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Purpose: Drug-induced interstitial lung disease (DILD) is a rare, but potentially fatal toxicity. Clinical and radiological features of DILD in the early experimental setting are poorly described. Patients and Methods: A total of 2,499 consecutive patients with advanced cancer on phase I clinical trials were included. DILD was identified by a dedicated radiologist and investigators, categorized per internationally recognized radiological patterns, and graded per Common Terminology Criteria for Adverse Events (CTCAE) and the Royal Marsden Hospital (RMH) DILD score. Clinical and radiological features of DILD were analyzed. Results: Sixty patients overall (2.4%) developed DILD. Median time to onset of DILD was 63 days (range, 14–336 days). A total of 45% of patients who developed DILD were clinically asymptomatic. Incidence was highest in patients receiving drug conjugates (7.4%), followed by inhibitors of the PI3K/AKT/mTOR pathway (3.9%). The most common pattern seen was hypersensitivity pneumonitis (33.3%), followed by nonspecific interstitial pneumonia (30%), and cryptogenic organizing pneumonia (26.7%). A higher DILD score [OR, 1.47, 95% confidence interval (CI), 1.19–1.81; P < 0.001] and the pattern of DILD (OR, 5.83 for acute interstitial pneumonia; 95% CI, 0.38–90.26; P = 0.002) were significantly associated with a higher CTCAE grading. The only predictive factor for an improvement in DILD was an interruption of treatment (OR, 0.05; 95% CI, 0.01–0.35; P = 0.01). Conclusions: DILD in early-phase clinical trials is a toxicity of variable onset, with diverse clinical and radiological findings. Radiological findings precede clinical symptoms. The extent of the affected lung parenchyma, scored by the RMH DILD score, correlates with clinical presentation. Most events are low grade, and improve with treatment interruption, which should be considered early.

BackgroundThe adverse impact of increasing brain tumor size on the efficacy of antibody-drug conjugates (ADCs) was investigated preclinically then validated with clinical data.Methods—Preclinical studyThe impact of tumor size on ADC tumor delivery and treatment response was evaluated in an EGFR-amplified patient-derived glioblastoma (GBM) model following treatment with Depatuxizumab mafadotin (Depatux-M). Biodistribution and imaging studies correlated drug distribution with starting treatment volume and anti-tumor activity.Methods—Clinical studyM12-356 was a Phase I study of Depatux-M in patients with GBM. Blinded volumetric analysis of baseline tumor volumes of M12-356 patients was undertaken by two reviewers and results correlated with response and survival.ResultsPreclinically, imaging and biodistribution studies showed specific and significantly higher tumor uptake of zirconium-89 labeled Depatux-M (89Zr-Depatux-M) in mice with smaller tumor volume (~98 mm3) versus those with larger volumes (~365 mm3); concordantly, mice with tumor volumes ≤100 mm3 at treatment commencement had significantly better growth inhibition by Depatux-M (93% vs 27%, P < .001) and significantly longer overall survival (P < .0001) compared to tumors ≥400 mm3. Clinically, patients with tumor volumes ConclusionBoth preclinical and clinical data showed intra-tumoral concentration and efficacy of Depatux-m inversely correlated with tumor size. This finding merit further investigation with pretreatment tumor volume as a predictor for response to ADCs, in both gliomas and other solid tumors.

BackgroundBromodomain and extra-terminal domain (BET) proteins are reported to be epigenetic anti-cancer drug targets. This first-in-human study evaluated the safety, pharmacokinetics and preliminary anti-tumour activity of the BET inhibitor ODM-207 in patients with selected solid tumours.MethodsThis was an open-label Phase 1 study comprised of a dose escalation part, and evaluation of the effect of food on pharmacokinetics. ODM-207 was administered orally once daily. The dose escalation part was initiated with a dose titration in the initial cohort, followed by a 3 + 3 design.ResultsThirty-five patients were treated with ODM-207, of whom 12 (34%) had castrate-resistant prostate cancer. One dose-limiting toxicity of intolerable fatigue was observed. The highest studied dose achieved was 2 mg/kg due to cumulative toxicity observed beyond the dose-limiting toxicity (DLT) treatment window. Common AEs included thrombocytopenia, asthenia, nausea, anorexia, diarrhoea, fatigue, and vomiting. Platelet count decreased proportionally to exposure with rapid recovery upon treatment discontinuation. No partial or complete responses were observed.ConclusionsODM-207 shows increasing exposure in dose escalation and was safe at doses up to 2 mg/kg but had a narrow therapeutic window.Clinical trial registrationThe clinical trial registration number is NCT03035591.

Background The incidence and clinical significance of electrolyte abnormalities (EAs) in phase I clinical trials are unknown. The objective of this study is to evaluate the incidence and severity of EAs, graded according to CTCAE, v4.03, to identify variables associated with EAs and their prognostic significance in a phase I population. Methods A retrospective chart review was performed of 1088 cases in 82 phase I clinical trials consecutively treated from 2011 to 2015 at the Drug Development Unit of the Royal Marsden Hospital. Cox regression analysis was performed to examine the relationship between overall survival (OS) and baseline characteristics, treating the occurrence of grade III/IV EAs as a time-varying covariate. Results The most common emergent EAs (all grades) were as follows: hyponatraemia 62%, hypokalaemia 40%, hypophosphataemia 32%, hypomagnesaemia 17% and hypocalcaemia 12%. Grade III/IV EAs occurred in 19% of cases. Grade III/IV EAs occurred during the dose-limiting toxicity window in 8.46% of cases. Diarrhoea was associated with hypomagnesaemia at all grades (p, Highlights • Patients who develop grade III/IV electrolyte abnormalities have poorer overall survival. • Hyponatraemia is linked to higher risk of developing other electrolyte abnormalities. • Hypoalbuminaemia is linked to higher risk of developing electrolyte abnormalities.

