Evaluating Debio 1347 in Patients with FGFR Fusion-Positive Advanced Solid Tumors from the FUZE Multicenter, Open-Label, Phase II Basket Trial.

PURPOSE: This multicenter phase II basket trial investigated the efficacy, safety and pharmacokinetics of Debio 1347, an investigational, oral, highly selective, ATP-competitive, small molecule inhibitor of FGFR1-3, in patients with solid tumors harboring a functional FGFR1-3 fusion. PATIENTS AND METHODS: Eligible adults had a previously treated locally advanced (unresectable) or metastatic biliary tract (cohort 1), urothelial (cohort 2) or other histologic cancer type (cohort 3). Debio 1347 was administered at 80 mg once daily, continuously, in 28-day cycles. The primary endpoint was the objective response rate (ORR). Secondary endpoints included duration of response, progression-free survival, overall survival, pharmacokinetics, and incidence of adverse events. RESULTS: Between March 22, 2019 and January 8, 2020, 63 patients were enrolled and treated, 30 in cohort 1, four in cohort 2, and 29 in cohort 3. An unplanned preliminary statistical review showed that the efficacy of Debio 1347 was lower than predicted and the trial was terminated. Three of 58 evaluable patients had partial responses, representing an ORR of 5%, with a further 26 (45%) having stable disease (≥6 weeks duration). Grade ≥3 treatment-related adverse events occurred in 22 (35%) of 63 patients, with the most common being hyperphosphatemia (13%) and stomatitis (5%). Two patients (3%) discontinued treatment due to adverse events. CONCLUSIONS: Debio 1347 had manageable toxicity; however, the efficacy in patients with tumors harboring FGFR fusions did not support further clinical evaluation in this setting. Our transcriptomic-based analysis characterized in detail the incidence and nature of FGFR fusions across solid tumors.

Single-cell multiomics profiling reveals heterogeneous transcriptional programs and microenvironment in DSRCTs.

Desmoplastic small round cell tumor (DSRCT) is a rare, aggressive sarcoma driven by the EWSR1::WT1 chimeric transcription factor. Despite this unique oncogenic driver, DSRCT displays a polyphenotypic differentiation of unknown causality. Using single-cell multi-omics on 12 samples from five patients, we find that DSRCT tumor cells cluster into consistent subpopulations with partially overlapping lineage- and metabolism-related transcriptional programs. In vitro modeling shows that high EWSR1::WT1 DNA-binding activity associates with most lineage-related states, in contrast to glycolytic and profibrotic states. Single-cell chromatin accessibility analysis suggests that EWSR1::WT1 binding site variability may drive distinct lineage-related transcriptional programs, supporting some level of cell-intrinsic plasticity. Spatial transcriptomics reveals that glycolytic and profibrotic states specifically localize within hypoxic niches at the periphery of tumor cell islets, suggesting an additional role of tumor cell-extrinsic microenvironmental cues. We finally identify a single-cell transcriptomics-derived epithelial signature associated with improved patient survival, highlighting the clinical relevance of our findings.

Reactions and adverse events induced by T-cell engagers as anti-cancer immunotherapies, a comprehensive review.

T-cell engagers (TCE) are cancer immunotherapies that have recently demonstrated meaningful benefit for patients with hematological malignancies and solid tumors. The anticipated widespread use of T cell engagers poses implementation challenges and highlights the need for guidance to anticipate, mitigate, and manage adverse events. By mobilizing T-cells directly at the contact of tumor cells, TCE mount an obligatory and immediate anti-tumor immune response that could result in diverse reactions and adverse events. Cytokine release syndrome (CRS) is the most common reaction and is largely confined to the first drug administrations during step-up dosage. Cytokine release syndrome should be distinguished from infusion related reaction by clinical symptoms, timing to occurrence, pathophysiological aspects, and clinical management. Other common reactions and adverse events with TCE are immune effector Cell-Associated Neurotoxicity Syndrome (ICANS), infections, tumor flare reaction and cytopenias. The toxicity profiles of TCE and CAR-T cells have commonalities and distinctions that we sum-up in this review. As compared with CAR-T cells, TCE are responsible for less frequently severe CRS or ICANS. This review recapitulates terminology, pathophysiology, severity grading system and management of reactions and adverse events related to TCE.

