Background

BRAF-V600E mt mCRC is an aggressive disease with poor OS under standard chemotherapy. Treatment with doublet and triplet targeted combinations, such as BRAF inhibitor+ antiEGFR+/- MEK inhibitor, has been shown to improve outcomes. Prognostic factors in this population have been already described. However, prognostic factors in a homogenous population under BRAF inhibitor-based treatment have not been previously described.

Methods

A prospective international cohort of patients who received doublet or triplet anti-BRAF combinations in clinical trials or as compassionate use. Univariate Cox models for OS were constructed and the strongest predictors in stepwise variable selection were used to develop a prognostic score. The final multivariate model with selected predictors was stratified by prior lines.

Results

In total, 77 pts were enrolled. Median age 60.3 y (33-83), 55.8% female, 66.2% right-sided tumors, 60% received 2 or more prior chemotherapy lines. Three patients (4%) achieved CR and 25.7% had PR. 50 patients received doublet, and 27 patients received triplet. Overall, median PFS was 4.9m (CI95% 4.3-6.5) and median OS was 8.2 months (m) (CI95% 7.3-11.6). ECOG performance status, stage, number of tumour sites, presence of liver metastases, WBC, neutrophils, albumin CEA and NLR levels were associated with OS (p-value <0.05 in the univariate analysis). In the multivariate analysis, the most parsimonious model included four factors: ECOG, presence of liver metastases, CEA, and NLR levels. We stratified patients into three risk prognostic groups based on their number of presenting risk factors: 0 low risk (n = 17); 1-2, intermediate risk (n = 39); 3 or 4, high risk (n = 21). These three prognostic groups showed differentiated OS outcomes, with a median OS of 23.2m, 9.8m [HR=6.6, p<0.001], and 5m [HR=39.9, p<0.001] respectively.

Conclusions

Patients characteristics such as ECOG and surrogates of tumor burden like CEA levels or the number of metastatic sites remain important OS determinants for this particular population. Our study suggests that these prognostic factors could help in clinical practice and may be considered as stratification factors in future clinical trials.

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

I. Baraibar: Financial Interests, Personal, Invited Speaker: Sanofi; Financial Interests, Personal, Other, Travel, Accommodations, Expenses: Amgen, Sanofi. D. Ciardiello: Financial Interests, Personal, Other, travel grant: Luigi Van Vitelli University. R.D.A. Toledo: Financial Interests, Personal, Research Grant: Novartis, AstraZeneca and Beigene. E. Martinelli: Financial Interests, Personal, Invited Speaker: AstraZeneca, Amgen, Bayer, Merck-Serono, Roche, Sanofi, Servier, Pierre-Fabre. F. Ciardiello: Financial Interests, Personal, Invited Speaker, Advisor and speaker: Roche, Amgen, Merck-Serono, Pfizer, Sanofi, Bayer, BMS, Cellgene, Lilly; Financial Interests, Institutional, Research Grant: Bayer, Roche, Merck-Serono, Amgen, AstraZeneca, Takeda. A. Vivancos: Financial Interests, Personal, Advisory Board, advisory role, travel grants, research grants: offman La - Roche, Bristol Myers Squibb, Servier, Amgen, Merck Serono, Array Biopharma, Sanofi, Bayer; Financial Interests, Institutional, Research Grant: Array Biopharma, MSD, AbbVie, Amgen, GlaxoSmithKline, AstraZeneca, Merck Sharp & Dohme Corp., Bristol Myers Squibb, Novartis, Boehringer Ingelheim, Hoffman La-Roche, Medimmune, Pierre-Fabre, Sanofi Aventis.. R. Dienstmann: Financial Interests, Personal, Advisory Board: Roche, Boehringer Ingelheim; Financial Interests, Personal, Invited Speaker: Roche, Ipsen, Amgen, Servier, Sanofi, Libbs, Merck Sharp & Dohme; Financial Interests, Personal, Research Grant: Merck and Pierre Fabre. J. Tabernero: Financial Interests, Personal, Advisory Board: array Biopharma, AstraZeneca, Avvinity, Bayer, Boehringer Ingelheim, Chugai, Diichi Sankyo, Roche, Genentech, HalioDX, Hutchinson MediPharma, Ikena Oncology, IQVIA, Lilly, Menarini, Merck Serono, Merus, MSD, Mirati, Neophore; Financial Interests, Institutional, Sponsor/Funding, Financial support for clinical trials or contracted research: Amgen Inc, Array Biopharma, AstraZeneca, BeiGene, Boehringer Ingelheim, BMS, Celgene, Debiopharm, Roche, Genentech Inc, Halio Dx SAS, Hutchinson MediPharma, Janssen-Cilag, MedImmune, Menarini, Merch Health KGAA, Merck Shapr and Dohme, MErus NV, Mirati, No; Non-Financial Interests, Personal and Institutional, Other: Role of Principal Investigator, Coordinating Investigator or Steering Committee member: Array Biopharma, AstraZeneca Pharmaceutical, BeiGene, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Debiopharm, F.Hoffmann-La Roche, Genentech, HalioDX, Hutchin. M.E. Elez Fernandez: Financial Interests, Personal, Invited Speaker: Hoffman La - Roche, Bristol Myers Squibb, Servier, Amgen, Merck Serono, Array Biopharma, Sanofi, Bayer, Hoffman La - Roche, Bristol Myers Squibb, Servier, Amgen, Merck Serono, Array Biopharma, Sanofi, Bayer; Financial Interests, Institutional, Research Grant: Array Biopharma, MSD, AbbVie, Amgen, GlaxoSmithKline, Astrazeneca, Merck Sharp & Dohme Corp., Bristol Myers Squibb, Novartis, Boehringer Ingelheim, Hoffman La-Roche, Medimmune, Pierre-Fabre, Sanofi Aventis. All other authors have declared no conflicts of interest.

Background

Young-onset colorectal cancer (YOCR) is defined as diagnosis below the age of 50. The incidence of YOCRC is increasing at an alarming rate, but causes and pathogenesis remain unknown and YOCRC is not well characterized. We aimed to characterize the molecular characteristics of YOCRC in patients (pts) diagnosed at our centre and to evaluate the impact of molecular tumor profiling (MTP) in ameliorating the current development in metastatic YOCR.

Methods

Pts with a diagnosis of metastatic YOCR visited for the first time at Vall d’Hebron University Hospital between January 2017 and October 2020 were included in the analysis. Data of MTP including alterations (mt) detected by VHIO-Card Amplicon panel and VHIO-Card-300-v3 panel and data concerning enrollment in phase I trials using molecular targeted agents (MTAs) were collected. Benefit was calculated comparing treatment failure of prior line (TTF1) to the MTAs’ one (TTF2). TTF2/TTF1≥1.3 supposed MTAs benefit.