Although the neutrophil-lymphocyte ratio (NLR) is prognostic in many oncological settings, its significance in the immunotherapy era is unknown. Mechanistically, PD-1/PD-L1 inhibitors may alter NLR. We sought to characterise NLR kinetics in patients with advanced solid tumours treated with PD-1/PD-L1 inhibitors.Electronic records of patients treated with PD-1/PD-L1 inhibitors on phase I trials across three sites were reviewed. A high NLR (hNLR) was predefined as5. Univariate logistic regression models were used for toxicity, response analyses and Cox models for overall survival (OS) and progression-free survival analyses. Landmark analyses were performed (cycle two, three). Longitudinal analysis of NLR was performed utilising a mixed effect regression model.The median OS for patients with hNLR was 8.5 months and 19.4 for patients with low NLR, (hazard ratio [HR] = 1.85, 95% confidence interval [CI] 1.15-2.96, p = 0.01). On landmark analysis, hNLR was significantly associated with inferior OS at all time points with a similar magnitude of effect over time (p 0.05). On multivariate analysis, NLR was associated with OS (HR 1.06, 95% CI 1.01-1.11, p = 0.01). NLR did not correlate with increased immune toxicity. Longitudinally, NLR correlated with response: NLR decreased by 0.09 (95% CI: -0.15 to -0.02; p = 0.01) per month in responders compared with non-responders.hNLR at baseline and during treatment is adversely prognostic in patients with advanced malignancies receiving PD-1/PD-L1 blockade. Importantly, NLR reduced over time in responders to immunotherapy. Taken together, these data suggest that baseline and longitudinal NLR may have utility as a unique biomarker to aid clinical decision-making in patients receiving immunotherapy.

Background: Methylation is reported to support cancer immune tolerance. We conducted a phase 1 dose-escalation trial [NCT02998567] of combination guadecitabine (G; DNA hypomethylating agent) and pembrolizumab (P) in patients (pts) with advanced cancers. We hypothesized that G can normalize the expression of epigenetically suppressed immune genes, increase interferon producing tumor-infiltrating lymphocytes (TILs), and enhance the anticancer activity of P. Methods: In dose escalation (Es), pts received G (45 mg/m2 or 30 mg/m2, administered SC on days 1-4) with P (200 mg, administered IV starting from cycle 2 onwards) as outpatient Q3W; in expansion (Ex), the RP2D of G (30 mg/m2) with P (200 mg) Q3W was administered. Pre-treatment and on-treatment tumor biopsies were evaluated for PD-L1 expression, tumor infiltrating lymphocytes, gene expression by RNAseq and methylome studies. Longitudinal analyses of peripheral blood CD3, CD4 and CD8 lymphocytes by flow cytometry were performed. Results: Overall, 34 pts (Es, n = 14; Ex, n = 20) were evaluable for safety. The most common treatment-related adverse events (TRAEs) were neutropenia (n = 21), fatigue (n = 6) and thrombocytopenia (n = 3), diarrhea (n = 2). G3+ TRAEs were neutropenia (n = 14), febrile neutropenia (n = 4), raised ALP (n = 1), raised AST (n=1), colitis (n = 1), diarrhoea (n = 1) and lung infection (n = 1). Two DLTs (neutropenia, febrile neutropenia) were reported at G 45mg/m2 with none reported at G 30mg/m2. There were no treatment-related deaths. In total, 28 pts (Es, n = 12; Ex, n = 16) were evaluable for antitumor activity studies (≥2 scans); ORR (CR+PR) and DCR (CR+PR+SD) were 3% and 57%; 10/15 pts with non-small cell lung cancer (13 pts resistant/refractory to PD-1/PD-L1 targeting agents) were evaluable, with a DCR of 80% and 5 pts having DCR > 6 months with 8 pts remaining on study treatment. Overall, 25 paired biopsies were obtained. Using LINE1 sequences to study global methylation, both tumor biopsies and peripheral blood showed reduced methylation post-G treatment. Preliminary data on tumor-infiltrating lymphocytes assessed by multicolor immunofluorescence in 9 paired biopsies showed a numerical increase in median values of T-helper (CD4+FOXP3-) (10.20 to 19.70, p = 0.5469), T-regulatory (CD4+FOXP3+) (5.1 to 6.7, p=0.8438), and T-cytotoxic (CD8+) cell densities (2.7 to 7.4, p=0.6523) . Comparing with matched pre-treatment, on treatment tumor had numerical increases in interferon alpha and gamma response pathway activation in serial biopsy RNAseq analyses but did not reach significance. Conclusions: G plus P resulted in no unexpected toxicities with evidence suggestive of biological and anti-cancer activity. Citation Format: Dionysis Papadatos-Pastos, Abhijit Pal, Melek Akay, Malaka Ameratunga, Sanjena Mithra, Joo-Ern Ang, Sofia Levva, Reece Caldwell, Ruth Riisnaes, Mateus Crespo, Wei Yuan, George Seed, Bora Gurel, Ines Figueiredo, Rita Pereira, Susana Miranda, Anna Ferreira, Suzanne Carreira, Claudia Bertan, Chloe Baker, Ricardo Morilla, Robert Brown, Nahal Masrour, Toby Prout, Anna Zachariou, Alison Turner, Mona Parmar, Mark Van de Velde, Ben Jenkins, Christina Yap, Nina Tunariu, Udai Banerji, Juanita Lopez, Anna Minchom, Johann De Bono. HyPeR: A phase 1, dose escalation and expansion trial of guadecitabine (SGI-110), a second-generation hypomethylating agent in combination with pembrolizumab (MK3475) in patients with refractory solid tumors [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT129.