Results of an Open-label, Phase Ia/b Study of Pembrolizumab plus Olaratumab in Patients with Unresectable, Locally Advanced, or Metastatic Soft-Tissue Sarcoma.

PURPOSE: The study evaluated safety and efficacy of olaratumab + pembrolizumab in patients with unresectable locally advanced/metastatic soft-tissue sarcoma (STS) with disease progression on standard treatment. PATIENTS AND METHODS: This was open-label, multicenter, nonrandomized, phase Ia/Ib dose-escalation study followed by cohort expansion (olaratumab + pembrolizumab intravenous infusion). Primary objectives were safety and tolerability. RESULTS: The majority of patients enrolled (n = 41) were female [phase Ia: 9 of 13, phase Ib/dose-expansion cohort (DEC), 17 of 28], aged < 65 years. In phases Ia and Ib, 13 and 26 patients received prior systemic therapy, respectively. Patients received olaratumab 15 mg/kg (phase Ia; cohort 1) or 20 mg/kg (phase Ia; cohort 2 and phase Ib) and pembrolizumab 200 mg (phase Ia/Ib). The median (Q1-Q3) duration of therapy (olaratumab) was 6.0 (3.0-11.9; cohort 1), 14.4 (12.4-20.9; cohort 2), and 14.0 (6.0-21.8) weeks (DEC). No dose-limiting toxicities and few grade ≥ 3 treatment-emergent adverse events [TEAE; 15 mg/kg: 2 (increased lipase); 20 mg/kg: 1 (increased lipase), 1 (colitis), 2 (diarrhea), 3 (anemia)] were reported. Two TEAEs (increased lipase) were related to study discontinuations. Twenty-one patients reported mild (grade ≤ 2) TEAEs [phase Ia, disease control rate (DCR):14.3% (1/7, cohort 1); 66.7% (4/6, cohort 2); no responses were reported; phase Ib, DCR: 53.6% (15/28); objective response rate: 21.4% (6/28; RECIST and irRECIST criteria)]. No response was observed in patients with programmed death ligand-1-positive tumors. CONCLUSIONS: Antitumor activity was observed in some patients in DEC, and combination was well tolerated with manageable safety profile. Further studies are warranted to evaluate the efficacy and mechanistic impact of platelet-derived growth factor receptor inhibitors with immune checkpoint modulator coadministration.

Resistance to Selective FGFR Inhibitors in FGFR-Driven Urothelial Cancer.

Several fibroblast growth factor receptor (FGFR) inhibitors are approved or in clinical development for the treatment of FGFR-driven urothelial cancer, and molecular mechanisms of resistance leading to patient relapses have not been fully explored. We identified 21 patients with FGFR-driven urothelial cancer treated with selective FGFR inhibitors and analyzed postprogression tissue and/or circulating tumor DNA (ctDNA). We detected single mutations in the FGFR tyrosine kinase domain in seven (33%) patients (FGFR3 N540K, V553L/M, V555L/M, E587Q; FGFR2 L551F) and multiple mutations in one (5%) case (FGFR3 N540K, V555L, and L608V). Using Ba/F3 cells, we defined their spectrum of resistance/sensitivity to multiple selective FGFR inhibitors. Eleven (52%) patients harbored alterations in the PI3K-mTOR pathway (n = 4 TSC1/2, n = 4 PIK3CA, n = 1 TSC1 and PIK3CA, n = 1 NF2, n = 1 PTEN). In patient-derived models, erdafitinib was synergistic with pictilisib in the presence of PIK3CA E545K, whereas erdafitinib-gefitinib combination was able to overcome bypass resistance mediated by EGFR activation. SIGNIFICANCE: In the largest study on the topic thus far, we detected a high frequency of FGFR kinase domain mutations responsible for resistance to FGFR inhibitors in urothelial cancer. Off-target resistance mechanisms involved primarily the PI3K-mTOR pathway. Our findings provide preclinical evidence sustaining combinatorial treatment strategies to overcome bypass resistance. See related commentary by Tripathi et al., p. 1964. This article is featured in Selected Articles from This Issue, p. 1949.