Results

177 pts presented metastatic YOCR of whom 105 patients had data of MTP. MTP status was: MSI-H: 2 (6%), P53mt 83 (79%), APCmt 61 (58%), KRASmt: 53 (50%), NRASmt: 4 (4%), BRAFmt: 5 (5%), PIK3CAmt: 16 (15%), RNF43mt: 4 (4%), FBXW7mt: 3 (3%), BRCA1mt: 3 (3%), NOTCH1mt: 2 (2%), CTNNB1mt: 1 (1%), ATMmt: 1 (1%). No Her2 alterations were observed. 33 pts (18.6%) were included in phase I trials (PhIT) testing BRAF inh (1), Wnt inh (3), VEGF inh (1), anti-tubulin agents (5), MET inh (1), antiEGFR (1), immunotherapy-based treatment (IT) (18) and others (3). Median of previous lines before inclusion in PhIT: 2 (1-5). Median (m)TTF1 was 28.3 weeks (w) (1.4w-105w), mTTF2 9.7w (2.1w-234w). 6 pts (18.2%) presented a TTF2/TTF1 ratio ≥1.3, of which 5 received IT. In 5 pts (15.2%), treatment was selected based on actionable molecular alterations (RAS/BRAF wt and MSI status), 3 presenting benefit.

Conclusions

YOCR does not present particular molecular alterations in our cohort in current screening programs (SP) and do not differ from historical data in overall mCRC population, hindering enrollment in PhIT using matched MTA. Specific SP for YOCR should be developed. Significant benefit is observed for YOCR included in PhIT treated with IT and intrinsic mechanisms should be further investigated.

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

I. Baraibar Argota: Financial Interests, Personal, Invited Speaker: Sanofi. J. Ros: Financial Interests, Personal, Invited Speaker: Sanofi. J. Capdevila: Financial Interests, Personal, Invited Speaker: Scientific consultancy role (speaker and advisory roles) from Novartis, Pfizer, Ipsen, Exelixis, Bayer, Eisai, Advanced Accelerator Applications, Amgen, Sanofi, ITM, Sirlex and Merck Serono. Research grants from Novartis, Pfizer, AstraZeneca, Advanced Acc. E. Garralda: Financial Interests, Other: Consulting or Advisory Role: Roche, Ellipses Pharma, Neomed Therapeutics, Janssen, Boehringer Ingelheim, Seattle Genetics, TFS, Alkermes, Thermo Fisher Scientific, Bristol-Myers Squibb; Speakers’ Bureau: MSD, Roche, Thermo Fisher Scientific Research Funding. P. Nuciforo: Financial Interests, Personal, Invited Speaker: Honoraria: Bayer, Novartis, MSD Oncology, MSD Oncology Consulting or Advisory Role: Bayer, MSD Oncology Travel, Accommodations, Expenses: Novartis. R. Dienstmann: Financial Interests, Personal, Invited Speaker: Consulting or Advisory Role: Roche Speakers’ Bureau: Roche, Ipsen, Sanofi, MSD Oncology, Servier, Amgen Research Funding: Merck. A. Vivancos: Financial Interests, Invited Speaker: Consulting or Advisory Role: Guardant Health, Novartis, Bayer Health. J. Tabernero: Financial Interests, Personal and Institutional, Other: Josep Tabernero reports personal financial interest in form of scientific consultancy role for Array Biopharma, AstraZeneca, Bayer, BeiGene, Boehringer Ingelheim, Chugai, Genentech, Inc., Genmab A/S, Halozyme, Imugene Limited, Inflection Biosciences Limi. M.E. Elez Fernandez: Financial Interests, Personal, Invited Speaker: Consulting or Advisory Role: Amgen, Roche, Merck Serono, Sanofi, Servier, Bayer, Pierre Fabre Research Funding: Merck Serono, Sanofi/Aventis (Inst) Travel, Accommodations, Expenses: Roche, Merck Serono, Sanofi, Amgen. All other authors have declared no conflicts of interest.

Background

Ra223 is a life-prolonging alpha-emitter bone targeted therapy for mCRPC patients with bone metastases. However, evidence on biomarkers that may help us in patient selection are lacking. Total ALP (tALP) appeared to be a potential marker of Ra223 effect in early studies (Sartor, Ann Oncol, 2017). Other bone-related markers, as bone-specific ALP (BALP), have demonstrated its prognostic value in mCRPC patients with bone metastases (Fizazi K, Eur Urol, 2015; Lara PN, J Natl Cancer Inst, 2014).

Methods

PRORADIUM (NCT022925702) is a prospective multicentre cohort study in mCRPC patients treated with radium-223. The primary aim was to assess the impact of baseline serum biomarkers of bone formation (BALP and C-terminal of type 1 collagen propeptide [CICP]) on overall survival (OS). Secondary aims include the correlation of progression-free survival (PFS), time to PSA progression (TTPP) and skeletal-related events free-survival (SRE-FS) with serum bone markers.

Results

169 pts were included, serum biomarkers were successfully analysed in 153 pts. Median age was 74.4 yrs, 85.2% pts had ECOG 0-1, 57.5% patients completed 5-6 cycles of Ra223. tALP was strongly correlated with shorter rPFS and OS (P<0.001). Higher baseline levels of BALP and CICP were associated to number of metastases in bone-scan (p=0.002 and p=0.001, respectively) and baseline pain (p=0.003, p=0.028, respectively). After a median follow-up of 31.1 months, 147 deaths were observed, with a median OS of 12.1 months (95%CI: 9.5-14.7). Continuous value of BALP and CICP correlated with a shorter TTPP (BALP: Q1 5.4m/Q4 3.3m, p=0.013; CICP: Q1 5.5m/Q4 3.6m, p=0.011) and rPFS (BALP: Q1 10.2m/Q4 5.4m, p=0.009; CICP: Q1 9.3m/Q4 6.9m, p=0.037), respectively. The elevation of 3-4 bone biomarkers over the median was significantly associated with worse OS (15.2 vs 9.9 m, HR 1.63, p=0.007, Fig 1). There were not associations found with SRE-FS.

Conclusions

Our results suggest that baseline serum markers of bone formation can serve as biomarkers for prognosis in mCRPC patients treated with Ra223.

Clinical trial identification

NCT022925702.

Legal entity responsible for the study

CNIO - Spanish National Cancer Research Centre.

Funding

Bayer + academic grants.