Background: Hyperactivation of the PI3K/AKT pathway correlates with impaired anti-tumor responses, including reduced T cell infiltration into tumor, and reduced efficacy of immune checkpoint inhibitors. Blockade of this pathway synergizes with PD-L1/PD-1 axis blockade preclinically. Methods: This Phase I clinical trial (NCT03673787) assessed the safety, pharmacodynamic, and preliminary clinical activity of Ipa (200mg or 400mg OD) given in combination with A 1200mg q3 wk in refractory pts. Serial paired blood and tumor samples were analysed to interrogate the effect of Ipa on the tumor micro-environment and host immune system prior to the addition of the immune check point inhibitor, A. Results: 18 adult pts were treated in dose escalation. Median age 49 yrs. All pts had ECOG PS 0-1 and median 7 prior therapies. Most common TRAEs (>15%) were mild Gr1-2 diarrhea (56%), rash (50%), fatigue (33%), nausea (33%), raised ALT/AST (33%), headache (28%) and arthralgia (22%). 1 pt had G2 systemic immune activation; 2 pts had G3 rash, both rapidly reversible. 1 DLT of G3 raised ALT seen at 200mg (1 DLT/9 evaluable pts) but none at 400mg (0 DLT/6). Of 14 RECIST evaluable patients, there were 2 confirmed PRs, and 5 SD (clinical benefit rate 50%). Reductions of CD4+FOXP3+ Tregs in tumor microenvironment were seen after 2wks of single agent Ipa, regardless of PIK3/AKT somatic mutation status (Table 1). Responding pts had a >400% median increase in intra-tumoral CD8+ Teff cell infiltration, effectively switching from a desert phenotype to an inflamed phenotype. Paired changes in FACS, transcriptome and cytokine will also be presented.Conclusions: The RP2D of Ipa 400mg OD combination with A was well tolerated with early efficacy signals. Further biomarker work is ongoing and will be evaluated in expansion cohorts. Table 1:Changes in immune cell populations as assessed by multicolour Immunofluorescence in paired biopsies of breast/gynae patients, % change in cell number/mm2 from baseline (median [min,max$])&Post 2 weeks single agent Ipatasertib(n=9)Post 1 cycle of combination Ipatasertib and Atezolizumab(n=7)CD4+FOXP3+Tregs cellsCD 8+ Teff cellsCD4+FOXP3+Tregs cellsCD 8+ Teff cellsIntra-tumourstromaIntra-tumourstromaIntra-tumourstromaIntra-tumourstromaAll patients-23.9*[-89.7, BL0]-30.0*[-91.6, BL0]-37.7*[-84.4, -24.5]-28.4[-92.4, 259.8]335.9[-44.0,BL0]45.4[-51.0, BL0]59.6[-60.6,493.3]64.7[-51.7,293.3]Stratified by somatic PI3K/AKT/PTEN mutational statusPathogenic mutations (mt)11.1[-82.2, BL0]#-10.7[-91.6, BL0]Φnsnsnsns-30.5[-60.6,-0.5]11.3[-51.7,50.0]Wildtype (wt)-63.1[-89.7,19.0]#-47.5[-77.0,11.1]Φnsnsnsns426.5[59.6,493.3]126.7[79.4,293.3]Stratified by responseResponders (PR + SD>4 cycles). 1 ER+ HER2+ breast cancer (wt), 1 ER+ HER2- breast cancer (wt)459.9[426.5,493.3]@103.1[79.4,126.7]Non-responders (PD at 4 cycles) 1 cervical cancer, 4 ER+ breast cancer-0.5[-60.6, 59.6]@30.6[-51.7,293.3]*significant change (p≤0.05; Wilcoxon sign-rank test) from baseline, $maximum values denoted by BL0indicate that the baseline value was zero, and so percentage change from baseline is not defined. For the analysis, the baseline value has been replaced by a nominal value of 0.1 so that a large percentage increase is associated with these cases. Note that these large percentage increases do not affect the non-parametric statistical tests used.#no significant difference in distribution of reduction in intra-tumoural CD4+ FOXP3+Tregsbetween pts with pathogenic mutations in PI3K/AKT and those without (p=0.30; Wilcoxon rank-sum test)Φno significant difference in distribution of reduction in stromal CD4+FOXP3+Tregsbetween pts with pathogenic mutations in PI3K/AKT and those without (p=0.44; Wilcoxon rank-sum test) @ difference between responders and non-responders p=0.083; Wilcoxon rank-sum test)mt pathogenic mutations in PI3K/AKT and PTEN as per COSMIC database present in tumour or PTEN loss by IHC. wt no pathogenic mutations in PI3K/AKT and PTEN as per COSMIC database detected in tumour and intact PTEN expression by IHC. &exploratory analyses with no adjustment for multiple testing Citation Format: Juanita S. Lopez, Andrea Biondo, Crescens Tiu, Mariana Scaranti, Malaka Ameratunga, Anna Zachariou, Alison Turner, Nina Tunariu, Toby Prout, Mona Parmar, Hannah Badham, Karen Swales, Wei Yuan, Ricardo Morilla, Mateus Crespo, Rob Daly, Ines Figueiredo, Bora Gurel, Rita Pereira, Ruth Riisnaes, Igor Vivanco, Anna Minchom, Ben Jenkins, Christina Yap, Udai Banerji, Johann De Bono. Proof-of-concept evidence of immune modulation by blockade of the phosphatidylinositol 3-kinase (PI3K)-AKT signaling pathway in the phase I dose escalation study of Ipatasertib (Ipa) in combination with atezolizumab (A) in patients (pts) with advanced solid tumors (Ice-CAP) [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT140.