Sequence analyses of relapsed or refractory diffuse large B-cell lymphomas unravel three genetic subgroups of patients and the GNA13 mutant as poor prognostic biomarker, results of LNH-EP1 study.

Advances in molecular profiling of newly diagnosed diffuse large B-cell lymphoma (DLBCL) have recently refine genetic subgroups. Genetic subgroups remain undetermined at the time of relapse or refractory (RR) disease. This study aims to decipher genetic subgroups and search for prognostic molecular biomarkers in patients with RR-DLBCL. From 2015 to 2021, targeted next-generation sequencing analyses of germline-matched tumor samples and fresh tissue from RR-DLBCL patients were performed. Unsupervised clustering of somatic mutations was performed and correlations with patient outcome were sought. A number of 120 patients with RR-DLBCL were included in LNH-EP1 study and a molecular tumor landscape was successfully analyzed in 87% of patients (104/120 tumor samples). The median age was 67.5 years (range 27.4-87.4), median number of previous treatments was 2 (range 1-9). The most frequently mutated genes were TP53 (n = 53 mutations; 42% of samples), CREBBP (n = 39; 32%), BCL2 (n = 86; 31%), KMT2D (n = 39; 28%) and PIM1 (n = 54; 22%). Unsupervised clustering separated three genetic subgroups entitled BST (enriched in BCL2, SOCS1, and TNFRSF14 mutations); TKS (enriched in TP53, KMT2D, and STAT6 mutations); and PCM (enriched in PIM1, CD79B, and MYD88 mutations). Median overall survival (OS) was 11.0 (95% confidence interval [CI]: 8.1-12.6) months. OS was not significantly different between the three genetic subgroups. GNA13 mutant was significantly associated with an increased risk of death (hazard ratio: 6.6 [95% CI: 2.1-20.6]; p = .0011) and shorter OS (p = .0340). At the time of relapse or refractory disease, three genetic subgroups of DLBCL patients were delineated, which could help advance precision molecular medicine programs.

Single-agent gemcitabine in patients with advanced, pre-treated angiosarcoma: A multicenter, retrospective study.

Gemcitabine has shown clinical activity against angiosarcoma in small series, alone, or combined with taxanes. We aimed to evaluate its activity as a single-agent in a larger series of patients with advanced angiosarcoma. We retrospectively reviewed the electronic medical records of consecutive adult patients with advanced angiosarcoma treated with single-agent gemcitabine at our institutions from January 2010 to January 2021. Response was evaluated according to RECIST 1.1, and toxicity was graded according to NCI-CTC v5.0. 42 patients were identified. 38 patients (90%) had received prior anthracyclines and weekly paclitaxel, and 9 (21%) had received pazopanib. The best tumor response was partial response (PR) in 16 patients (38%), or stable disease (10 patients, 24%). All 8 patients with cardiac angiosarcoma experienced a PR. Median PFS was 5.4 months (95%CI: 3.1-6.5), and median OS was 9.9 months (95%CI: 6.6-13.4). Single-agent gemcitabine has clinically meaningful activity in advanced, heavily pre-treated angiosarcoma.

Safety, recommended dose, efficacy and immune correlates for nintedanib in combination with pembrolizumab in patients with advanced cancers.