Disclosure

N. Romero Laorden: Financial Interests, Personal and Institutional, Research Grant: Janssen; Financial Interests, Personal and Institutional, Research Grant: Pfizer; Financial Interests, Personal and Institutional, Advisory Role: AstraZeneca; Financial Interests, Personal and Institutional, Research Grant: Bayer; Financial Interests, Personal and Institutional, Advisory Role: MSD; Financial Interests, Personal and Institutional, Advisory Role: Sanofi; Financial Interests, Personal and Institutional, Advisory Role: Astellas; Financial Interests, Personal and Institutional, Advisory Role: Ipsen; Financial Interests, Personal and Institutional, Invited Speaker: Roche. D. Lorente: Financial Interests, Personal and Institutional, Advisory Role: Janssen; Financial Interests, Personal and Institutional, Advisory Role: Sanofi; Financial Interests, Personal and Institutional, Advisory Role: Bayer; Financial Interests, Personal and Institutional, Invited Speaker: Astellas; Financial Interests, Personal and Institutional, Invited Speaker: BMS; Financial Interests, Personal and Institutional, Sponsor/Funding: Pfizer. J. Puente: Financial Interests, Personal and Institutional, Research Grant: Astellas; Financial Interests, Personal and Institutional, Advisory Role: Janssen; Financial Interests, Personal and Institutional, Advisory Role: MSD; Financial Interests, Personal and Institutional, Advisory Role: AstraZeneca; Financial Interests, Personal and Institutional, Advisory Role: Bayer; Non-Financial Interests, Personal and Institutional, Research Grant: Pfizer; Financial Interests, Personal and Institutional, Advisory Role: Eisai; Financial Interests, Personal and Institutional, Advisory Role: Ipsen; Financial Interests, Personal and Institutional, Invited Speaker: Sanofi; Financial Interests, Personal and Institutional, Invited Speaker: Roche; Financial Interests, Personal and Institutional, Invited Speaker: BMS; Financial Interests, Personal and Institutional, Invited Speaker: Merck Serono; Financial Interests, Personal and Institutional, Invited Speaker: Pierre Fabre. P. Borrega: Financial Interests, Personal and Institutional, Advisory Role: Sanofi; Financial Interests, Personal and Institutional, Advisory Role: Bayer; Financial Interests, Personal and Institutional, Advisory Role: Pfizer. F. Lopez Campos: Financial Interests, Personal and Institutional, Advisory Role: Astellas; Financial Interests, Personal and Institutional, Advisory Role: Janssen; Financial Interests, Personal and Institutional, Advisory Role: MSD. O. Fernandez Calvo: Financial Interests, Personal and Institutional, Advisory Role: Astellas; Financial Interests, Personal and Institutional, Advisory Role: Roche; Financial Interests, Personal and Institutional, Advisory Role: Pfizer; Financial Interests, Personal and Institutional, Advisory Role: BMS; Financial Interests, Personal and Institutional, Advisory Role: Sanofi; Financial Interests, Personal and Institutional, Advisory Role: EUSA; Financial Interests, Personal and Institutional, Invited Speaker: Pierre-Fabre; Financial Interests, Personal and Institutional, Invited Speaker: Novartis; Financial Interests, Personal and Institutional, Invited Speaker: Ipsen; Financial Interests, Personal and Institutional, Invited Speaker: Bayer; Financial Interests, Personal and Institutional, Invited Speaker: Janssen. R. Luque: Financial Interests, Personal and Institutional, Advisory Role: Astellas; Financial Interests, Personal and Institutional, Advisory Role: Janssen; Financial Interests, Personal and Institutional, Advisory Role: Sanofi; Financial Interests, Personal and Institutional, Advisory Role: BMS; Financial Interests, Personal and Institutional, Advisory Role: Roche; Financial Interests, Personal and Institutional, Advisory Role: Pfizer; Financial Interests, Personal and Institutional, Advisory Role: EUSA; Financial Interests, Personal and Institutional, Advisory Role: Novartis; Financial Interests, Personal and Institutional, Advisory Role: Ipsen. S. Ros Martínez: Financial Interests, Personal and Institutional, Advisory Role: Astellas; Financial Interests, Personal and Institutional, Advisory Role: Janssen; Financial Interests, Personal and Institutional, Advisory Role: AstraZeneca; Financial Interests, Personal and Institutional, Advisory Role: MSD; Financial Interests, Personal and Institutional, Advisory Role: Bayer; Financial Interests, Personal and Institutional, Advisory Role: Pfizer; Financial Interests, Personal and Institutional, Advisory Role: Sanofi; Financial Interests, Personal and Institutional, Advisory Role: Eisai; Financial Interests, Personal and Institutional, Advisory Role: Ipsen; Financial Interests, Personal and Institutional, Advisory Role: Roche; Financial Interests, Personal and Institutional, Advisory Role: BMS. E. Castro: Financial Interests, Personal and Institutional, Research Grant: Bayer; Financial Interests, Personal and Institutional, Research Grant: Janssen; Financial Interests, Personal and Institutional, Advisory Role: AstraZeneca. D. Olmos: Financial Interests, Personal and Institutional, Research Grant: Bayer; Financial Interests, Personal and Institutional, Research Grant: Janssen; Financial Interests, Personal and Institutional, Advisory Role: AstraZeneca. All other authors have declared no conflicts of interest.

Background

Changes in prevalence and therapeutic landscapes of mCRC have translated into a progressive increase of refMCRC population. The efficacy of the available therapies in this setting is limited. Prognostic groups have been evaluated to determine better which patients (pts) could benefit from late-line treatments. We aim to explore the numeric representation of these groups in a real population that would support this strategy as a tool in daily care.

Methods

A cohort of mCRC pts treated at our hospital was retrospectively reviewed using medical charts from 2010 to 2020. Clinical, laboratory and molecular data were evaluated. We divided pts into 3 clinical groups according to previously reported prognostic characteristics: Good Prognostic Characteristics (GPC) defined as ≥18 m since metastatic disease debut, <3 metastatic sites and presence of liver metastasis, Best Prognostic Characteristics (BPC) defined as ≥18 m, since metastatic disease debut, < 3 metastatic sites and absence of liver metastases and Poor Prognostic Characteristics (PPC) defined as < 18m since metastatic disease debut and/or ≥3 metastatic sites. Statistical analysis was done using R version 4.

Results

A total of 735 out of 2365 mCRC pts (35%) were identified as refMCRC. Median age at diagnosis was 59 years, 130 pts (18%) were < 50y. Molecular profiles were: KRAS mutant (mt): 339 (46%), BRAF mt: 87 (12%) and MSI-H 29 (4%). In our cohort, 408/735 (55.51%) pts received > 3 lines of therapy (median lines 4, IQR 3-8) and 50.98% of these pts were included in clinical trials. The prognostic subgroup classification was: 266 pts (36%) GPC, 136 (19%) BPC and 333 (45%) PPC. The mOS of the cohort was 12.6m (11.4-13.9) and OS according to Prognostic Characteristics was: GPC 14.1m (11.8-16.4), BPC 16m (14.6-19.4) and PPC 10m (8.3-11.5).

Conclusions

According to data previously reported, prognostic characteristic subgroups are well represented in this cohort with a similar distribution and survival outcomes. We should further explore the potential utility of this tool in routine clinical practice or clinical trials. Of note, 35% of the pts in our series received a third-line therapy and more than a half were included in clinical trials with longer mOS compared to previous data.

