIS study (NCT02474355).

BACKGROUND Preclinical work suggests SRC proteins have a role in the development of resistance to vascular endothelial growth factor (VEGF) targeted therapy in metastatic clear-cell renal cancer (mRCC). This hypothesis was tested in this trial using the SRC inhibitor saracatinib and the VEGF inhibitor cediranib. PATIENTS AND METHODS Patients with disease progression after ≥1 VEGF-targeted therapy were eligible to participate in this double-blind, randomized (1:1) phase II study. The study compared the combination cediranib 30 mg once daily (o.d.) and saracatinib 175 mg o.d. (CS) (n = 69) or cediranib 45 mg o.d. and placebo o.d. (C) (n = 69). Archived tissue was used for biomarker analysis [SRC, focal adhesion kinase (FAK), von Hippel-Lindau, protein tyrosine phosphatase 1b and hypoxia-inducible factor 2α : n = 86]. The primary end point was progression-free survival (PFS) by RECIST v1.1. RESULTS Between 2010 and 2012, 138 patients were randomized across 16 UK sites. The characteristics of the two groups were well balanced. Partial responses were seen in 13.0% for C and 14.5% for CS (P > 0.05). There was no significant difference in PFS [5.4 months (3.6-7.3 months) for C and 3.9 (2.4-5.3 months) for CS; hazard ratio (HR) 1.18 (0.94-1.48)] or overall survival (OS) [14.2 months (11.2-16.8 months) for C and 10.0 (6.7-13.2 months) for CS; HR 1.28 (1.00-1.63)]. There was no significant difference in the frequency of key adverse events, dose reductions or drug discontinuations. None of the biomarkers were prognostic for PFS or OS. FAK overexpression correlated with an OS benefit [HR 2.29 (1.09-4.82), P > 0.05], but not PFS, for CS. CONCLUSIONS Saracatinib did not increase the efficacy of a VEGF-targeted therapy (cediranib) in this setting. Biomarker analysis did not identify consistent predictive biomarkers. CLINICALTRIALSGOV NCT00942877.

BACKGROUND: Preclinical work suggests Src proteins have a role in the development of resistance to vascular endothelial growth factor (VEGF) targeted therapy in metastatic clear cell renal cancer (mRCC) OBJECTIVE: To test the hypothesis that the addition of a Src tyrosine kinase inhibitor (TKI) saracatinib to VEGF targeted therapy (cediranib) improves outcomes in VEGF resistant mRCC. DESIGN, SETTING, AND PARTICIPANTS: Patients with disease progression after ≥1 VEGF targeted therapy were eligible to participate in this investigator-led, doubleblind, randomised (1:1) phase II study. Between 2010 and 2012, 138 patients were randomised across 16 UK sites. Archived tissue was used for biomarker analysis (SRC, FAK, VHL, PTB1b and HIF2α: n=86). INTERVENTION: Patients received cediranib 30mg once daily (OD) and saracatinib 175mg OD (CS) (n=69) or cediranib 45mg OD and placebo OD (C) (n=69). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary endpoint was progression free survival (PFS) by RECIST v1.1 (Response Evaluation Criteria in Solid Tumours v1.1). Secondary endpoints included tolerability, response rates, overall survival (OS). Biomarker analysis was performed. RESULTS AND LIMITATIONS: The characteristics of the two groups were well balanced. Partial responses were seen in 13.0% for C and 14.5% for CS respectively (P>0.05). There was no significant difference in PFS [5.4 months (3.6-7.3 months) for C and 3.9 (2.4-5.3 months) for CS; Hazard Ratio (HR) 1.18 (0.94-1.48)], or overall survival (OS) [14.2 months (11.2-16.8 months) for C and 10.0 (6.7-13.2 months) for CS; [HR 1.28 (1.00-1.63)]. There was no significant difference in the frequency of key adverse events, dose reductions or drug discontinuations. None of the biomarkers were prognostic for PFS or OS. Focal adhesion kinase (FAK) overexpression correlated with an OS benefit [HR 2.29 (1.09-4.82)], but not PFS, for CS. CONCLUSIONS: Saracatinib did not increase the efficacy of a VEGF targeted therapy (cediranib) in this setting. Biomarker analysis did not identify consistent predictive biomarkers. ClinicalTrials.gov number NCT00942877.