BACKGROUND: This is an updated version of the original Cochrane Review published in September 2014. The most common primary brain tumours in adults are gliomas. Gliomas span a spectrum from low to high grade and are graded pathologically on a scale of one to four according to the World Health Organization (WHO) classification. High‐grade glioma (HGG) carries a poor prognosis. Grade IV glioma is known as glioblastoma and carries a median survival in treated patients of about 15 months. Glioblastomas are rich in blood vessels (i.e. highly vascular) and also rich in a protein known as vascular endothelial growth factor (VEGF) that promotes new blood vessel formation (the process of angiogenesis). Anti‐angiogenic agents inhibit the process of new blood vessel formation and promote regression of existing vessels. Several anti‐angiogenic agents have been investigated in clinical trials, both in newly diagnosed and recurrent HGG, showing preliminary promising results. This review was undertaken to report on the benefits and harms associated with the use of anti‐angiogenic agents in the treatment of HGGs. OBJECTIVES: To evaluate the efficacy and toxicity of anti‐angiogenic therapy in people with high‐grade glioma (HGG). The intervention can be used in two broad groups: at first diagnosis as part of 'adjuvant' therapy, or in the setting of recurrent disease. SEARCH METHODS: We conducted updated searches to identify published and unpublished randomised controlled trials (RCTs), including the Cochrane Central Register of Controlled Trials (CENTRAL; 2018, Issue 9), MEDLINE and Embase to October 2018. We handsearched proceedings of relevant oncology conferences up to 2018. We also searched trial registries for ongoing studies. SELECTION CRITERIA: RCTs evaluating the use of anti‐angiogenic therapy to treat HGG versus the same therapy without anti‐angiogenic therapy. DATA COLLECTION AND ANALYSIS: Review authors screened the search results and reviewed the abstracts of potentially relevant articles before retrieving the full text of eligible articles. MAIN RESULTS: After a comprehensive literature search, we identified 11 eligible RCTs (3743 participants), of which 7 were included in the original review (2987 participants). There was significant design heterogeneity in the included studies, especially in the response assessment criteria used. All eligible studies were restricted to glioblastomas and there were no eligible studies evaluating other HGGs. Ten studies were available as fully published peer‐reviewed manuscripts, and one study was available in abstract form. The overall risk of bias in included studies was low. This risk was based upon low rates of selection bias, detection bias, attrition bias and reporting bias. The 11 studies included in this review did not show an improvement in overall survival with the addition of anti‐angiogenic therapy (pooled hazard ratio (HR) of 0.95, 95% confidence interval (CI) 0.88 to 1.02; P = 0.16; 11 studies, 3743 participants; high‐certainty evidence). However, pooled analysis from 10 studies (3595 participants) showed improvement in progression‐free survival with the addition of anti‐angiogenic therapy (HR 0.73, 95% CI 0.68 to 0.79; P < 0.00001; high‐certainty evidence). We carried out additional analyses of overall survival and progression‐free survival according to treatment setting and for anti‐angiogenic therapy combined with chemotherapy compared to chemotherapy alone. Pooled analysis of overall survival in either the adjuvant or recurrent setting did not show an improvement (HR 0.93, 95% CI 0.86 to 1.02; P = 0.12; 8 studies, 2833 participants; high‐certainty evidence and HR 0.99, 95% CI 0.85 to 1.16; P = 0.90; 3 studies, 910 participants; moderate‐certainty evidence, respectively). Pooled analysis of overall survival for anti‐angiogenic therapy combined with chemotherapy compared to chemotherapy also did not clearly show an improvement (HR 0.92, 95% CI 0.85 to 1.00; P = 0.05; 11 studies, 3506 participants; low‐certainty evidence). The progression‐free survival in the subgroups all showed findings that demonstrated improvements in progression‐free survival with the addition of anti‐angiogenic therapy. Pooled analysis of progression‐free survival in both the adjuvant and recurrent setting showed an improvement (HR 0.75, 95% CI 0.69 to 0.82; P < 0.00001; 8 studies, 2833 participants; high‐certainty evidence and HR 0.64, 95% CI 0.54 to 0.76; P < 0.00001; 2 studies, 762 participants; moderate‐certainty evidence, respectively). Pooled analysis of progression‐free survival for anti‐angiogenic therapy combined with chemotherapy compared to chemotherapy alone showed an improvement (HR 0.72, 95% CI 0.66 to 0.77; P < 0.00001; 10 studies, 3464 participants). Similar to trials of anti‐angiogenic therapies in other solid tumours, adverse events related to this class of therapy included hypertension and proteinuria, poor wound healing, and the potential for thromboembolic events, although generally, the rate of grade 3 and 4 adverse events was low (< 14.1%) and in keeping with the literature. The impact of anti‐angiogenic therapy on quality of life varied between studies. AUTHORS' CONCLUSIONS: The use of anti‐angiogenic therapy does not significantly improve overall survival in newly diagnosed people with glioblastoma. Thus, there is insufficient evidence to support the use of anti‐angiogenic therapy for people with newly diagnosed glioblastoma at this time. Overall there is a lack of evidence of a survival advantage for anti‐angiogenic therapy over chemotherapy in recurrent glioblastoma. When considering the combination anti‐angiogenic therapy with chemotherapy compared with the same chemotherapy alone, there may possibly be a small improvement in overall survival. While there is strong evidence that bevacizumab (an anti‐angiogenic drug) prolongs progression‐free survival in newly diagnosed and recurrent glioblastoma, the impact of this on quality of life and net clinical benefit for patients remains unclear. Not addressed here is whether subsets of people with glioblastoma may benefit from anti‐angiogenic therapies, nor their utility in other HGG histologies.

Item does not contain fulltext BACKGROUND: Adolescent and young adult (AYA) patients with advanced solid tumours are often considered for phase I clinical trials with novel agents. The outcome of AYAs in these trials have not been described before. AIM: To study the outcome of AYA patients in phase I clinical trials. METHODS: Clinical trial data of AYAs (defined as aged 15-39 years at diagnosis) treated at the Drug Development Unit, Royal Marsden Hospital, between 2002 and 2016, were analysed. RESULTS: From a prospectively maintained database of 2631 patients treated in phase I trials, 219 AYA patients (8%) were identified. Major tumour types included gynaecological cancer (25%) and sarcoma (18%). Twenty-five (11%) had a known hereditary cancer syndrome (most commonly BRCA). Molecular characterisation of tumours (n = 45) identified mutations most commonly in TP53 (33%), PI3KCA (18%) and KRAS (9%). Therapeutic targets of trials included DNA damage repair (16%), phosphoinositide 3-kinase (PI3K) (16%) and angiogenesis (16%). Grade 3/4 toxicities were experienced in 26% of patients. Of the 214 evaluable patients, objective response rate was 12%, with clinical benefit rate at 6 months of 22%. Median overall survival (OS) was 7.5 months (95% confidence interval: 6.3-9.5), and 2-year OS was 11%. Of patients with responses, 36% were matched to phase I trials based on germline or somatic genetic aberrations. CONCLUSION: We describe the outcome of the largest cohort of AYA patients treated in phase I trials. A subgroup of these patients demonstrates benefit, with several durable responses beyond 2 years. A sizeable proportion of AYA patients have cancer syndromes, significant family history or somatic molecular aberrancies which may influence novel therapeutic treatment options.

