Dabrafenib plus trametinib in patients with relapsed/refractory BRAF V600E mutation-positive hairy cell leukemia.

BRAF V600E is the key oncogenic driver mutation in hairy cell leukemia (HCL). We report the efficacy and safety of dabrafenib plus trametinib in patients with relapsed/refractory BRAF V600E mutation-positive HCL. This open-label, phase 2 study enrolled patients with BRAF V600E mutation-positive HCL refractory to first-line treatment with a purine analog or relapsed after ≥2 prior lines of treatment. Patients received dabrafenib 150 mg twice daily plus trametinib 2 mg once daily until disease progression, unacceptable toxicity, or death. The primary endpoint was investigator-assessed objective response rate (ORR) per criteria adapted from National Comprehensive Cancer Network-Consensus Resolution guidelines. Secondary endpoints included duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety. Fifty-five patients with BRAF V600E mutation-positive HCL were enrolled. The investigator-assessed ORR was 89.0% (95% confidence interval, 77.8%-95.9%); 65.5% of patients had a complete response (without minimal residual disease [MRD]: 9.1% [negative immunohistochemistry of bone marrow {BM} biopsy], 12.7% [negative BM aspirate flow cytometry {FC}], 16.4% [negative immunohistochemistry and/or FC results]; with MRD, 49.1%), and 23.6% had a partial response. The 24-month DOR was 97.7% with 24-month PFS and OS rates of 94.4% and 94.5%, respectively. The most common treatment-related adverse events were pyrexia (58.2%), chills (47.3%), and hyperglycemia (40.0%). Dabrafenib plus trametinib demonstrated durable responses with a manageable safety profile consistent with previous observations in other indications and should be considered as a rituximab-free therapeutic option for patients with relapsed/refractory BRAF V600E mutation-positive HCL. This trial is registered at www.clinicaltrials.gov as #NCT02034110.

Olaparib maintenance versus placebo in platinum-sensitive non-small cell lung cancer: the Phase 2 randomized PIPSeN trial.

BACKGROUND: Platinum-sensitivity is a phenotypic biomarker of Poly (ADP-ribose) polymerase inhibitors (PARPi) sensitivity in histotypes where PARPi are approved. Approximately one-third of non-small cell lung cancers (NSCLC) are platinum-sensitive. The double-blind, randomized phase II PIPSeN (NCT02679963) study evaluated olaparib, a PARPi, as maintenance therapy for patients with platinum-sensitive advanced NSCLC. METHODS: Chemonaïve patients with ECOG performance status of 0-1, platinum-sensitive, EGFR- and ALK-wild-type, stage IIIB-IV NSCLC were randomized (R) to receive either olaparib (O) maintenance or a placebo (P). The primary objective was progression-free survival (PFS) from R. Secondary objectives included overall survival (OS) and safety. With an anticipated hazard ratio of 0.65, 144 patients were required to be randomized, and approximately 500 patients enrolled. RESULTS: The trial was prematurely terminated because anti-PD(L)1 therapy was approved during the trial recruitment. A total of 182 patients were enrolled, with 60 patients randomized: 33 and 27 in the O and P arms, respectively. Patient and tumor characteristics were well-balanced between arms, except for alcohol intake (33% vs 11% in the O and P arms, respectively, p = 0.043). The median PFS was 2.9 and 2.0 months in the O and P arms, respectively (logrank p = 0.99). The median OS was 9.4 and 9.5 months in the O and P arms, respectively (p = 0.28). Grade ≥3 toxicities occurred in 15 and 8 patients in O and P arms, with no new safety concerns. CONCLUSION: PIPSeN was terminated early after enrollment of only 50% of the pre-planned population, thus being statistically underpowered. Olaparib maintenance did neither improve median PFS nor OS in this patient population.

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.

Dabrafenib plus trametinib in patients with BRAFV600E-mutant low-grade and high-grade glioma (ROAR): a multicentre, open-label, single-arm, phase 2, basket trial.

