There currently are no internationally recognised treatment guidelines for patients with advanced gastric cancer/gastro-oesophageal junction cancer (GC/GEJC) in whom two prior lines of therapy have ...failed. The randomised, phase III JAVELIN Gastric 300 trial compared avelumab versus physician’s choice of chemotherapy as third-line therapy in patients with advanced GC/GEJC.
Patients with unresectable, recurrent, locally advanced, or metastatic GC/GEJC were recruited at 147 sites globally. All patients were randomised to receive either avelumab 10mg/kg by intravenous infusion every 2weeks or physician’s choice of chemotherapy (paclitaxel 80mg/m2 on days 1, 8, and 15 or irinotecan 150mg/m2 on days 1 and 15, each of a 4-week treatment cycle); patients ineligible for chemotherapy received best supportive care. The primary end point was overall survival (OS). Secondary end points included progression-free survival (PFS), objective response rate (ORR), and safety.
A total of 371 patients were randomised. The trial did not meet its primary end point of improving OS {median, 4.6 versus 5.0months; hazard ratio (HR)=1.1 95% confidence interval (CI) 0.9–1.4; P=0.81} or the secondary end points of PFS median, 1.4 versus 2.7months; HR=1.73 (95% CI 1.4–2.2); P>0.99 or ORR (2.2% versus 4.3%) in the avelumab versus chemotherapy arms, respectively. Treatment-related adverse events (TRAEs) of any grade occurred in 90 patients (48.9%) and 131 patients (74.0%) in the avelumab and chemotherapy arms, respectively. Grade ≥3 TRAEs occurred in 17 patients (9.2%) in the avelumab arm and in 56 patients (31.6%) in the chemotherapy arm.
Treatment of patients with GC/GEJC with single-agent avelumab in the third-line setting did not result in an improvement in OS or PFS compared with chemotherapy. Avelumab showed a more manageable safety profile than chemotherapy.
ClinicalTrials.gov: NCT02625623.
After surgical resection of pancreatic ductal adenocarcinoma (PDAC), patients are predominantly treated with adjuvant chemotherapy, commonly consisting of gemcitabine (GEM)-based regimens or the ...modified FOLFIRINOX (mFFX) regimen. While mFFX regimen has been shown to be more effective than GEM-based regimens, it is also associated with higher toxicity. Current treatment decisions are based on patient performance status rather than on the molecular characteristics of the tumor. To address this gap, the goal of this study was to develop drug-specific transcriptomic signatures for personalized chemotherapy treatment.
We used PDAC datasets from preclinical models, encompassing chemotherapy response profiles for the mFFX regimen components. From them we identified specific gene transcripts associated with chemotherapy response. Three transcriptomic artificial intelligence signatures were obtained by combining independent component analysis and the least absolute shrinkage and selection operator-random forest approach. We integrated a previously developed GEM signature with three newly developed ones. The machine learning strategy employed to enhance these signatures incorporates transcriptomic features from the tumor microenvironment, leading to the development of the ‘Pancreas-View’ tool ultimately clinically validated in a cohort of 343 patients from the PRODIGE-24/CCTG PA6 trial.
Patients who were predicted to be sensitive to the administered drugs (n = 164; 47.8%) had longer disease-free survival (DFS) than the other patients. The median DFS in the mFFX-sensitive group treated with mFFX was 50.0 months stratified hazard ratio (HR) 0.31, 95% confidence interval (CI) 0.21-0.44, P < 0.001 and 33.7 months (stratified HR 0.40, 95% CI 0.17-0.59, P < 0.001) in the GEM-sensitive group when treated with GEM. Comparatively patients with signature predictions unmatched with the treatments (n = 86; 25.1%) or those resistant to all drugs (n = 93; 27.1%) had shorter DFS (10.6 and 10.8 months, respectively).
This study presents a transcriptome-based tool that was developed using preclinical models and machine learning to accurately predict sensitivity to mFFX and GEM.
•Transcriptomic signatures were developed for key pancreatic cancer drugs to enable personalized treatment.•The Pancreas-View tool integrates four drug signatures to assist informed therapeutic decisions.•Signatures accurately identify high responder patients, indicative of improved DFS and cancer-specific survival.•Clinical validation involving a cohort of 343 patients confirms the efficacy of this signature approach.•Transcriptomic signatures that integrate predictors from preclinical models and machine learning offer a rationalized treatment strategy.
Purpose
Anemia is common in oncology and negatively impacts quality of life. However, there is lack of knowledge about iron deficiency (ID) epidemiology. The aim of this study was to prospectively ...assess iron status in patients with locally advanced or metastatic cancer beginning chemotherapy.
Methods
In this prospective, multicenter cohort study, anemia and ID were evaluated in patients with locally advanced or metastatic solid tumors and lymphoma before starting chemotherapy. Blood samples were collected at inclusion (W0), 6 weeks (W6), and 12 weeks (W12). Prevalence was evaluated in the general population, according to tumor location and was correlated with tumor response.