Multi-disciplinary team meetings (MDTs) are considered essential to quality cancer care. For some malignancies, MDTs have been associated with improved outcomes, but data regarding the neuro-oncology MDT is limited. We prospectively described the MDT at our institution and evaluated its impact on clinical management. Cases were discussed amongst the treating team and a pre-MDT plan and reason for discussion (RFD) was documented before the MDT. Patient specific clinical data was captured prospectively, with further pathological and radiological information captured during the MDT. Subsequently, the MDT consensus decision was recorded. High impact decisions (HID) were those in which the pre-MDT plan was substantially modified. A HID rate of >10% was considered clinically significant. Adherence to MDT recommendations was recorded. Seventy-nine cases were discussed at the MDT. Fifty-two cases (66%) were male. The median age was 53 (17–84). Thirty-three cases were new diagnoses and the remainder were relapsed/progressive disease. Thirty-nine cases were primary brain tumours, 25 were metastatic tumours and 15 were other. Twenty-eight (35%) had HID. No RFDs were statistically significantly associated with a HID (p = 0.265). Adherence data was collected for 95% (75) of cases. Treatment concordance with the MDT plan occurred in 90% (67) of cases. For cases of non-concordance, six out of eight (75%) were due to patient choice. Overall, a clinically significant proportion of treatment modifications are made at the neuro-oncology MDT. There were no case types which did not benefit from MDT discussion. MDT recommendations were largely adhered to, and in cases of non-concordance, were largely due to patient choice.

Aim Tyrosine kinase inhibitors (TKIs) targeting the epidermal growth factor receptor (EGFR) are well established in treating metastatic pulmonary adenocarcinoma, especially patients with activating EGFR mutations. EGFR mutations are rare in pulmonary squamous cell carcinomas (SCCs). There are conflicting data supporting the efficacy of EGFR-TKIs in advanced lung SCC. We analyzed the impact of EGFR-TKIs on progression-free survival (PFS) and overall survival (OS) in unselected patients with lung SCC. Methods We searched for randomized controlled trials (RCTs) comparing EGFR-TKIs alone with placebo in patients with metastatic non-small cell lung cancer. RCTs in all settings (front line/maintenance/subsequent) were included. The primary outcome was OS in the SCC population. We used published hazard ratios (HRs), and when unavailable, unpublished data were sought. Pooled estimates of treatment effect on OS and PFS were calculated using the fixed-effects inverse variance weighted method. Results Eight eligible RCTs were included: 2 first-line, 6 second-line or beyond, evaluating 1781 patients. Data were available for OS in four studies (second-line; N = 1420) and for PFS in four studies (3 second-line, 1 first-line; N = 788). EGFR-TKIs significantly prolonged OS with a HR of 0.88 (95% confidence interval [CI] 0.78–1.00, P = 0.04), and significantly prolonged PFS with a HR of 0.77 (95% CI 0.65–0.92, P = 0.004). Conclusion EGFR mutations are rare in lung SCC. However, EGFR-TKIs have a modest therapeutic effect compared to placebo in unselected patients with advanced pulmonary SCC, and can be considered in these patients. EGFR-mutation-independent mechanisms may explain efficacy of EGFR inhibitors in this setting.

3088 Background: We studied clinical and radiological parameters influencing DIP in patients (pts) participating in phase I clinical trials, aiming to investigate predictive factors affecting DIP, in particular those affecting outcome. Methods: 2439 consecutive stage IV cancer pts on phase I clinical trials from 2007 to 2017 were identified. Pts with respiratory symptoms or abnormal lung imaging were reviewed in detail, with longitudinal analysis of imaging by an experienced radiologist. R-DIP was categorized according to internationally recognized criteria. Results: 60 pts developed R-DIP (overall incidence 2.5%); most frequent in pts receiving drug conjugates (31.1%) followed by targeted therapies (8.3%). Hypersensitivity pneumonitis was most common (33.3%) followed by non-specific interstitial pneumonitis (30%) and cryptogenic organising pneumonitis (26.7%). 45% pts who developed R-DIP were clinically asymptomatic. The number of affected lobes (OR 1.47, 95% CI: 1.19-1.81, p < 0.001) and the pattern of R-DIP (OR 5.83 for ARDS, 95% CI: 0.38-90.26, p = 0.002) were significantly associated with a higher CTCAE pneumonitis grading. 23% pts (14/60) had investigational medicinal product (IMP) temporarily discontinued or had a dose reduction while 42% pts (25/60) had IMP permanently discontinued. 48% pts were treated with steroids. The number of affected lobes, pattern of R-DIP and steroid therapy did not influence an improvement in R-DIP (p = 0.65, 0.27 and 0.23 respectively). Continuation of treatment resulted in worsening of DIP in 42.9% of cases. The only predictive factor for an improvement in DIP was an interruption of treatment (OR 0.05, 95% CI: 0.01-0.35, p = 0.01). 14 pts were retreated with a reoccurrence of R-DIP in 4 pts (28.6%). Conclusions: R-DIP from novel agents in early phase clinical trials presents in varied radiological patterns, with findings often preceding clinical symptoms. Treatment interruption leads to improvement of DIP and should be considered early. Close clinical and radiological surveillance is recommended should IMP be restarted.