BACKGROUND: We aimed to determine the safety and efficacy of nintedanib, an oral anti-angiogenic tyrosine kinase inhibitor, in combination with pembrolizumab, an anti-PD1 immunotherapy, in patients with advanced solid tumors (PEMBIB trial; NCT02856425). METHODS: In this monocentric phase Ib dose escalation cohort, we evaluated escalating doses of nintedanib (Dose level 1 (DL1) = 150 mg bid [bis in die, as twice a day]; DL2 = 200 mg bid, oral delivery) in combination with pembrolizumab (200 mg Q3W, IV). Patients received a 1-week lead-in dose of nintedanib monotherapy prior starting pembrolizumab. The primary objective was to establish the maximum tolerated dose (MTD) of the combination based on dose limiting toxicity (DLT) occurrence during the first 4 weeks. Secondary objectives were to assess the anti-tumor efficacy and to identify the associated immune and angiogenic parameters in order to establish the recommended nintedanib dose for expansion cohorts. Flow cytometry (FC), Immuno-Histo-Chemistry (IHC) and electrochemiluminescence multi-arrays were prospectively performed on baseline & on-treatment tumor and blood samples to identify immune correlates of efficacy. RESULTS: A total of 12/13 patients enrolled were evaluable for DLT (1 patient withdrew consent prior receiving pembrolizumab). Three patients at 200 mg bid experienced a DLT (grade 3 liver enzymes increase). Four patients developed grade 1-2 immune related adverse events (irAE). Eight patients died because of cancer progression. Median follow-up was 23.7 months (95%CI: 5.55-40.5). Three patients developed a partial response (PR) (ORR = 25%) and five patients (42%) had durable clinical benefit (DCB), defined as PR or stable disease (SD) ≥ 6 months. At baseline, patients with DCB had higher plasma levels of Tie2, CXCL10, CCL22 and circulating CD4+ PD1+ OX40+ T cells than patients without DCB. Patients with DCB presented also with more DC-LAMP+ dendritic cells, CD3+ T cells and FOXP3+ Tregs in baseline tumor biopsies. For DCB patients, the nintedanib lead-in monotherapy resulted in higher blood CCL3, Tregs and CCR4+ CXCR3+ CXCR5- memory CD4 T cells. After the first pembrolizumab infusion, patients with DCB showed lower IL-6, IL-8, IL-27 plasma levels. CONCLUSION: Nintedanib 150 mg bid is the recommended dose for combination with pembrolizumab and is currently investigated in multiple expansion cohorts. Early tumoral and circulating immune factors were associated with cancer outcome under nintedanib & pembrolizumab therapy. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02856425 . Registered August 4, 2016 - Prospectively registered.

Genome-driven medicine for patients with recurrent glioma enrolled in early phase trials.

BACKGROUND: Recent studies showed that patients with glioma can safely participate in early phase clinical trials; however, clinical benefits in this population were limited. We aimed to evaluate the benefit of molecular profiling to guide enrolment in early phase trials for patients with recurrent glioma. METHODS: Records of patients enrolled in early phase trials of cytotoxic therapies, small molecule inhibitors or monoclonal antibodies from 2008 to 2018 were reviewed for clinico-pathological characteristics, toxicity, response, progression-free survival and overall survival (OS). The primary objective was to evaluate response rates in molecularly-oriented versus non-molecularly-oriented patients. RESULTS: Eighty-eight patients were enrolled, of whom 45 (51.1%) patients were molecularly-oriented. Targets included IDH1/2 (n = 15), BRAF (n = 11), and FGFR1 (n = 3) mutations, FGFR2-3 fusions (n = 9), and mismatch repair deficiency (n = 7). Among patients with high-grade glioma (n = 74), the rate of stable disease ≥6 months and partial or complete response was 25.7% in molecularly-oriented versus 5.1% in non-molecularly-oriented patients (p = 0.02). Upon multivariable adjustment, baseline steroid use ≥20 mg prednisone equivalent per day was associated with shorter OS (OR 3.15 [95% CI 1.62-6.13], p = 0.0008), while molecular enrichment strategy was associated with longer OS (OR 0.40 [95% CI 0.22-0.73], p = 0.003). Nine (10.2%) patients experienced grade 3-4 toxicity and no dose limiting toxicity (DLT) occurred in both cohorts. CONCLUSION: The use of molecular profiling to guide enrolment in early phase trials is feasible and might provide benefits to selected patients with glioma. Further studies are warranted to confirm these results in larger randomised settings and identify the patients most likely to benefit from this approach.