BACKGROUND: Effective treatments are needed to improve outcomes for high-grade glioma and low-grade glioma. The activity and safety of dabrafenib plus trametinib were evaluated in adult patients with recurrent or progressive BRAFV600E mutation-positive high-grade glioma and low-grade glioma. METHODS: This study is part of an ongoing open-label, single-arm, phase 2 Rare Oncology Agnostic Research (ROAR) basket trial at 27 community and academic cancer centres in 13 countries (Austria, Belgium, Canada, France, Germany, Italy, Japan, the Netherlands, Norway, South Korea, Spain, Sweden, and the USA). The study enrolled patients aged 18 years or older with an Eastern Cooperative Oncology Group performance status of 0, 1, or 2. Patients with BRAFV600E mutation-positive high-grade glioma and low-grade glioma received dabrafenib 150 mg twice daily plus trametinib 2 mg once daily orally until unacceptable toxicity, disease progression, or death. In the high-grade glioma cohort, patients were required to have measurable disease at baseline using the Response Assessment in Neuro-Oncology high-grade glioma response criteria and have been treated previously with radiotherapy and first-line chemotherapy or concurrent chemoradiotherapy. Patients with low-grade glioma were required to have measurable non-enhancing disease (except pilocytic astrocytoma) at baseline using the Response Assessment in Neuro-Oncology low-grade glioma criteria. The primary endpoint, in the evaluable intention-to-treat population, was investigator-assessed objective response rate (complete response plus partial response for high-grade glioma and complete response plus partial response plus minor response for low-grade glioma). This trial is ongoing, but is closed for enrolment, NCT02034110. FINDINGS: Between April 17, 2014, and July 25, 2018, 45 patients (31 with glioblastoma) were enrolled into the high-grade glioma cohort and 13 patients were enrolled into the low-grade glioma cohort. The results presented here are based on interim analysis 16 (data cutoff Sept 14, 2020). In the high-grade glioma cohort, median follow-up was 12·7 months (IQR 5·4-32·3) and 15 (33%; 95% CI 20-49) of 45 patients had an objective response by investigator assessment, including three complete responses and 12 partial responses. In the low-grade glioma cohort, median follow-up was 32·2 months (IQR 25·1-47·8). Nine (69%; 95% CI 39-91) of 13 patients had an objective response by investigator assessment, including one complete response, six partial responses, and two minor responses. Grade 3 or worse adverse events were reported in 31 (53%) patients, the most common being fatigue (five [9%]), decreased neutrophil count (five [9%]), headache (three [5%]), and neutropenia (three [5%]). INTERPRETATION: Dabrafenib plus trametinib showed clinically meaningful activity in patients with BRAFV600E mutation-positive recurrent or refractory high-grade glioma and low-grade glioma, with a safety profile consistent with that in other indications. BRAFV600E testing could potentially be adopted in clinical practice for patients with glioma. FUNDING: Novartis.

First-in-human phase 1 study of budigalimab, an anti-PD-1 inhibitor, in patients with non-small cell lung cancer and head and neck squamous cell carcinoma.