Results of recent clinical studies of immune checkpoint inhibitors in malignant pleural mesothelioma (MPM) have dampened initial enthusiasm. However, the immune environment and targets of these treatments such as programmed cell death protein 1 and its ligand programmed death ligand 1 (PD-L1) have not been well characterized in MPM. Using a large cohort of patients, we investigated PD-L1 expression, immune infiltrates, and genome-wide copy number status and correlated them to clinicopathological features.Tissue microarrays were constructed and stained with PD-L1(clone E1L3N [Cell Signaling Technology, Danvers, MA]), cluster of differentiation 4, cluster of differentiation 8, and forkhead box P3 antibodies. PD-L1 positivity was defined as at least 5% membranous staining regardless of intensity, and high PD-L1 positivity was defined as at least 50%. Genomic DNA from a representative subset of 113 patients was used for genome-wide copy number analysis. The percent genome alteration was computed as a proxy for genomic instability, and statistical analyses were used to relate copy number aberrations to other variables.Among 329 patients evaluated, PD-L1 positivity was detected in 130 of 311 (41.7%), but high PD-L1 positivity was seen in only 30 of 311 (9.6%). PD-L1 positivity correlated with nonepithelioid histological subtype and increased infiltration with cluster of differentiation 4-positive, cluster of differentiation 8-positive, and forkhead box P3-positive lymphocytes. High PD-L1-positive expression correlated with worse prognosis (hazard ratio = 2.37, 95% confidence interval: 1.57-3.56, p0.001) in univariate analysis but not in multivariate analysis. Higher percent genome alteration was associated with epithelioid histological subtype and poorer survival (hazard ratio = 1.59, 95% confidence interval: 1.01-2.5, p = 0.04) but not PD-L1 expression.PD-L1 expression was associated with nonepithelioid MPM, poor clinical outcome, and increased immunological infiltrates. Increased genomic instability did not correlate with PD-L1 expression but was associated with poorer survival.

Neuroendocrine carcinoma (NEC) of the head and neck is rare. We report a case of a 56-year-old man with a 6-week history of dysphagia, a neck mass and weight loss. He was diagnosed with a hypopharyngeal large cell NEC (LCNEC) with metastases to multiple sites. He received two cycles of cisplatin and etoposide. Subsequent restaging scan revealed progressive disease. The patient declined further chemotherapy and died shortly after. This is the third case of LCNEC of hypopharynx reported in the English literature and the first to progress on platinum-based chemotherapy. Although LCNEC of the head and neck is still classified as an atypical carcinoid, there is increasing evidence it is a distinct clinicohistopathological entity that carries an especially poor prognosis. Currently, there is a paucity of data to guide treatment of this rare malignancy.

BACKGROUND: Neurofibromatosis type 1 (NF1), is a common inherited autosomal dominant genetic disorder, and has been associated with glioma. Neurofibromin, encoded by the NF1 gene, downregulates the RAS-MAPK (MEK) pathway. Its loss in NF1 leads to activation of the Ras signalling pathway and has been associated with the development of multiple tumours. Preclinical testing suggests activity of MEK inhibitors in NF-1 associated tumors, but no clinical data is available. We report a case of disease control by a MEK inhibitor in recurrent NF1-associated GBM. METHODS: Case report. RESULTS: A 28 year old male with a past history of NF1 associated optic glioma, presented with a left cerebellar glioblastoma (GBM) in October 2011. The patient underwent subtotal resection, chemoradiotherapy and adjuvant temozolomide initially. He developed recurrence in June 2014 which was resected and complicated by hydrocephalus requiring a ventriculo-peritoneal shunt. He progressed on second-line carboplatin and had re-resection in August 2014. He was trialled on everolimus with stable disease for 2 months. Temozolomide was added in November 2014 and controlled disease until progression in February 2015. He was trialled on a MEK inhibitor (trametinib) and since February 2015 the patient has maintained stable disease on MRI, with reduction in oedema and size of the lesion not meeting RANO response criteria. The patient had developed an acneiform rash, which has been managed with doxycycline but has otherwise tolerated treatment well. He has had some minor clinical improvement and has been able to reduce steroid dose. CONCLUSION: NF1 associated GBM is rare. Preclinical data has suggested abnormal signalling of the RAS-MEK pathway as contributory. Here we describe the first case of substantial clinical benefit at minimal toxicity to a MEK inhibitor in a patient with treatment refractory NF1 associated GBM. This case highlights a potential promising new therapy for NF1 GBM.