Futibatinib, an Irreversible FGFR1-4 Inhibitor, in Patients with Advanced Solid Tumors Harboring FGF/FGFR Aberrations: A Phase I Dose-Expansion Study.

Futibatinib, a highly selective, irreversible FGFR1-4 inhibitor, was evaluated in a large multihistology phase I dose-expansion trial that enrolled 197 patients with advanced solid tumors. Futibatinib demonstrated an objective response rate (ORR) of 13.7%, with responses in a broad spectrum of tumors (cholangiocarcinoma and gastric, urothelial, central nervous system, head and neck, and breast cancer) bearing both known and previously uncharacterized FGFR1-3 aberrations. The greatest activity was observed in FGFR2 fusion/rearrangement-positive intrahepatic cholangiocarcinoma (ORR, 25.4%). Some patients with acquired resistance to a prior FGFR inhibitor also experienced responses with futibatinib. Futibatinib demonstrated a manageable safety profile. The most common treatment-emergent adverse events were hyperphosphatemia (81.2%), diarrhea (33.5%), and nausea (30.4%). These results formed the basis for ongoing futibatinib phase II/III trials and demonstrate the potential of genomically selected early-phase trials to help identify molecular subsets likely to benefit from targeted therapy. SIGNIFICANCE: This phase I dose-expansion trial demonstrated clinical activity and tolerability of the irreversible FGFR1-4 inhibitor futibatinib across a broad spectrum of FGFR-aberrant tumors. These results formed the rationale for ongoing phase II/III futibatinib trials in cholangiocarcinoma, breast cancer, gastroesophageal cancer, and a genomically selected disease-agnostic population.This article is highlighted in the In This Issue feature, p. 275.

Improving Immunotherapy Efficacy in Soft-Tissue Sarcomas: A Biomarker Driven and Histotype Tailored Review.

Anti-PD-(L)1 therapies yield a disappointing response rate of 15% across soft-tissue sarcomas, even if some subtypes benefit more than others. The proportions of TAMs and TILs in their tumor microenvironment are variable, and this heterogeneity correlates to histotype. Tumors with a richer CD8+ T cell, M1 macrophage, and CD20+ cells infiltrate have a better prognosis than those infiltrated by M0/M2 macrophages and a high immune checkpoint protein expression. PD-L1 and CD8+ infiltrate seem correlated to response to immune checkpoint inhibitors (ICI), but tertiary lymphoid structures have the best predictive value and have been validated prospectively. Trials for combination therapies are ongoing and focus on the association of ICI with chemotherapy, achieving encouraging results especially with pembrolizumab and doxorubicin at an early stage, or ICI with antiangiogenics. A synergy with oncolytic viruses is seen and intratumoral talimogene laherpavec yields an impressive 35% ORR when associated to pembrolizumab. Adoptive cellular therapies are also of great interest in tumors with a high expression of cancer-testis antigens (CTA), such as synovial sarcomas or myxoid round cell liposarcomas with an ORR ranging from 20 to 50%. It seems crucial to adapt the design of clinical trials to histology. Leiomyosarcomas are characterized by complex genomics but are poorly infiltrated by immune cells and do not benefit from ICI. They should be tested with PIK3CA/AKT inhibition, IDO blockade, or treatments aiming at increasing antigenicity (radiotherapy, PARP inhibitors). DDLPS are more infiltrated and have higher PD-L1 expression, but responses to ICI remain variable across clinical studies. Combinations with MDM2 antagonists or CDK4/6 inhibitors may improve responses for DDLPS. UPS harbor the highest copy number alterations (CNA) and mutation rates, with a rich immune infiltrate containing TLS. They have a promising 15-40% ORR to ICI. Trials for ICB should focus on immune-high UPS. Association of ICI with FGFR inhibitors warrants further exploration in the immune-low group of UPS. Finally translocation-related sarcomas are heterogeneous, and although synovial sarcomas a poorly infiltrated and have a poor response rate to ICI, ASPS largely benefit from ICB monotherapy or its association with antiangiogenics agents. Targeting specific neoantigens through vaccine or adoptive cellular therapies is probably the most promising approach in synovial sarcomas.