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

F. Salva: Financial Interests, Personal, Research Grant: Hoffman-La Roche; Sanofi Aventin; Amgen; Merck Serono; Servier; Bristol-Myers Squibb; Financial Interests, Personal, Advisory Board: Hoffman-La Roche; Sanofi Aventin; Amgen; Merck Serono; Servier; Bristol-Myers Squibb; Financial Interests, Personal, Sponsor/Funding: Hoffman-La Roche; Sanofi Aventin; Amgen; Merck Serono; Servier; Bristol-Myers Squibb; Financial Interests, Institutional, Other: Hoffman La-Roche. J. Ros: Financial Interests, Personal, Advisory Role: Sanofi; Financial Interests, Institutional, Other, Clinical trial investigator: Bristol-Myers Squibb; Financial Interests, Institutional, Advisory Role: Servier; Financial Interests, Personal, Other, Travel, Accommodations, Expenses: Sanofi. I. Baraibar: Financial Interests, Personal, Advisory Role: Sanofi; Financial Interests, Personal, Other, Travel, Accommodations, Expenses: Amgen; Sanofi; Financial Interests, Personal, Other, Honoraria: Sanofi. G. Argiles Martinez: Financial Interests, Personal, Advisory Role: Bayer; Bristol-Myers Squibb; Genentech/Roche; Roche; Servier; Financial Interests, Personal, Other, Travel, Accommodations, Expenses: Servier; Roche; Bayer; Amgen. J.L. Cuadra Urteaga: Financial Interests, Personal and Institutional, Sponsor/Funding: Amgen; Lilly. J. Capdevila: Financial Interests, Personal, Advisory Role: Novartis; Ipsen; Exelixis; Bayer; Eisai; AAA; Amgen; Sanofi; Merck; Financial Interests, Institutional, Other, Honoraria: Eisai; Novartis; Ipsen; AstraZeneca; Pfizer; AAA. D. Paez: Financial Interests, Personal, Speaker’s Bureau: Merck Serono; F. Hoffmann-La Roche Ltd; Financial Interests, Personal, Advisory Role: Amgen; Sanofi. G. Villacampa Javierre: Financial Interests, Personal, Speaker’s Bureau: Merck; Astra-Zeneca. Financial Interests, Personal, Expert Testimony: Merck; Financial Interests, Personal, Advisory Role: Astra-Zeneca; R. Dienstmann: Financial Interests, Personal, Advisory Role: Roche; Boehringer Ingelheim; Financial Interests, Personal, Speaker’s Bureau: Roche; Ipsen; Amgen; Sanofi; Libbs; Merck Sharp & Dohme; Financial Interests, Personal, Research Grant: Merck; Pierre Fabre. M.E. Elez Fernandez: Financial Interests, Personal, Advisory Role: Hoffman La - Roche; Bristol Myers Squibb; Servier; Amgen; Merck Serono; Sanofi; Bayer; Array Biopharma; Financial Interests, Personal, Research Grant: Hoffman La - Roche; Bristol Myers Squibb; Servier; Amgen; Merck Serono; Sanofi; Bayer; Array Biopharma; Financial Interests, Personal, Other, Travel grants: Hoffman La - Roche; Bristol Myers Squibb; Servier; Amgen; Merck Serono; Sanofi; Bayer; Financial Interests, Institutional, Other, Investigator contribution in clinical trials: Array Biopharma; MSD; AbbVie; Amgen; GlaxoSmithKline; AstraZeneca; Merck Sharp & Dohme Corp; Bristol Myers Squibb; Novartis; Boehringer Ingelheim; Hoffman La-Roche; Medimmune; Pierre-Fabre; Sanofi Aventis. J. Tabernero: Financial Interests, Personal, Advisory Role: Array Biopharma; AstraZeneca; Avvinity; Bayer; Boehringer Ingelheim; Chugai; Daiichi Sankyo; F. Hoffmann-La Roche Ltd; Genentech Inc; HalioDX SAS; Hutchison MediPharma International; Ikena Oncology; IQVIA; Lilly; Menarini; Merck Serono; Merus; MSD; Mirati; Neophore; Novartis; Orion Biotechnology; Peptomyc; Pfizer; Pierre Fabre; Samsung Bioepis; Sanofi; Seattle Genetics; Servier; Taiho; Tessa Therapeutics; TheraMyc; Financial Interests, Personal, Other: Imedex; Medscape Education; MJH Life Sciences; PeerView Institute for Medical Education and Physicians Education Resource (PER). All other authors have declared no conflicts of interest.

Background

Endocrine neoplasms encompass a heterogeneous group of tumors, some of which lack optimal therapeutic options. The emergence of new targeted agents directed against specific genetic alterations may change their clinical outcome. We evaluated the prevalence of genetic alterations among advanced endocrine tumors and outcomes of patients treated with targeted agents.

Methods

Retrospective study of patients with advanced endocrine tumors evaluated with a DNA-based next generation sequencing (NGS) platform for a molecular and personalized therapeutic approach during 2020.

Results

The analysis of 27 endocrine tumors identified 76 pathogenic alterations and 175 variants of uncertain significance. Most mutations occurred in genes involved in tyrosine kinase pathways (50%), chromatin remodeling (17%), DNA damage repair (12%) and transcription regulation (12%). In 5 patients (pts) with neuroendocrine carcinomas, mutations in PIK3CA (N=2) and TP53 (N=2) were found. Among 7 pts with papillary thyroid cancer, 5 had a BRAFV600E mutation (3 with concomitant TERT promoter mutations) and 2 other tumors had alterations in NRAS (N=1) (with concomitant TERT promoter mutation) and RET genes (N=1). Three out of 4 follicular thyroid cancers harbored a potentially targetable mutation, such as PIK3CA, KRAS and PTEN. A RET mutation was identified in 5 out of 6 medullary thyroid cancers (M918T in 4/5 and C630R in 1/5) and a co-mutation in NTRK1 was also found in 1 patient. All 3 patients with anaplastic thyroid cancer (ATC) harbored a TERT promoter mutation. Two of them had a BRAFV600E mutation. Seven out of 27 pts (26%) received targeted therapy. Two pts with BRAF mutated ATC received treatment with dabrafenib + trametinib, reaching an ORR of 100% and median PFS of 10 months. Five pts with RET mutated medullary thyroid cancer were treated with a selective RET inhibitor, achieving an ORR of 80%. All responders continued on treatment at the time of this analysis.

Conclusions

70% of pts harbored an actionable mutation. Targeted therapy resulted in outstanding response rates and may have a significant survival benefit in aggressive tumors, such as ATC. Genetic alterations in targetable genes should be routinely evaluated in advanced endocrine tumors.