Introduction Small cell lung cancer (SCLC) is aggressive and relapse is inevitable. Novel therapies in the context of phase I (Ph1) clinical trials should be considered in this setting. Next generation sequencing (NGS) identifying putative driver mutations may aid therapy allocation in such trial settings. Methods Retrospective analysis of characteristics and clinical outcomes of patients (pts) with advanced SCLC referred to the Phase I Clinical Trials Drug Development Unit at the Royal Marsden Hospital between 1992 and 2016, using electronic patient records Results 85 pts with advanced SCLC were included, of which 45 pts were allocated to ≥1 trial each (48 allocations). Of these, 21 (46.7%) pts started ≥1 trial, with a total of 24 trials commenced. Of the 64 pts who were unable to commence trials, 43 (67.2%) had rapid disease progression, 11 (17.2%) sought other therapies, 5 (7.8%) declined Ph1 trials, and 5 pts did not enrol for other reasons. Pts had a median of 2 previous lines of treatment (range:1-3). 13 pts had tumor molecular profiling with high coverage targeted NGS, yielding 22 distinct mutations; Aberrations in DNA damage repair (DDR) pathway were most common: TP53 (53.8%), FANC (30.8%), ATM (15.4%), ATR, BARD1 and CHEK2 (7.7% each). All pts found to have ≥1 DDR pathway mutation had platinum sensitive disease (disease progression ≥90 days from last platinum dose) in first line setting. Other mutations found include ALK, APC, AR, AXIN1, DDB2, ERBB2, mTOR, PI3K, NOTCH, NTRK17, PDGFR, RB1, RET, STK11, FKT3 and VGFR2. Pts were most commonly treated with novel inhibitors against PARP (n=9), PI3K/AKT (n=3), PD-1 (n=2) and BCL (n=2). Therapies were generally well tolerated with no dose limiting toxicities observed. Of 9 pts who received PARP inhibitors, 1 achieved a RECIST partial response (PR) and remained on trial for 16 weeks; 4 achieved RECIST stable disease (SD) for a median of 17 weeks (range:10.9-31.1 weeks). 1 exceptional responder whose tumor harbored multiple somatic aberrations (TP53, FANCF, AR, ERBB2, NOTCH2) was enrolled on 3 sequential phase I trials - she achieved durable RECIST SD on a PARP inhibitor (31.1 weeks), RECIST PR with a PD-1 inhibitor (38.7 weeks), and durable RECIST SD with carboplatin/ATR inhibitor (27.9 weeks). Platinum sensitivity in the first line setting predicted for improved disease control (RECIST PR/SD 73.3% vs 0%, p Discussion Novel therapeutic agents within the context of a dedicated Ph1 trials unit were well tolerated and led to preliminary signals of antitumor activity. Targeted NGS may aid in the identification of pts with putative gene aberrations, potentially predicting for response to novel therapies. Ph1 trials should be considered earlier in the pt's disease course to maximize their prospects of trial enrolment. Citation Format: Joline S. Lim, Samuel J. Harris, Malaka Ameratunga, Raghav Sundar, Joo Ern Ang, Dearbhaile Collins, Maxime Chénard-Poirier, Alvaro I. Garces, Stan B. Kaye, Juanita Lopez, Udai Banerji, Johann S. de Bono, Timothy A. Yap. Precision medicine for patients with advanced small cell lung cancer treated with novel therapeutic agents in a phase I clinical trials unit [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3081. doi:10.1158/1538-7445.AM2017-3081

e13512 Background: Multi-disciplinary team (MDT) meetings are considered essential to quality cancer care. For some malignancies, MDTs have been associated with improved outcomes, but data is limited for their utility in neuro-oncology. The aim of this study was to prospectively describe the MDT at our institution and evaluate its impact on clinical management. Methods: All cases discussed over three months at the Austin Health neuro-oncology MDT were prospectively evaluated. Cases were discussed amongst the treating team and a provisional plan (PP) and reason for discussion (RFD) was documented preceding the MDT. The PP was recorded as: surgery, radiation, chemoradiation, further diagnostic tests, surveillance and other. Patient specific clinical data was captured prospectively, with further pathological and radiological information captured during the MDT. Subsequently, the MDT reached a consensus decision, which was recorded. High impact decisions (HID) were those in which a substantial modification to the PP was made. Subsequent data regarding patient adherence to the MDT plan was recorded. Results: Over the period 79 cases were discussed at the MDT. Twenty-seven (34%) cases were female, 52 (66%) were male. The median age was 53. Six patients were discussed more than once. Forty-three cases were new diagnoses. Forty-two cases were primary brain tumours, twenty-five were metastatic solid organ malignancies. Thirty-four per cent of cases had HID. On chi-square analysis, the RFD was not statistically associated with HID (p = 0.28), nor was the primary versus recurrent setting (p = 0.80) however, the nature of the PP was (p = 0.023). Adherence data was collected for 95% (75) of cases. Adherence to the MDT plan occurred 90% (67) of cases. For cases of non-adherence, six out of eight (75%) were due to patient choice. Conclusions: A significant proportion of treatment modifications are made following discussion at the neuro-oncology MDT. The nature of the provisional treatment plan may influence which cases are likely to have a change in management determined in the MDT. MDT recommendations are broadly adhered to, and in cases of non-adherence, are largely due to patient factors.

2542 Background: The use of oral anticancer therapies has increased substantially in recent years. Nonadherence can impair the efficacy of such therapies as well as confound the interpretation of toxicity and pharmacokinetic data in phase I trials. However, there is a paucity of data regarding adherence patterns and barriers in this specific setting. Methods: We included patients treated in Phase I trials involving oral investigational medicinal products (IMPs) in the Drug Development Unit, Royal Marsden Hospital, UK, between 2012 and 2014. Patient, disease and treatment characteristics as well as compliance data from prospectively collected trial diary cards and drug accountability were recorded. Relationships between adherence rate and other variables were explored using logistic regression. Results: We collected data for 2819 patient-weeks, pertaining to 169 patients treated on 18 different phase I trials. Median age was 61 years (range 18-79), females predominated (60%), median number of previous systemic therapy was 3 (0-12) and median time on trial was 9 weeks (0.3-212.4). Hundred-percent adherence rate was 88% in the first cycle and 79% overall. Nonadherence occurred in 83 of 2819 patient-weeks (3.0%); including 75 (2.7 %) missed doses and 8 (0.3 %) overdoses. In univariate analysis, longer time on trial and a continuous treatment schedule were associated with poorer adherence, whereas fasting requirements pre- or post-dosing was associated with improved adherence. Known intracranial metastases, number of concomitant medications and opiates or anti-emetics use were not significantly associated to adherence. In multivariate analysis, fasting requirements (OR 5.347, 95%CI : 1.443-20.019, p = 0.012) and longer time on trial (OR 0.98, 95%IC : 0.961-0.996, p = 0.017) were statistically significant. Conclusions: This is the first report on adherence rates to oral anticancer IMPs in a large phase I trial population. Our observed adherence rates are at the higher end of published data in the general cancer population. Factors influencing adherence in phase I trials appear to be distinct, with fasting requirements being a unique finding. These findings may impact future early-phase trial design and conduct.