Phase I Trial of Debio 1143, an Antagonist of Inhibitor of Apoptosis Proteins, Combined with Cisplatin Chemoradiotherapy in Patients with Locally Advanced Squamous Cell Carcinoma of the Head and Neck.

PURPOSE: Debio 1143 is an oral antagonist of inhibitor of apoptosis proteins, which enhances tumor response with concomitant chemoradiotherapy. Addition of Debio 1143 to cisplatin-based chemoradiotherapy in locally advanced squamous cell carcinomas of the head and neck (LA-SCCHN) was evaluated in a phase I/II study to determine the MTD and recommended phase II dose (RP2D). Here, phase I results are reported. PATIENTS AND METHODS: Treatment-naïve patients with LA-SCCHN (stages III/IVA/IVB) received Debio 1143 (100, 200, 300 mg/day), for 14 days every 3 weeks, with cisplatin (100 mg/m², every 3 weeks), for three cycles, and concomitant conventional fractionation radiotherapy (70 Gy/7 weeks). Dose-limiting toxicity (DLT) was evaluated over 9 weeks using continual reassessment. RESULTS: Fourteen patients were treated/evaluable for DLT. Median age was 64.5 years, and all patients were current/former smokers. Primary tumors were hypopharynx, oropharynx (all human papillomavirus/p16 negative), larynx, and oral cavity. Two of six patients at 200 mg/day had DLT (grade 3 tubular necrosis, grade 3 aspartate aminotransferase/alanine aminotransferase increase, grade 4 febrile neutropenia, and grade 3 lipase increase), which was considered the MTD and RP2D. Common grade 3-4 adverse events were dysphagia (36%) and mucositis (29%). Laboratory abnormalities were frequent and generally mild, including anemia, white blood cell decrease, and increased creatinine. Addition of Debio 1143 did not compromise chemotherapy administration. Overall locoregional control rate at 18 months was 85%. Overall response rate was 85%, including 69% complete responses. Progression-free survival rate at 24 months was 74%. CONCLUSIONS: The RP2D of Debio 1143 is 200 mg/day for 14 days, every 3 weeks, when combined with concomitant high-dose cisplatin chemoradiotherapy in LA-SCCHN. Debio 1143 addition to chemoradiotherapy was safe and manageable. Preliminary efficacy is encouraging and supports further development.

Feasibility and first reports of the MATCH-R repeated biopsy trial at Gustave Roussy.

Unravelling the biological processes driving tumour resistance is necessary to support the development of innovative treatment strategies. We report the design and feasibility of the MATCH-R prospective trial led by Gustave Roussy with the primary objective of characterizing the molecular mechanisms of resistance to cancer treatments. The primary clinical endpoints consist of analyzing the type and frequency of molecular alterations in resistant tumours and compare these to samples prior to treatment. Patients experiencing disease progression after an initial partial response or stable disease for at least 24 weeks underwent a tumour biopsy guided by CT or ultrasound. Molecular profiling of tumours was performed using whole exome sequencing, RNA sequencing and panel sequencing. At data cut-off for feasibility analysis, out of 333 inclusions, tumour biopsies were obtained in 303 cases (91%). From these biopsies, 278 (83%) had sufficient quality for analysis by high-throughput next generation sequencing (NGS). All 278 samples underwent targeted NGS, 215 (70.9%) RNA sequencing and 222 (73.2%) whole exome sequencing. In total, 163 tumours were implanted in NOD scid gamma (NSG) or nude mice and 54 patient-derived xenograft (PDX) models were established, with a success rate of 33%. Adverse events secondary to invasive tumour sampling occurred in 24 patients (7.6%). Study recruitment is still ongoing. Systematic molecular profiling of tumours and the development of patient-derived models of acquired resistance to targeted agents and immunotherapy is feasible and can drive the selection of the next therapeutic strategy.