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

J. Molina-Cerrillo: Financial Interests, Personal, Invited Speaker: IPSEN; Financial Interests, Personal, Invited Speaker: Roche; Financial Interests, Personal, Invited Speaker: Pfizer; Financial Interests, Personal, Invited Speaker: BMS; Financial Interests, Personal, Invited Speaker: Sanofi; Financial Interests, Personal, Invited Speaker: Janssen; Financial Interests, Personal, Invited Speaker: Astellas; Financial Interests, Personal, Invited Speaker: EISAI; Financial Interests, Personal, Research Grant: Pfizer; Financial Interests, Personal, Research Grant: IPSEN. P. Valderrábano: Financial Interests, Personal, Writing Engagements: Sanofi-Genzyme; Financial Interests, Personal, Invited Speaker: Esteve. A. Carrato Mena: Non-Financial Interests, Institutional, Advisory Role: Roche; Non-Financial Interests, Institutional, Advisory Role: Bayer; Non-Financial Interests, Institutional, Advisory Role: Merk; Non-Financial Interests, Institutional, Advisory Role: MSD; Non-Financial Interests, Institutional, Advisory Role: BMS; Non-Financial Interests, Institutional, Advisory Role: Servier; Non-Financial Interests, Institutional, Advisory Role: Celgene; Non-Financial Interests, Institutional, Advisory Role: Shire; Non-Financial Interests, Institutional, Advisory Role: Mylan. P. Garrido Lopez: Financial Interests, Personal, Advisory Board: Abbvie; Financial Interests, Personal, Advisory Board: Amgen; Financial Interests, Personal, Invited Speaker: AstraZeneca; Financial Interests, Personal, Advisory Board: Bayer; Financial Interests, Personal, Invited Speaker: BMS; Financial Interests, Personal, Invited Speaker: Boehringer Ingelheim; Financial Interests, Personal, Advisory Board: Gebro; Financial Interests, Personal, Advisory Board: GlaxoSmithKline; Financial Interests, Personal, Invited Speaker: Janssen; Financial Interests, Personal, Advisory Board: Lilly; Financial Interests, Personal, Invited Speaker: MSD; Financial Interests, Personal, Advisory Board: Nordic; Financial Interests, Personal, Advisory Board: Novartis; Financial Interests, Personal, Advisory Board: Pfizer; Financial Interests, Personal, Invited Speaker: Roche; Financial Interests, Personal, Invited Speaker: Takeda; Financial Interests, Personal, Principal Investigator: Apollomics; Financial Interests, Personal, Principal Investigator: Array Biopharma; Financial Interests, Personal, Principal Investigator: BluePrint; Financial Interests, Personal, Principal Investigator: IO Biotech; Non-Financial Interests, Personal, Leadership Role: AECC; Non-Financial Interests, Personal, Leadership Role: ESMO; Non-Financial Interests, Personal, Leadership Role: FACME; Non-Financial Interests, Personal, Leadership Role: IASLC; Non-Financial Interests, Personal, Leadership Role: SEOM. T. Alonso-Gordoa: Financial Interests, Personal, Invited Speaker: IPSEN; Financial Interests, Personal, Invited Speaker: Pfizer; Financial Interests, Personal, Advisory Role: Roche; Financial Interests, Personal, Advisory Role: Sanofi; Financial Interests, Personal, Advisory Role: Bayer; Financial Interests, Personal, Advisory Role: Astellas; Financial Interests, Personal, Advisory Role: Janssen-Cilag; Financial Interests, Personal, Advisory Role: MSD; Financial Interests, Personal, Invited Speaker: BMS; Financial Interests, Personal, Invited Speaker: EISAI; Financial Interests, Personal, Invited Speaker: Merck. All other authors have declared no conflicts of interest.

Background

Death at home is an increasingly more common measure for improving the quality of palliative care services. The study analyzes the factors that may influence the place of death of oncology patients in palliative care (hospital/home), focusing on clinical characteristics.

Methods

Study design: longitudinal, prospective single-cohort, analytical. 427 people were studied in 2018 in the Bahia de Cadiz-La Janda District (Andalusia, Spain). Data were collected during initial evaluation, follow-up, Last Days and Hours of Life (LDHL) and after death. Among the data gathered: place of death, Palliative Performance Scale (PPS), Palliative Care Complexity Index (IDC-Pal), Charlson Comorbidity Index (CCI), hospital admissions, advanced treatments and symptoms during follow-up and LDHL.

Results

52.2% of patients died at home and 47.8% died in the hospital. Among the individuals who died at home, the results reveal: - A less complex situation (IDC-Pal) throughout the entire process (60.9%, 84.1% and 88.4%; p<0.02 in all these cases). - Less prognosis of survival at initial evaluation (PPS) (57.2 vs 52.4; p=0.003). - Absence of hospital admissions (26.8% vs 78.6%; p<0.001) or a lower number of admissions (0.32 vs 1.12; p<0.001). - Absence of toxicity to opioids (p=0.05), as well as lower pain intensity during LDHL (3.45 vs 4.31; p=0.01), dyspnea (2.94 vs 3.89; p=0.009), nausea/vomiting (1.31 vs 1.72; p=0.031) and anxiety (4.31 vs 5.10; p=0.030). No significant differences were found in place of death (home/hospital) according to age, sex, advanced complementary treatment and other symptoms/complications studied.

Conclusions

The main clinical characteristics that have been found to influence the place of death are: case complexity, survival prognosis, hospital admissions and number of admissions during the process, toxicity to opioids, and intensity of certain symptoms in LDHL, such as: pain, dyspnea, nausea/vomiting and anxiety. It is essential to conduct a thorough evaluation of this type of patient and process, but it may prove especially important to prioritize the aspects herein identified.

Legal entity responsible for the study

The authors.

Funding

Biomedical Research and Innovation Institute of Cádiz (INiBICA). Project subsidized within the framework of the Integrated Territorial Initiative (ITI) 2014-2020 for Cádiz by the Andalusian Consejería de Salud and by the European Regional Development Fund (FEDER).

Disclosure

All authors have declared no conflicts of interest.

Background

The literature reviewed show discord between the preferences of place of death expressed by people in Palliative Care and the actual place of death. It is necessary to analyze this situation, highlighting the importance of the wishes and preferences of patients and their caregivers.

Methods

Study design: longitudinal, prospective single-cohort, analytical. 427 people were studied in 2018 in the Bahia de Cadiz-La Janda District (Andalusia, Spain). Among other variables, this investigation studied the preferences of place of death expressed by the patient and their caregiver (home, hospital or undefined) during the initial evaluation (IE) and Last Days and Hours of Life (LDHL), as well as the actual place of death (home or hospital).

Results

52.2% of patients died at home and 47.8% died in the hospital. The place preferred by patients and caregivers is home, which is the case both at the time of the IE (Patient: 36.5% home, 11.8% hospital and 51.8% undefined; Caregiver: 40.3%, 21.3% and 38.4%) and LDHL (Patient: 41.9%, 15.9% and 42.2%; Caregiver: 51.2%, 32.0% and 16.8%). (See Table) A significant association is found (p<0.05) between the preference stated during IE and during LDHL and the actual place of death, both for the patient (59.5% and 81.3% congruence, respectively) and the caregiver (68.9% and 87.7%). This relationship is more intense in the case of the wishes expressed during LDHL, both by the patient (59.9% vs 81.3%) and the caregiver (68.9% vs 87.7%), and more intense in the case of the caregiver’s preference (87.7%) than that of the patient (81.3%). Table: CN10

Congruence between actual and preferred place of death by patient and caregiver at time of initial evaluation (IE) and last days and hours of life (LDHL)

Conclusions

There is a significant relationship/congruence between the actual and preferred place of death by patients and caregivers. This relationship is stronger in the case of preferences during LDHL and for caregivers, which must be taken into consideration when planning care prior to death.