Bladder cancer is a disease of the elderly. Older patients might potentially be undertreated due to assumptions about benefit versus risk. Our objective was to determine outcomes in older patients receiving neoadjuvant chemotherapy for muscle-invasive bladder cancer (MIBC). We hypothesised that appropriately selected elderly patients (≥70 years) with MIBC could have similar clinical outcomes, and be safely treated, with standard neoadjuvant chemotherapy prior to definitive cystectomy or radiotherapy. We utilised a single institution case series analysis of patients with T2-4a N0 M0 transitional cell carcinoma of the bladder treated with cisplatin-based neoadjuvant chemotherapy between 2005 and 2011. Eighty-three patients were eligible. Median age was 68 (range 48-80), 33 patients (40%) were ≥70 years. Overall survival at 3 years was 65.8% (≥70) and 63.2% (<70) (P = 0.653), relapse-free survival at 3 years was 61.6% and 54.8% respectively (P = 0.471). The rates going forward to definitive local therapy (87.9% ≥ 70 and 84.0% < 70) and the pathological complete response rate (31.3% ≥ 70 and 40% < 70) were similar. Disease relapse rate was also similar (63.6% ≥ 70 vs. 60% < 70, P = 0.906). Elderly patients with good functional status and limited comorbidities diagnosed with MIBC receiving standard neoadjuvant chemotherapy followed by cystectomy or radiotherapy can have similar clinical outcomes as their younger counterparts. Prospective studies evaluating the optimum curative management in this elderly population are warranted.

BACKGROUND Following inguinal orchidectomy, management options for patients with stage I seminoma include initial surveillance or treatment with adjuvant radiotherapy or chemotherapy. The anticipated relapse rate for patients followed by surveillance alone is ∼15%, with adjuvant treatment this risk is reduced to ∼4%-5% at 5 years. After carboplatin treatment, follow-up strategies vary and there are no validated, predictive markers of relapse. PATIENTS AND METHODS We conducted a retrospective analysis of all patients presenting with stage I seminoma who received a single cycle of adjuvant carboplatin in South Central England between 1996 and 2013. We report on outcome and the results of univariate and multivariate analysis evaluating possible risk factors for post carboplatin relapse. RESULTS A total of 517 eligible patients were identified. All underwent nuclear medicine estimation of glomerular filtration rate before treatment with carboplatin (dosed at area under the curve × 7). With a median follow-up of 47.2 months (range 0.4-214 months), 21/517 patients have relapsed resulting in a 5-year estimated relapse-free survival of 95.0% (95% confidence interval 92.8% to 97.3%). Median time to relapse was 22.7 months (range 12.5-109.5 months). Relapse beyond 3 years was rare (4/517; 0.8%). Twenty of 21 (95%) relapsed patients had retroperitoneal lymph node metastases. The majority (16/21; 76%) of patients had elevated tumour markers at relapse. Twenty of 517 (3.9%) patients developed a new contralateral testicular germ-cell cancer. There were no seminoma-related deaths. Tumour size was the only variable significantly associated with an increased risk of relapse. CONCLUSIONS Overall results for this large cohort of patients confirm an excellent prognosis for these patients with outcomes equivalent to those seen in prospective clinical trials. Increasing tumour size alone appears to be associated with an increased risk of post chemotherapy relapse.

ABSTRACT Aim: The prognosis for stage 1 seminoma is excellent with a cure rate approaching 100%, but without adjuvant therapy, approximately 15-20% of patients may relapse and require salvage treatment. The TE19 trial confirmed the efficacy of a single dose of adjuvant carboplatin (AUC 7) in reducing recurrence rate. This study reviews our regional experience, with a focus on the presentation, management and outcome of relapsed patients. Methods: A retrospective clinical database was constructed for patients who have received one cycle of adjuvant carboplatin (AUC 7) between 1996 and 2013 for stage 1 seminoma. Tumour characteristics, clinical outcomes and patient relapse were evaluated. Results: 518 patients were eligible for inclusion. All patients underwent nuclear medicine measurement of GFR. Median age of diagnosis was 38 (range 18 – 73). Median tumour size was 32mm (range 4 – 110) and 57% had rete testis invasion. Median time from orchidectomy to chemotherapy was 44.5 days (range 10 – 174). 18 patients (3.5%) presented with bilateral disease or developed a contralateral germ cell tumour during follow up; median 94 months (range 0 – 265). With a median follow up of 43.2 months (range 0 – 199), 22 patients (4.2%) have relapsed. Median time to relapse was 22.4 months (range 11 – 108) with the majority of patients (13/518; 2.5%) relapsing within 2 years. Relapse beyond 4 years was very uncommon (4/518: Conclusions: This is, to our knowledge, the biggest non-trial series describing the clinical outcome and relapse data of patients with stage 1 seminoma treated with a single cycle of adjuvant carboplatin chemotherapy. Our results confirm the excellent prognosis for these patients with outcomes similar to those of prospective clinical trials. Disclosure: All authors have declared no conflicts of interest.