BACKGROUND: Budigalimab is a humanized, recombinant immunoglobulin G1 monoclonal antibody targeting programmed cell death protein 1 (PD-1). We present the safety, efficacy, pharmacokinetic (PK), and pharmacodynamic data from patients enrolled in the head and neck squamous cell carcinoma (HNSCC) and non-small cell lung cancer (NSCLC) expansion cohorts of the phase 1 first-in-human study of budigalimab monotherapy (NCT03000257; registered 15 December 2016). PATIENTS AND METHODS: Patients with recurrent/metastatic HNSCC or locally advanced/metastatic NSCLC naive to PD-1/PD-1-ligand inhibitors were enrolled; patients were not selected on the basis of oncogene driver mutations or PD-L1 status. Budigalimab was administered at 250 mg intravenously Q2W or 500 mg intravenously Q4W until disease progression/unacceptable toxicity. The primary endpoints were safety and PK; the secondary endpoint was efficacy. Exploratory endpoints included biomarker assessments. RESULTS: In total, 81 patients were enrolled (HNSCC: N = 41 [PD-L1 positive: n = 19]; NSCLC: N = 40 [PD-L1 positive: n = 16]); median treatment duration was 72 days (range, 1-617) and 71 days (range, 1-490) for the HNSCC and NSCLC cohorts, respectively. The most frequent grade ≥ 3 treatment-emergent adverse event was anemia (HNSCC: n = 9, 22%; NSCLC: n = 5, 13%). Both dosing regimens had comparable drug exposure and increased interferon gamma-induced chemokines, monokine induced by gamma interferon, and interferon-gamma-inducible protein 10. Objective response rates were 13% (90% CI, 5.1-24.5) in the HNSCC cohort and 19% (90% CI, 9.2-32.6) in the NSCLC cohort. Median progression-free survival was 3.6 months (95% CI, 1.7-4.7) and 1.9 months (95% CI, 1.7-3.7) in the HNSCC and NSCLC cohorts. CONCLUSIONS: The safety, efficacy and biomarker profiles of budigalimab are similar to other PD-1 inhibitors. Development of budigalimab in combination with novel anticancer agents is ongoing.

Patterns of progression in patients treated for immuno-oncology antibodies combination.

BACKGROUND: New patterns of progression under immune-oncology (IO) antibodies (mAb) have been described such as pseudoprogression. Except for melanoma, variations between studies reveal difficulties to establish their prevalence. METHODS: This retrospective study enrolled patients participating in IO phase I trials at Gustave Roussy cancer center for solid tumors excluding melanoma. Radiological assessment according to iRECIST was correlated with prospectively registered patient characteristics and outcomes. Pseudoprogression (PsPD) was defined as RECIST-defined progression followed by stabilization or decrease at the next imaging, and dissociated response (DisR) as concomitant decrease in some tumor lesions and increase in others at a same timepoint. RESULTS: Among 360 patients included, 74% received IO mAb combination: 45% with another IO mAb, 20% with targeted therapy and 10% with radiotherapy. The overall response rate was 19.7%. PsPD were observed in 10 (2.8%) patients and DisR in 12 (3.3%) patients. Atypical responses (AR), including PsPD and DisR, were not associated with any patient's baseline characteristics. Compare with typical responder patients, patients experiencing AR presented a shorter iPFS (HR 0.34; p < 0.001) and OS (HR 0.27; p = 0.026). Among the 203 patients who progressed in 12 weeks, 80 (39.4%) patients were treated beyond progression. PD was confirmed in 80% of cases, while 10% of patients presented a response. CONCLUSION: Pseudoprogression and dissociated response are uncommon patterns of progression. Their prevalence should be balanced with the rate of real progressing patients treated beyond progression. Prognosis or on-treatment biomarkers are needed to identify early patients who will benefit from immunotherapy.

Association of metastatic pattern and molecular status in stage IV non-small cell lung cancer adenocarcinoma.