Legal entity responsible for the study

The authors.

Funding

Biomedical Research Management Foundation of Cádiz (INiBICA). Project subsidized within the framework of the Integrated Territorial Initiative (ITI) 2014-2020 for Cádiz by the Andalusian Consejería de Salud and by the European Regional Development Fund (FEDER)

Disclosure

All authors have declared no conflicts of interest.

Background

Cemiplimab is a programmed cell death receptor-1 inhibitor with antitumour activity for cutaneous squamous cell carcinoma (CSCC) and acceptable safety proved in its pivotal trial. We provide the first data on cemiplimab safety in daily practice from the named patient programme (NPP) for advanced CSCC in Spain.

Methods

This cemiplimab NPP was performed from March 2019 to March 2020. It included patients aged ≥18 years with advanced CSCC and ineligible for surgery, radiation therapy or clinical trials. The cemiplimab safety was assessed according to treatment-emergent adverse events (TEAEs) reported until March 2021.

Results

140 patients were included (median age [interquartile range, IQR] 77.0 [65.0-84.0] years; age ≥80 38%; men 71.7%; ≥1 comorbidity 83%; ECOG 0-1 86.3%; locally advanced CSCC 60.7%; cemiplimab as first-line therapy 67.7%). Cemiplimab was received for a median (IQR) of 8.0 (3.0-14.0) cycles. Fifty-eight (41.4%) patients showed ≥1 of the 163 TEAEs reported, which most frequently included diarrhoea n=7, asthenia n=6, constipation n=4 and abdominal pain n=4. Fourteen (8.6%) were immune-mediated, mainly bronchitis n=2, pneumonitis n=2 and hepatitis n=2. Seventy-eight (47.9%) TEAEs were grade ≥3, most frequently pneumonia n=3, COVID-19 n=3, general physical health deterioration n=2, pyrexia n=2, renal transplant failure n=2, sepsis n=2, acute kidney injury n=2 and respiratory failure n=2. Twenty-one (12.9%) were treatment-related (TREAEs): 11 (6.7%) were grade 1-2 (diarrhoea n=3 and asthenia, hepatotoxicity, malnutrition, odynophagia, polymyalgia rheumatica, pneumonitis, pruritus, and skin toxicity), 9 (5.5%) grade 3 (acute kidney injury, adrenal insufficiency, abdominal pain, blood creatinine increased, dysphagia, haematuria, immune-mediated enterocolitis, panniculitis, surgical wound infection) and 1 (0.6%) unknown grade. Cemiplimab was withdrawn due to TREAEs in only 5 (3.6%) patients. The TEAE outcome was fatal in 29 (17.8%); none related to cemiplimab.

Conclusions

This NPP supports the real-life safety of cemiplimab for CSCC, showing an acceptable safety profile consistent with previous reports.

Editorial acknowledgement

Editorial assistance was provided by Esther Álvarez-García at Dynamic Science S.L., funded by Sanofi.

Legal entity responsible for the study

Sanofi.

Funding

Sanofi.