10536 Background: AYA cancer patients are relatively under-represented in clinical trials, with no published data regarding their outcomes in phase I studies. Trials utilizing novel therapeutic agents are often considered in these patients, due to their tendency to have good organ reserve, and ability to tolerate additional lines of therapy. This study describes the experience of AYA patients with advanced solid tumors treated in a specialized drug development unit. Methods: Patient characteristics and clinical outcomes of AYA patients (defined as age 15 to 39 years at time of initial cancer diagnosis) treated at the Drug Development Unit, Royal Marsden Hospital, United Kingdom, between 2002 and 2016, were captured and analyzed from case and trial records. Results: From a database of 2631 patients treated on phase I trials, 219 AYA patients (8%) were identified. Major tumor types included gynaecological cancer (24%), sarcoma (18%), gastrointestinal (16%) and breast cancer (11%). Patients had a median of 3 previous lines of systemic chemotherapy (range 0 – 6), and 19% participated in 2 or more phase I studies. Twenty (9%) had a known hereditary cancer syndrome (most commonly BRCA), 27% had a family history (FH) of cancer, 15% no FH and 49% no FH documented. Molecular characterization of tumors (n = 45) identified mutations most commonly in p53 (33%) , PI3KCA (18%) and KRAS (9%) . Major trial categories included DNA damage repair (16%), PI3K (16%) and anti-angiogenesis (15%) agents. Grade 3/4 toxicities were experienced in 25% of patients (10% hematological). Of the 214 evaluable patients, objective response rate was 12%, with clinical benefit rate at 6 months of 22%. Median progression free survival was 2.3 months (95% CI: 1.9 to 2.8), median OS was 7.6 months (95% CI: 6.3 to 9.5), and 2-year OS was 11%. Of patients with responses, 35% were matched to phase I trials based on germline or somatic genetic aberrations. Conclusions: A sub-group of AYA patients with advanced solid tumors derive considerable benefit from participating in trials involving novel therapeutics. Future research must focus on predictive biomarkers and molecular profiling to identify those that would benefit from novel therapies.

Gliomas are highly vascular and rich in VEGF, which promotes angiogenesis. Bevacizumab is a monoclonal antibody against VEGF, inhibiting angiogenesis by preventing receptor activation. Early Phase II clinical trials using bevacizumab in both newly diagnosed and recurrent high-grade gliomas (HGG) showed promising results, but these have not been confirmed in recent Phase III trials. This review is an update including recently reported Phase II and III study results.This is a review of clinical trials investigating bevacizumab in newly diagnosed and recurrent HGG with a focus on outcome results. A future perspective about the expected future role of bevacizumab is given. Bevacizumab efficacy, safety and tolerability, the combination of radiation and bevacizumab, as well as the use of bevacizumab to treat pseudoprogression are discussed. Further criteria of response evaluation needed to be adjusted in the age of antiangiogenic therapy are also discussed.Bevacizumab has been shown to be safe and tolerable in HGG. In the recurrent disease setting, bevacizumab might offer clinical benefits and is currently approved as a single agent for this indication. Although clinical trials demonstrate a prolonged progression-free survival (PFS) in bevacizumab-treated HGG, a benefit on overall survival has not been demonstrated. Research so far shows that bevacizumab appears to prolong PFS in newly diagnosed glioblastoma. Available data do not demonstrate a survival benefit in newly diagnosed patients. In the recurrent setting, there is no adequately powered randomized clinical trial to address whether there is a PFS or survival benefit with bevacizumab. Bevacizumab has also been introduced into other settings in neuro-oncology, including concurrent administration with re-irradiation for recurrent HGG.

INTRODUCTION:Immune checkpoint inhibition has shifted treatment paradigms in non-small cell lung cancer (NSCLC). Conflicting results have been reported regarding the immune infiltrate and programmed death-ligand 1 (PD-L1) as a prognostic marker. We correlated the immune infiltrate and PD-L1 expression with clinicopathologic characteristics in a cohort of resected NSCLC. METHODS:A tissue microarray was constructed using triplicate cores from consecutive resected NSCLC. Immunohistochemistry was performed for CD8, FOXP3 and PD-L1. Strong PD-L1 expression was predefined as greater than 50% tumor cell positivity. Matched nodal samples were assessed for concordance of PD-L1 expression. RESULTS:Of 522 patients, 346 were node-negative (N0), 72 N1 and 109 N2; 265 were adenocarcinomas (AC), 182 squamous cell cancers (SCC) and 75 other. Strong PD-L1 expression was found in 24% cases. In the overall cohort, PD-L1 expression was not associated with survival. In patients with N2 disease, strong PD-L1 expression was associated with significantly improved disease-free (DFS) and overall survival (OS) in multivariate analysis (HR 0.49, 95%CI 0.36-0.94, p = 0.031; HR 0.46, 95%CI 0.26-0.80, p = 0.006). In this resected cohort only 5% harboured EGFR mutations, whereas 19% harboured KRAS and 23% other. KRAS mutated tumors were more likely to highly express PD-L1 compared to EGFR (22% vs 3%). A stromal CD8 infiltrate was associated with significantly improved DFS in SCC (HR 0.70, 95%CI 0.50-0.97, p = 0.034), but not AC, whereas FOXP3 was not prognostic. Matched nodal specimens (N = 53) were highly concordant for PD-L1 expression (89%). CONCLUSION:PD-L1 expression was not prognostic in the overall cohort. PD-L1 expression in primary tumor and matched nodal specimens were highly concordant. The observed survival benefit in N2 disease requires confirmation.

11051 Background: The prognostic significance of tumor infiltrating lymphocytes (TILs) in non-small cell lung cancer (NSCLC) remains unclear. Immunotherapies in NSCLC have recently shown therapeuti...

2047 Background: Overall Survival (OS) and Progression Free Survival (PFS) results of randomized controlled trials (RCTs) are available of anti-angiogenic therapy (AAT) in GBM, especially Bevacizum...