OBJECTIVES: The aim of our study was to investigate the association between driver oncogene alterations and metastatic patterns on imaging assessment, in a large cohort of metastatic lung adenocarcinoma patients. METHODS: From January 2010 to May 2017, 550 patients with stage IV lung adenocarcinoma with molecular analysis were studied retrospectively including 135 EGFR-mutated, 81 ALK-rearrangement, 47 BRAF-mutated, 141 KRAS-mutated, and 146 negative tumors for these 4 mutations (4N). After review of the complete imaging report by two radiologists (junior and senior) to identify metastatic sites, univariate correlation analyzes were performed. RESULTS: We found differences in metastatic tropism depending on the molecular alteration type when compared with the non-mutated 4N group: in the EGFR group, pleural metastases were more frequent (32% versus 20%; p = 0.021), and adrenal and node metastases less common (6% versus 23%; p < 0.001 and 11% versus 23%; p = 0.011). In the ALK group, there were more brain and lung metastases (respectively 42% versus 29%; p = 0.043 and 37% versus 24%; p = 0.037). In the BRAF group, pleural and pericardial metastases were more common (respectively 47% versus 20%; p < 0.001 and 11% versus 3%; p = 0.04) and bone metastases were rarer (21% versus 42%; p = 0.011). Lymphangitis was more frequent in EGFR, ALK, and BRAF groups (respectively 6%, 7%, and 15% versus 1%); p = 0.016; p = 0.009; and p < 0.001. CONCLUSION: The application of these correlations between molecular status and metastatic tropism in clinical practice may lead to earlier and more accurate identification of patients for targeted therapy. KEY POINTS: • Bone and brain metastasis are the most common organs involved in lung adenocarcinoma but the relative incidence of each metastatic site depends on the molecular alteration. • EGFR-mutated tumors preferentially spread to the pleura and less commonly to adrenals, ALK-rearrangement tumors usually spread to the brain and the lungs, whereas BRAF-mutated tumors are unlikely to spread to bones and have a serous (pericardial ad pleural) tropism. • These correlations could help in the clinical management of patients with metastatic lung adenocarcinoma.

A phase Ib dose-finding, pharmacokinetic study of the focal adhesion kinase inhibitor GSK2256098 and trametinib in patients with advanced solid tumours.

BACKGROUND: Combined focal adhesion kinase (FAK) and MEK inhibition may provide greater anticancer effect than FAK monotherapy. METHODS: This dose-finding phase Ib study (adaptive 3 + 3 design) determined the maximum tolerated dose (MTD) of trametinib and the FAK inhibitor GSK2256098 in combination. Eligible patients had mesothelioma or other solid tumours with probable mitogen activated protein kinase pathway activation. Adverse events (AEs), dose-limiting toxicities, disease progression and pharmacokinetics/pharmacodynamics were analysed. RESULTS: Thirty-four subjects were enrolled. The GSK2256098/trametinib MTDs were 500 mg twice daily (BID)/0.375 mg once daily (QD) (high/low) and 250 mg BID/0.5 mg QD (low/high). The most common AEs were nausea, diarrhoea, decreased appetite, pruritus, fatigue and rash; none were grade 4. Systemic exposure to trametinib increased when co-administered with GSK2256098, versus trametinib monotherapy; GSK2256098 pharmacokinetics were unaffected by concomitant trametinib. Median progression-free survival (PFS) was 11.8 weeks (95% CI: 6.1-24.1) in subjects with mesothelioma and was longer with Merlin-negative versus Merlin-positive tumours (15.0 vs 7.3 weeks). CONCLUSIONS: Trametinib exposure increased when co-administered with GSK2256098, but not vice versa. Mesothelioma patients with loss of Merlin had longer PFS than subjects with wild-type, although support for efficacy with this combination was limited. Safety profiles were acceptable up to the MTD.

Phase I trial of bortezomib daily dose: safety, pharmacokinetic profile, biological effects and early clinical evaluation in patients with advanced solid tumors.