Disclosure

E. Muñoz Couselo: Financial Interests, Personal, Advisory Board: Amgen; Financial Interests, Personal, Advisory Board: Bristol-Myers Squibb; Financial Interests, Personal, Advisory Board: Merck Sharp & Dohme; Financial Interests, Personal, Advisory Board: Novartis; Financial Interests, Personal, Advisory Board: Pierre Fabre; Financial Interests, Personal, Advisory Board: Roche; Financial Interests, Personal, Advisory Board: Sanofi; Financial Interests, Personal, Other, Honoraria: Amgen; Financial Interests, Personal, Other, Honoraria: Bristol-Myers Squibb; Financial Interests, Personal, Other, Honoraria: Merck Sharp & Dohme; Financial Interests, Personal, Other, Honoraria: Novartis; Financial Interests, Personal, Other, Honoraria: Pierre Fabre; Financial Interests, Personal, Other, Honoraria: Roche; Financial Interests, Personal, Principal Investigator: Amgen; Financial Interests, Personal, Principal Investigator: Bristol-Myers Squibb; Financial Interests, Personal, Principal Investigator: GlaxoSmithKline; Financial Interests, Personal, Principal Investigator: Merck Sharp & Dohme; Financial Interests, Personal, Principal Investigator: Novartis; Financial Interests, Personal, Principal Investigator: Pierre Fabre; Financial Interests, Personal, Principal Investigator: Roche; Financial Interests, Personal, Principal Investigator: Sanofi. A. Soria: Financial Interests, Personal, Invited Speaker: Novartis; Financial Interests, Personal, Invited Speaker: Sanofi Aventis; Financial Interests, Personal, Invited Speaker: Roche Pharma; Financial Interests, Personal, Invited Speaker: Merck Serono; Financial Interests, Personal, Invited Speaker: Merck Sharp & Dohme; Financial Interests, Personal, Invited Speaker: Bristol-Myers Squibb; Financial Interests, Personal, Invited Speaker: Pierre Fabre; Financial Interests, Personal, Advisory Board: Novartis; Financial Interests, Personal, Advisory Board: Sanofi Aventis; Financial Interests, Personal, Advisory Board: Roche Pharma; Financial Interests, Personal, Advisory Board: Merck Serono; Financial Interests, Personal, Advisory Board: Merck Sharp & Dohme; Financial Interests, Personal, Advisory Board: Bristol-Myers Squibb; Financial Interests, Personal, Advisory Board: Pierre Fabre; Financial Interests, Personal, Principal Investigator: Novartis; Financial Interests, Personal, Principal Investigator: Sanofi Aventis; Financial Interests, Personal, Principal Investigator: Roche Pharma; Financial Interests, Personal, Principal Investigator: Merck Serono; Financial Interests, Personal, Principal Investigator: Merck Sharp & Dohme; Financial Interests, Personal, Principal Investigator: Bristol-Myers Squibb; Financial Interests, Personal, Principal Investigator: Pierre Fabre. O. Sanmartin: Financial Interests, Personal, Invited Speaker: Sanofi Genzyme; Financial Interests, Personal, Advisory Board: Sanofi Genzyme; Financial Interests, Personal, Officer: Sanofi Genzyme; Financial Interests, Personal, Principal Investigator: Sanofi Genzyme; Financial Interests, Personal, Invited Speaker: Roche Pharma; Financial Interests, Personal, Advisory Board: Roche Pharma; Financial Interests, Personal, Officer: Roche Pharma; Financial Interests, Personal, Principal Investigator: Roche Pharma. J. Cañueto: Financial Interests, Personal, Invited Speaker: Hoffman-La Roche; Financial Interests, Personal, Invited Speaker: Sanofi-Genzyme; Financial Interests, Personal, Invited Speaker: AbbVie; Financial Interests, Personal, Invited Speaker: LeoPharma; Financial Interests, Personal, Other, Consultancy: Sanofi-Genzyme; Financial Interests, Personal, Other, Consultancy: InflaRx; Financial Interests, Personal, Other, Consultancy: Almirall. S. Beá Ardébol: Financial Interests, Personal, Invited Speaker: Meda; Financial Interests, Personal, Advisory Board: Sanofi; Financial Interests, Personal, Advisory Board: SunPharma; Financial Interests, Personal, Other, Trial subinvestigator: Sanofi Aventis; Financial Interests, Personal, Other, Trial subinvestigator: SunPharma; Financial Interests, Personal, Other, Trial subinvestigator: PellePharma. R. Fernández-de-Misa Cabrera: Financial Interests, Personal, Advisory Board: Sanofi. A.J. Cunquero-Tomás: Financial Interests, Personal, Invited Speaker: BMS; Financial Interests, Personal, Invited Speaker: Pierre-Fabre; Financial Interests, Personal, Writing Engagements: Sanofi; Financial Interests, Personal, Other, 2021 EADO/WMC Congress inscription fee: Sanofi. L. Fernández Franco: Non-Financial Interests, Personal, Invited Speaker: Merck; Non-Financial Interests, Personal, Invited Speaker: Sanofi; Non-Financial Interests, Personal, Invited Speaker: Servier. I. Romero: Financial Interests, Personal, Invited Speaker: Pharmamar; Financial Interests, Personal, Invited Speaker: Roche; Financial Interests, Personal, Invited Speaker: GSK; Financial Interests, Personal, Invited Speaker: Clovis; Financial Interests, Personal, Invited Speaker: AstraZeneca; Financial Interests, Personal, Advisory Board: Pharmamar; Financial Interests, Personal, Advisory Board: Roche; Financial Interests, Personal, Advisory Board: GSK; Financial Interests, Personal, Advisory Board: Clovis; Financial Interests, Personal, Advisory Board: AstraZeneca. J. Medina Martínez: Non-Financial Interests, Personal, Invited Speaker: Roche; Non-Financial Interests, Personal, Speaker’s Bureau: Roche; Non-Financial Interests, Personal, Advisory Board: Roche; Non-Financial Interests, Personal, Invited Speaker: Novartis; Non-Financial Interests, Personal, Speaker’s Bureau: Novartis; Non-Financial Interests, Personal, Advisory Board: Novartis; Non-Financial Interests, Personal, Invited Speaker: BMS; Non-Financial Interests, Personal, Speaker’s Bureau: BMS; Non-Financial Interests, Personal, Advisory Board: BMS; Non-Financial Interests, Personal, Invited Speaker: MSD; Non-Financial Interests, Personal, Speaker’s Bureau: MSD; Non-Financial Interests, Personal, Invited Speaker: Pierre Fabre; Non-Financial Interests, Personal, Speaker’s Bureau: Pierre Fabre; Non-Financial Interests, Personal, Advisory Board: Pierre Fabre; Non-Financial Interests, Personal, Invited Speaker: Merk; Non-Financial Interests, Personal, Speaker’s Bureau: Merk; Non-Financial Interests, Personal, Invited Speaker: Sanofi; Non-Financial Interests, Personal, Speaker’s Bureau: Sanofi; Non-Financial Interests, Personal, Advisory Board: Sanofi; Non-Financial Interests, Personal, Invited Speaker: Servier. All other authors have declared no conflicts of interest.

Background

Over the last decades the incidence of EOCRC (< 50 years old) has dramatically increased. Thus, scientific interest in this field has risen. The aim of this study was to show differences in clinical characteristics, co-morbidities, prognostic factors, and survival among EOCRC compared to the rest of colorectal cancer (CRC) patients in a Spanish hospital.

Methods

We conducted a retrospective analysis of 554 patients with metastatic colorectal cancer (mCRC) in a tumor registry from 2015 to 2021, analyzing the clinical and molecular characteristics, as well as progression-free survival (PFS) and overall survival (OS) of EOCRC patients versus the rest of CRC patients. We applied the exact test of Fisher in order to identify differences between categoric variables, and Mann-Whitney test to detect differences between quantitative variables. PFS and OS were compared using a long-rank test, and the estimate of hazard ratio (HR) between studied groups was calculated by means of Cox proportional hazards model.

Results

We found 554 mCRC patients of which 68 (12.25 %) were EOCRC patients. Several characteristics were significantly more frequent in patients with EOCRC: BMI < 18.5 (n = 16, OR 1.9, P = 0.046), primary tumor site at transverse colon (n = 9, OR 2.61, p = 0.03) and ECOG 0 (n = 32, OR 2.21, p = 0.003). Moreover, mean values of LDH at diagnosis were significantly higher in EOCRC patients (359 U/L vs 280 U/L, p = 0.015). EOCRC patients received a significantly higher number of lines of chemotherapy (2.94 vs 2.38, p = 0.027) and underwent more surgeries (2.42 vs 1.24, p < 0,001) than patients with > 50 years. Significant differences in tumor mutational status (BRAF, KRAS, NRAS, MSI, PI3K and HER2) between groups were not found. PFS was longer in EOCRC patients (median, 16.2 vs 11.3 months; HR for progress 0.77; 95 % confidence interval (CI) 0.56 to 0.99; p = 0.043), as well as overall survival (median 121.5 vs 58.1; HR for death 0.58; 95 % CI, 0.39 to 0.88; p = 0.011).

Conclusions

Our study showed that EOCRC patients had more frequently BMI < 18.5, primary tumor located at transverse colon and ECOG 0, along with a statistically significant higher PFS in first line and higher OS than the rest of CRC patients.

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

Background

Approximately 20% of patients with early-stage breast cancer (ESBC) have amplification of the HER2 gene and over-expression of the HER2 protein, alterations which are associated with (1) more aggressive behaviour (2) a higher frequency of metastasis (3) a substantial therapeutic benefit from anti HER2 targeted adjuvant and neoadjuvant therapies. We hypothesised that the proportion of all MBC which is HER2+ should have decreased since the introduction of widespread anti HER2 adjuvant treatment for ESBC.

Methods

We conducted a retrospective audit of all patients with a pathological diagnosis of MBC in two time cohorts 2000-2002 (before routine adjuvant HER-2 therapy was introduced) and 2018-2020. HER2+ was defined by FISH amplification and/or 3+ immune-histochemistry.