Chemotherapy beyond immune checkpoint inhibitors in patients with metastatic colorectal cancer.

BACKGROUND: Immune checkpoint inhibitors (ICIs) alone or in combination with chemotherapy (CT) are the current standard of therapy in several cancer types. Patients (pts) with lung cancer display higher response rates to CT when given after ICIs. Although ICIs have failed to demonstrate antitumour activity in microsatellite stable (MSS) metastatic colorectal cancer (mCRC), little is known about CT effect after ICIs. We aimed to assess whether sequential ICIs followed by CT may be an alternative therapeutic approach in a population of pts with mCRC. MATERIAL AND METHODS: We retrospectively assessed CT after ICI (CAICI) failure in pts with mCRC. The ICI regimen consisted of anti-PD(L)1 alone or in combination. The primary end-point was objective response rate. Progression-free survival (PFS) and overall survival (OS) were secondary end-points. RESULTS: Between 2014 and 2018, 29 pts with mCRC received CAICI (MSS tumours, 27 pts [86%]). The median number of previous lines was 4 (range, 2-7). Regimens included TAS-102 (n = 14), FOLFIRI (irinotecan, leucovorin, and fluorouracil; n = 6) or FOLFOX (oxaliplatin, leucovorin, and fluorouracil; n = 4), regorafenib (n = 3) and carboplatin (1 pt with BRCA mutation). Partial response and stable disease were observed in 4 (19%) and 9 (43%) pts, respectively (disease control rate, 62%). The median PFS and OS were 3.8 months (95% confidence interval [CI] = 1.5-5.4) and 8.0 months (95% CI = 4.2-14.0), respectively. CONCLUSION: ICIs administered before CT might enhance cytotoxic effects even in pts with immunorefractory MSS mCRC. The results of this small cohort need to be validated in independent prospective cohorts. The role of ICIs as modifiers of both tumour cells and microenvironment in mCRC deserves further research.

Facts and New Hopes on Selective FGFR Inhibitors in Solid Tumors.

Precision oncology relies on the identification of molecular alterations, responsible for tumor initiation and growth, which are suitable targets of specific inhibitors. The development of FGFR inhibitors represents an edifying example of the rapid evolution in the field of targeted oncology, with 10 different FGFR tyrosine kinase inhibitors actually under clinical investigation. In parallel, the discovery of FGFR activating molecular alterations (mainly FGFR3 mutations and FGFR2 fusions) across many tumor types, especially urothelial carcinomas and intrahepatic cholangiocarcinomas, widens the selection of patients that might benefit from selective FGFR inhibitors. The ongoing concomitant clinical evaluation of selective FGFR inhibitors in molecularly selected solid tumors brings new hopes for patients with metastatic cancer, for tumors so far excluded from molecularly guided treatments. Matching molecularly selected tumors with selective FGFR inhibitors has indeed led to promising results in phase I and II trials, justifying their registration to be expected in a near future, such as the recent accelerated approval of erdafitinib granted by the FDA for urothelial cancer. Widening our knowledge of the activity, efficacy, and toxicities relative to the selective FGFR tyrosine kinase inhibitors under clinical investigation, according to the exact FGFR molecular alteration, will be crucial to determine the optimal therapeutic strategy for patients suffering from FGFR-driven tumors. Similarly, identifying with appropriate molecular diagnostic, every single tumor harboring targetable FGFR alterations will be of utmost importance to attain the best outcomes for patients with FGFR-driven cancer.