Purpose This phase I study investigated bortezomib in solid tumors used as a daily subcutaneous regimen. Previous regimens showed only modest activity in solid tumors which was potentially related to sub-optimal tumor penetration. We aimed at exploring if daily low dose administration of bortezomib may allow a greater and tolerable pharmacokinetic exposure which might be required for antitumor activity in solid tumors. Patients and methods This 3 + 3 design, dose escalation, monocentric study aimed at defining the maximum tolerated dose of daily low dose schedule of bortezomib. Tolerability, pharmacokinetics, pharmacodynamics, antitumor activity, biomarkers for proteasome inhibition, pre- and post-treatment tumor biopsies were also evaluated. Results A total of eighteen patients were dosed in 3 bortezomib cohorts (0.5, 0.6 and 0.7 mg/m2), with 3, 11 and 4 patients respectively. Three patients experienced dose-limiting toxicities: Grade (G) 3 Sweet's syndrome (at 0.6 mg/m2), G3 asthenia and anorexia or ataxia (2 patients at 0.7 mg/m2). The most common study drug-related adverse events (all grades) were thrombocytopenia (72%), fatigue (56%), neuropathy (50%), anorexia (44%) and rash (39%). Dose 0.6 mg/m2 of bortezomib was considered as the recommended phase II dose. A significant tumor shrinkage (-36% according to WHO criteria) was observed in one patient with heavily pre-treated GIST, and 2 minor responses (-20%) were recorded in two patients with melanoma and mesothelioma. Conclusion This daily subcutaneous regimen of bortezomib showed a dose dependent plasma exposure, evidence of target inhibition and preliminary signs of clinical activity. However, cumulative neurological toxicity of this dose-dense daily regimen might preclude its further clinical development.

Outcomes and prognostic factors for relapsed or refractory lymphoma patients in phase I clinical trials.

Background Although safety and prognostic factors for overall survival (OS) have been extensively studied in Phase I clinical trials on patients with solid tumours, data on lymphoma trials are scarce. Here, we investigated safety, outcomes and prognostic factors in relapsed or refractory lymphoma patients included in a series of Phase I trials. Method and patients All consecutive adult patients with recurrent/refractory lymphoma enrolled in 26 Phase I trials at a single cancer centre in France between January 2008 and June 2016 were retrospectively assessed. Results 133 patients (males: 65%) were included in the analysis. The median (range) age was 65 (23-86). Aggressive non-Hodgkin, indolent non-Hodgkin and Hodgkin types accounted for 64%, 25% and 11% of the patients, respectively. The patients had received a median (range) of 3 (1-13) lines of treatment prior to trial entry. The median [95% confidence interval] progression-free survival and OS times were 3.0 [1.8-3.6] and 17.8 [12.7-30.4] months, respectively. High-grade toxicity (grade 3 or higher, according to the National Cancer Institute's Common Terminology Criteria for Adverse Events classification) was experienced by 56 of the 133 patients (42%) and was related to the investigational drug in 44 of these cases (79%). No toxicity-related deaths occurred. Dose-limiting toxicity (DLT) was encountered in 11 (9%) of the 116 evaluable patients. High-grade toxicity occurred during the DLT period for 34 of the 56 patients (61%) and after the DLT period in the remaining 22 (39%). The main prognostic factors for poor OS were the histological type (i.e. tumour aggressiveness), an elevated serum LDH level, and a low serum albumin level. Early withdrawal from a trial was correlated with the performance status score, the histological type and the serum LDH level. The overall objective response and disease control rates were 24% and 57%, respectively. Conclusion Performance status, LDH, albumin and histological type (tumour aggressiveness) appear to be the most relevant prognostic factors for enrolling Phase I participants with relapsed or refractory lymphoma. 39% of the patients experienced a first high-grade toxic event after the dose-limiting toxicity period, suggesting that the conventional concept of dose-limiting toxicity (designed for chemotherapy) should be redefined in the era of modern cancer therapies.

Predictive factors of renal toxicities related to anti-VEGFR multikinase inhibitors in phase 1 trials.