Results

We identified 231 and 183 patients in the two cohorts 2000-2002 and 2018-2020. The table shows HER2 status. The proportion of all MBC which was HER2+ has reduced from 33.76%-16.69% during that time, a difference which is highly statistically significant (Fischer exact test p<0.0000). The significance remains when adjusting for the HER2 unknowns. Table: 310P

Conclusions

The proportion of MBC which is HER2+ has decreased substantially since the introduction of anti HER2 therapy for ESBC. These data tend to support the hypothesis that adjuvant anti HER2 therapy of ESBC prevents rather than merely delays MBC. We have previously reported that the percentage of HER2 altered MBC which is diagnosed “de novo” has increased during this time, and that de novo MBC has a better prognosis. Much of the improvement in BC survival may be due to (1) a decreased incidence of HER2+ MBC, (previously the worst prognosis), and (2) a shift within HER2+ MBC to better prognosis de novo disease. Anti HER-2 therapy in ESBC has produced a substantial alteration in the molecular profile and prognosis of metastatic breast cancer.

Legal entity responsible for the study

St Vincent's University Hospital, Dublin, Ireland.

Funding

Cancer Clinical Research Trust (CCRT) - The Caroline Foundation.

Disclosure

C.M. Quinn, D. Skrobo M. Higgins: Financial Interests, Personal, Invited Speaker, conference attendance support: Roche. G. Gullo: Financial Interests, Personal, Full or part-time Employment, full time employee and shareholder of Regeneron Pharmaceuticals Inc: Regeneron Pharmaceuticals Inc. J.M. Walshe: Financial Interests, Personal, Other, Boards and travel conference attendance: Roche, AstraZeneca, Pfizer. J.P. Crown: Other, Personal, Invited Speaker, conference attendance support: Roche. All other authors have declared no conflicts of interest.

Background

PD1 is an inhibitory receptor exposed on the surface of T cells and other immune cells. In non-small cell lung cancer and melanoma P, as well as after stem cell transplantation, higher levels of CD4+ T cells (TCD4) expressing PD1 (PD1+) correlated with poor survival outcomes. Nonetheless, in vitro PD1 blockade enhanced antitumor immunity. Finally, subpopulations of TCD4 with higher or lower PD1+ levels were identified and associated with differential functional effects and prognosis in follicular lymphoma. We thus aimed at elucidating the prognostic role of peripheral TCD4PD1+ and TCD4PD1H in cancer P treated with ICI-based regimens.

Methods

From 69 consecutive P with solid tumors treated with ICI, we prospectively collected baseline blood samples and evaluated with flow cytometry the proportion (%) of TCD4PD1+ and TCD4PD1H. We performed univariate Cox regressions to detect an association with progression-free survival (PFS) and overall survival (OS). A maximally selected rank statistic method was applied to define a cut-off to identify patients with low and high levels of the specific T cell subpopulation of interest. An association with PFS, OS, and overall response rates (ORR) was then explored according to subgroups. Significance was set at p<0.05.

Results

Median proportion of TCD4PD1+ was 13.9% (interquartile range [IQR]: 9.3–17.4%) and of TCD4PD1H was 0.7% (IQR: 0.3-1.3%). A significant association of TCD4PD1H% levels with OS was observed (hazard ratio [HR]:1.15, p=0.048). A cut-off of 1.1% defined 2 prognostically significant subgroups of P (above and below the threshold, 19 vs. 50 P, respectively). TCD4PD1H_Below vs. TCD4PD1H_Above presented with better PFS (adjusted HR [aHR]: 0.52, 95% confidence intervals [CI]: 0.28 – 0.98, p=0.041), OS (aHR: 0.39, 95%CI: 0.21 - 0.72, p=0.003) and ORR (20.0% vs 0.0%, χ² p=0.035).

Conclusions

Low levels of TCD4PD1H in solid tumors before starting ICI seem to correlate with better ORR, PFS and OS, independently from cancer type, metastatic patterns, P and treatment characteristics. The recruitment of a validation cohort is ongoing, as well as a sub-analysis focused on anti-PD1/antiPDL1.

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

J. Garcia-Corbacho: Financial Interests, Personal, Advisory Role: Johnson and Johnson Pharmaceutical; Financial Interests, Personal, Project Lead, Local PI: Amgen, Astellas, AstraZeneca, Bayer, Boehringer, Cytomx, Daichii Sankyo, Incyte, Lilly, Menarini, Merck. L. Mezquita: Financial Interests, Personal, Advisory Role: Roche, Roche Diagnostics, Takeda; Financial Interests, Personal, Invited Speaker: Roche, Bristol Myers Squibb, Tecnofarma; Financial Interests, Personal, Other, travel/accomodation expenses: Roche, Bristol Myers Squibb. A. Prat: Financial Interests, Personal, Advisory Role: Novartis, Roche, AstraZeneca, BMS, Daiichi Sankyo, Guardant Health, Oncolytics Biotech, Foundation Medicine and Nanostring Technologies. All other authors have declared no conflicts of interest.

Background

Radiotherapy association with immunotherapy has a strong rationale. This study evaluates this combination before surgery in locally advanced rectal cancer (RC).

Methods

R-IMMUNE (NCT03127007), a multicentric phase Ib/II prospective trial includes patients with stage II/III RC treated with a preoperative combination of radio-chemotherapy (45-50 Gy/25 fractions, 5FU 225 mg/m2/d, 5d/w from week 1-5) + atezolizumab 1200 mg/infusion (ATZ). The phase Ib had a 3+3 design with a safety period up to surgery and evaluated a single infusion of ATZ at week 3. The phase II, in progress, evaluates 4 infusions of ATZ at weeks 3, 6, 9 and 12. Surgery is planned at week 15. Primary objectives are safety and efficacy based on pathological complete response rate (pCR). Based on a 2-stage Simon design, 36 patients are needed in the phase II to detect a pCR rate increase from 15% to 35% (α = 0.1 and β = 0.1). At least 4 pCRs must be observed among 19 patients treated in the 1^st stage to move the 2^nd stage.

Results

This analysis concerns 26 patients treated with the study treatment (median age 66 y-old, 48% male, 88% stage III). Safety was evaluated in 6 patients from phase Ib and 20 from phase II. Overall, 151 AEs were reported and 20 (13%) were grade 3-4 on 9/26 patients, including 2/20 (10%) anastomotic leakage/infections, 4/20 (20%) urinary infections, 1/20 (5%) renal function impairment and 1/20 (5%) immune thrombocytopenia. Three grade 2 immune endocrine disorders were observed. Efficacy was evaluable on 25/26 patients after 1 exclusion for inclusion criteria deviation. Four among 19 patients included in the 1^st stage of phase II had a pCR. Overall, 6/25 (24%) pCRs were observed.

Conclusions

R-IMMUNE interim analysis reveals an acceptable safety profile. Observed pCR rate until now supports the pursuit of the trial.

Clinical trial identification

NCT03127007.

Legal entity responsible for the study

Grand Hôpital de Charleroi.

Funding

Roche.

Disclosure

J. Carrasco: Non-Financial Interests, Institutional, Research Grant: Roche. All other authors have declared no conflicts of interest.