Multicenter Phase I Study of Erdafitinib (JNJ-42756493), Oral Pan-Fibroblast Growth Factor Receptor Inhibitor, in Patients with Advanced or Refractory Solid Tumors.

PURPOSE: Here, we report results of the first phase I study of erdafitinib, a potent, oral pan-FGFR inhibitor. PATIENTS AND METHODS: Patients age ≥18 years with advanced solid tumors for which standard antineoplastic therapy was no longer effective were enrolled (NCT01703481). Parts 2 to 4 employed molecular screening for activating FGFR genomic alterations. In patients with such alterations, two selected doses/schedules identified during part 1 dose-escalation [9 mg once daily and 10 mg intermittently (7 days on/7 days off), as previously published (Tabernero JCO 2015;33:3401-8)] were tested. RESULTS: The study included 187 patients. The most common treatment-related adverse events were hyperphosphatemia (64%), dry mouth (42%), and asthenia (28%), generally grade 1/2 severity. All cases of hyperphosphatemia were grade 1/2 except for 1 grade 3 event. Skin, nail, and eye changes were observed in 43%, 33%, and 28% of patients, respectively (mostly grade 1/2 and reversible after temporary dosing interruption). Urothelial carcinoma and cholangiocarcinoma were most responsive to erdafitinib, with objective response rates (ORR) of 46.2% (12/26) and 27.3% (3/11), respectively, in response-evaluable patients with FGFR mutations or fusions. All patients with urothelial carcinoma and cholangiocarcinoma who responded to erdafitinib carried FGFR mutations or fusions. Median response duration was 5.6 months for urothelial carcinoma and 11.4 months for cholangiocarcinoma. ORRs in other tumor types were <10%. CONCLUSIONS: Erdafitinib shows tolerability and preliminary clinical activity in advanced solid tumors with genomic changes in the FGFR pathway, at two different dosing schedules and with particularly encouraging responses in urothelial carcinoma and cholangiocarcinoma.

A phase 1b study of afatinib in combination with standard-dose cetuximab in patients with advanced solid tumours.

This phase 1b, open-label trial assessed the combination of afatinib, an ErbB family blocker, with cetuximab, an epidermal growth factor receptor (EGFR) monoclonal antibody, in heavily pretreated patients with unselected/EGFR wild-type, advanced solid tumours. In Part A, the maximum tolerated dose (MTD) of afatinib + cetuximab was evaluated using a 3 + 3 dose-escalation design; the starting dose was afatinib 30 mg/day plus cetuximab 250 mg/m2/week (after cetuximab 400 mg/m2 loading dose), escalating to afatinib 40 mg/day. Part B further evaluated safety and tolerability at the MTD and preliminary anti-tumour activity in three patient cohorts with squamous non-small cell lung cancer (NSCLC), head and neck squamous cell carcinoma (HNSCC) and other solid tumours. Nine patients were treated in Part A; the MTD and recommended dose was determined as afatinib 40 mg/day plus cetuximab 250 mg/m2/week. In Part B, 49 patients were treated at the recommended dose (12 with squamous NSCLC, 15 with HNSCC and 22 with other tumours). The most common treatment-related adverse events (AEs) across all 58 patients were diarrhoea (63.8%) and acneiform dermatitis (43.1%). Overall, the best confirmed response was stable disease (SD; 53.4%); mean duration of disease control was 4.5 months; median progression-free survival was 2.6 months. In Part B, 55.1% of patients had SD (squamous NSCLC, 75.0%; HNSCC, 66.7%; other tumours; 36.4%). In conclusion, the recommended phase 2 dose was determined as afatinib 40 mg/day plus cetuximab 250 mg/m2/week. AEs were predictable and manageable, and anti-tumour activity was observed in some patients, particularly in those with squamous NSCLC and HNSCC. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov NCT02020577.