Purpose Renal toxicities are common with angiogenesis multikinase inhibitors (AMKI), and can be limiting in phase I trials. Factors associated with such toxicities are poorly known. The aims of this exploratory study were to describe renovascular toxicities associated with AMKI, impact on drug development and to identify baseline parameters associated with the occurrence of renal toxicities in phase I trials. Methods Consecutive patients treated with AMKI in Gustave Roussy phase I unit between October 2005 and August 2013 were included. We retrospectively collected baseline characteristics and renovascular side effects. Associations were assessed in univariate and multivariate analyses. Results Overall, 168 patients were included: male 53.0 %, mean age 55.5 years old, history of hypertension 26.8 %, diabetes 6.0 %, atherosclerosis 13.6 %, stage 3 Chronic Kidney Disease (CKD, NKF-KDOQI) 17.2 %. Incidences of reno-vascular side effects were: hypertension 47.6 %, proteinuria 19.0 %, renal failure 11.9 % and thrombotic microangiopathy 10.1 %. Eighty percent of dose limiting toxicities (DLTs) were related to a renal toxicity. Multivariate analysis showed that onset of renal failure was associated with history of hypertension (p = 0.0003) and stage 3 CKD (p = 0.032). Conclusions A majority of the DLTs associated with AMKI in phase 1 trials are renal toxicities. Baseline hypertension and stage 3 CKD (NKF-KDOQI) might help to better identify patients at risk of AMKI-related renal toxicities.

Prognostic factors and outcome of patients with hematological malignancies in phase I trials: the Gustave Roussy scoring system.

Despite considerable progress in hematological malignancies (HM) biology during the last decades, translation into clinical benefit remains a major challenge. To improve patient selection and identify patients most likely to benefit from phase I trials, we designed and validated, in an independent cohort, a simple prognostic score. Treatment outcome, toxicity, and survival data from 82 consecutive patients enrolled in 14 phase I trials were reviewed (January 2008-February 2012). We validated these results on a prospectively collected cohort (17 phase I trials, February 2012-May 2014, 88 patients). Within a median follow-up of 19.1 months (range: 2.1-43.8 months), the median progression-free and overall survival (OS) were, respectively, 4.1 months [95% confidence interval (CI): 3.0-5.3] and 19.8 months (95% CI: 16.1-36.8). Best overall response and disease control rates were similar to HM salvage regimens (28 and 64%, respectively). Through multivariate analysis of independent prognostic factors, we designed and prospectively validated a simple prognostic score based on histological subtype, performance status, and albumin. Patients with a low-risk score experienced significantly better OS compared with patients with an intermediate or a high score (median OS: 37 vs. 17 vs. 5 months; hazard ratio=11.68, 95% CI: 4.09-33.3). Our data indicate the safety and efficacy of phase I trials in a significant number of relapsed/refractory HM patients, with clinical benefit achieved in more than half of patients. Our simple scoring system offers a valuable selection tool encouraging HM patient inclusions in phase I trials.

Patients aged over 75 years enrolled in Phase I clinical trials: the Gustave Roussy experience.

Although a third of all cancers are diagnosed after the age of 75, only 9% of elderly people are recruited in clinical trials, because of fear of the risk of toxicity. The aim of this study was to compare the tolerance and efficacy observed in Phase I trials among patients aged over 75 years with that observed in younger patients. Patients treated from 2007 to 2012 at Institut Gustave Roussy in Phase I trials were included. The conditional Cox proportional hazards model was used to compare the occurrence of AE and overall survival in a subpopulation of elderly people (EP, aged >75 years) matched with patients aged <75 years (YP) according to the same Phase I protocol and the same Royal Marsden Hospital (RMH) prognostic score. Among the 32 EP and the 158 YP, 63% and 61% experienced Grade 3-4 AEs and dose-limiting toxicities occurred in 6% and 11% in each group respectively. Age over 75 years was neither associated with a greater risk of high toxicity (HR=0.90 [CI95%, 0.47-1.70], p = 0.74) nor of death (HR=0.86; CI95%: 0.38-1.93; p = 0.71). Age over 75 years had no impact on the occurrence of either high toxicity or of death.

A never-smoker lung adenocarcinoma patient with a MET exon 14 mutation (D1028N) and a rapid partial response after crizotinib.

During the past decade, the treatment of lung adenocarcinomas has been revolutionized with novel molecular targeted therapies. We describe a case of clinical activity of crizotinib in a female patient with a lung adenocarcinoma displaying a MET exon 14 donor splice site mutation (D1028N) detected using next generation sequencing. Within 5 weeks of crizotinib therapy, a partial response was observed in this 67 year-old woman. Further clinical trials of crizotinib are needed for non-small cell lung cancer exhibiting MET mutations.

Phase I study of afatinib combined with nintedanib in patients with advanced solid tumours.

BACKGROUND: This Phase I study evaluated continuous- and intermittent-dosing (every other week) of afatinib plus nintedanib in patients with advanced solid tumours. METHODS: In the dose-escalation phase (n=45), maximum tolerated doses (MTDs) were determined for continuous/intermittent afatinib 10, 20, 30 or 40 mg once daily plus continuous nintedanib 150 or 200 mg twice daily. Secondary objectives included safety and efficacy. Clinical activity of continuous afatinib plus nintedanib at the MTD was further evaluated in an expansion phase (n=25). RESULTS: The most frequent dose-limiting toxicities were diarrhoea (11%) and transaminase elevations (7%). Maximum tolerated doses were afatinib 30 mg continuously plus nintedanib 150 mg, and afatinib 40 mg intermittently plus nintedanib 150 mg. Treatment-related adverse events (mostly Grade⩽3) included diarrhoea (98%), asthenia (64%), nausea (62%) and vomiting (60%). In the dose-escalation phase, two patients had partial responses (PRs) and 27 (60%) had stable disease (SD). In the expansion phase, one complete response and three PRs were observed (all non-small cell lung cancer), with SD in 13 (52%) patients. No pharmacokinetic interactions were observed. CONCLUSIONS: MTDs of continuous or intermittent afatinib plus nintedanib demonstrated a manageable safety profile with proactive management of diarrhoea. Antitumour activity was observed in patients with solid tumours.

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.

Antibody drug conjugates in older patients: State of the art.

More than half of cancer cases occur in patients aged 65 years or older. The efficacy and safety of antibody drug conjugates (ADCs) in older patients remains an unclear subject as available evidence is limited. Geriatric population is underrepresented in clinical trials. Consequently, most of our knowledge regarding innovative therapeutics was studied on a younger population. In this review of published literature, we report the available information on efficacy, safety and pharmacokinetics of FDA approved ADCs for hematologic malignancies and solid tumors in the geriatric population. We explore the results of clinical trials dedicated for older individuals as well as subgroup analyses of the geriatric population in major trials evaluating these drugs. Available data suggest a similar efficacy in older adults as compared to general population. However, older patients might be prone to a higher rate of adverse events in incidence with a potential impact on quality of life. We lack data to support primary dose reductions or schedule modifications in this category of patients. No pharmacokinetic differences were reported between age groups. It is crucial to encourage the development of clinical trials dedicated to older patients with geriatric parameters (G8 score, G-CODE…) so that results can be more representative of this population outside of clinical trials.

TROP-2 directed antibody-drug conjugates (ADCs): The revolution of smart drug delivery in advanced non-small cell lung cancer (NSCLC).

BACKGROUND: Antibody drug conjugates (ADCs) represent a revolutionary drug class in cancer therapy, combining the precision of targeted therapy with the cytotoxic effects of chemotherapy. Promising activity of novel ADCs, namely Trastuzumab Deruxtecan and Patritumab Deruxtecan, has been observed in hard-to treat molecular subtypes, such as HER2-positive and heavily pretreated EGFR-mutant Non-Small Cell Lung Cancer (NSCLC). However, therapeutic advances are expected in certain subgroups of lung cancer patients, including non-oncogene-addicted NSCLC after failure of current standard of care (e.g., immunotherapy with or without chemotherapy, chemo-antiangiogenic treatment). Trophoblastic Cell Surface Antigen 2 (TROP-2) is a surface transmembrane glycoprotein member of the epithelial cell adhesion molecule (EpCAM) family. TROP-2 represents a promising therapeutic target in refractory non-oncogene-addicted NSCLC. METHODOLOGY: We performed a systematic literature search of the clinical trials about TROP-2 directed ADCs in NSCLC referenced in the pubmed.gov database, Cochrane Library database and clinicaltrial.gov database. RESULTS: First-in-humans ADCs targeting TROP-2, namely Sacituzumab Govitecan (SN-38) and Datopotamab Deruxtecan (Dxd), yielded promising activity signals in NSCLC with a manageable safety profile. Most common grade ≥ 3 adverse events (AEs) of Sacituzumab Govitecan included neutropenia (28 %), diarrhea (7 %), nausea (7 %), fatigue (6 %), and febrile neutropenia (4 %). Nausea and stomatitis were the most common all grade AEs with Datopotamab Deruxtecan; dyspnea, amylase increase, hyperglycemia and lymphopenia were reported as grade ≥ 3 AEs in less than 12 % of patients. CONCLUSION: As more effective strategies are needed for patients with refractory non-oncogene-addicted NSCLC, the design of novel clinical trials with ADCs targeting TROP-2 is encouraged as both a monotherapy or combination strategy with existing agents (e.g., monoclonal antibodies targeting immune checkpoint inhibitors or chemotherapy).

Tusamitamab Ravtansine in Patients with Advanced Solid Tumors: Phase I Study of Safety, Pharmacokinetics, and Antitumor Activity Using Alternative Dosing Regimens.

Purpose: Tusamitamab ravtansine is an antibody-drug conjugate that targets carcinoembryonic antigen-related cell adhesion molecule 5 (CEACAM5) and delivers a cytotoxic maytansinoid payload. In a phase I dose-escalation study, the maximum tolerated dose (MTD) was 100 mg/m2 every 2 weeks (Q2W). Here we report results for two alternative schedules. Experimental Design: Adults ages ≥18 years (range, 34-73) with locally advanced/metastatic solid tumors (N = 43; colon/rectum, 29; stomach, 7; pancreas, 4; other, 3) expressing/likely to express CEACAM5 received intravenous tusamitamab ravtansine 120-170 mg/m2 [loading dose (LD)], then 100 mg/m2 Q2W (Q2W-LD, n = 28), or 120-190 mg/m2 fixed dose [every 3 weeks (Q3W), n = 15]. The primary endpoint was dose-limiting toxicities (DLTs) during cycles 1-2 (Q2W-LD) and cycle 1 (Q3W). Results: Reversible DLTs were observed in 2 of 9 patients (grade 2 keratopathy; grade 2 keratitis) with 170 mg/m2 in Q2W-LD and in 2 of 3 patients (grade 2 keratopathy; grade 3 transaminase elevation) with 190 mg/m2 in Q3W. Nineteen (67.9%) patients in Q2W-LD and 13 (86.7%) patients in Q3W experienced treatment-related adverse events (AE); 3 of 43 patients discontinued treatment because of AEs. The most common AEs were asthenia, gastrointestinal complaints, keratopathy, keratitis, and peripheral sensory neuropathy. In this small, heavily pretreated population, no confirmed responses were observed; however, stable disease occurred in 35.7% of patients in Q2W-LD and 40.0% of patients in Q3W. Conclusions: Tusamitamab ravtansine had a favorable safety profile with both alternative administration schedules; MTDs were 170 mg/m2 (LD) followed by 100 mg/m2 Q2W, and 170 mg/m2 Q3W as a fixed dose. (NCT02187848). Significance: The collective results of this phase I dose-escalation study will inform further studies of tusamitamab ravtansine in patients with solid tumors with CEACAM5 expression, including patients with non-small cell lung cancer.