Results
One hundred twenty-nine patients were enrolled between 2013 and 2015; 119 had solid tumors and 10 lymphomas. At W0, there were no significant difference between locations with a prevalence around 50–60% (range 47.2–70.4%) and only a trend for colorectal cancer (70.4%,
P
= 0.069) due to a higher prevalence of absolute ID (18.5%). Prevalence of ID+ decreased between W0 and W6 and remained stable until W12 due to the proportion of patients with ID and without anemia. However, anemia prevalence increased during W0 and W6 and remained stable to W6 from W12 due to patients with anemia but without ID. A significant correlation between tumor response and ID prevalence was found (
P
= 0.036).
Conclusions
We confirm the high prevalence of ID and anemia in cancer patients. ID status is correlated to tumor response providing a strong rationale for iron monitoring during cancer management.
Locally advanced or metastatic squamous carcinoma of the anal canal (SCAC) has poor prognosis following platinum-based chemotherapy. Retifanlimab (INCMGA00012), a humanized monoclonal antibody ...targeting programmed death protein-1 (PD-1), demonstrated clinical activity across a range of solid tumors in clinical trials. We present results from POD1UM-202 (NCT03597295), an open-label, single-arm, multicenter, phase II study evaluating retifanlimab in patients with previously treated advanced or metastatic SCAC.
Patients ≥18 years of age had measurable disease and had progressed following, or were ineligible for, platinum-based therapy. Retifanlimab 500 mg was administered intravenously every 4 weeks. The primary endpoint was overall response rate (ORR) by independent central review. Secondary endpoints were duration of response (DOR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and safety.
Overall, 94 patients were enrolled. At a median follow-up of 7.1 months (range, 0.9-19.4 months), ORR was 13.8% 95% confidence interval (CI) 7.6% to 22.5%, with one complete response (1.1%) and 12 partial responses (12.8%). Responses were observed regardless of human immunodeficiency virus or human papillomavirus status, programmed death ligand 1 (PD-L1) expression, or liver metastases. Stable disease was observed in 33 patients (35.1%) for a DCR of 48.9% (95% CI 38.5% to 59.5%). Median DOR was 9.5 months (range, 5.6 months-not estimable). Median (95% CI) PFS and OS were 2.3 (1.9-3.6) and 10.1 (7.9-not estimable) months, respectively. Retifanlimab safety in this population was consistent with previous experience for the PD-(L)1 inhibitor class.
Retifanlimab demonstrated clinically meaningful and durable antitumor activity, and an acceptable safety profile in patients with previously treated locally advanced or metastatic SCAC who have progressed on or are intolerant to platinum-based chemotherapy.
•Retifanlimab (PD-1 inhibitor) monotherapy demonstrated encouraging results in patients with platinum-refractory SCAC.•Clinically meaningful antitumor activity was reported with ORR of 13.8% and stable disease in 35.1%, for a DCR of 48.9%.•Observed responses in advanced SCAC were durable (median 9.5 months).•Acceptable safety profile consistent with that reported for the PD-(L)1 inhibitor class.•Promising results warrant further investigation of retifanlimab in advanced SCAC as well as earlier stages of disease.
Up to 40% of patients who have received radiation for a pelvic malignancy will develop locoregional recurrence in the previously irradiated volume. Stereotactic body radiotherapy (SBRT) has been used ...in the oligometastatic setting, and provides an ablative approach ideal for reirradiation. The purpose of this study was to evaluate the outcomes after SBRT reirradiation of extraosseous recurrences in the pelvis.
This single institution retrospective study evaluated patients treated with SBRT reirradiation in the pelvis from January 2011 to February 2018. Patients with more than five oligometastatic lesions, >7 cm in size, and recurrence within the prostate were excluded.
In total, 30 patients were treated with SBRT with a median follow-up of 29.4 months. The primary tumour sites were most commonly rectum (30.8%) and prostate (30.8%). The median time interval between irradiation for the primary and SBRT reirradiation was 48 months (3–245). The typical reirradiation treatment was 35 Gy in five fractions, the median gross tumour volume size was 10.2 (0.3–110.5) ml and the most common target was the iliac nodes (40%). There were three (10%) acute grade 3 toxicities and no late grade 3 or more toxicities. At 12/24 months, local relapse-free survival, metastasis-free survival, progression-free survival and overall survival were 67.7%/50.7%, 67%/41.7%, 34.8%/14.9% and 83.2%/62.5%, respectively. On univariate analysis, improved local control was associated with low gross tumour volume (<10 ml) (P = 0.003) and prostate primary (P = 0.02), but was no longer significant on multivariate analysis. The proximity of organ at risk to the target did not significantly correlate with worse toxicity (P = 0.14) or tumour coverage (gross tumour volume: P = 0.8, planning target volume: P = 0.4).
SBRT pelvic reirradiation in oligometastatic patients is a safe and effective treatment modality. Careful consideration should be taken with larger tumour size, as it may be associated with worse oncological and toxicity outcome.
•35 Gy in five fractions was a safe and effective regimen for stereotactic pelvic reirradiation.•Reirradiation permitted a local control of 68% at 12 months and 42% at 24 months.•Acute and late grade 3 toxicity rates were low: 10% and 0%, respectively.
De nombreux effets indésirables liés à l’immunité (EILI) ont été décrits avec les anticorps thérapeutiques spécifiques de molécules de costimulation négatives (check-point inhibiteur) dans le cadre ...de l’immunothérapie antinéoplasique. Nous rapportons le cas peu décrit d’une nécrose digitale bilatérale imputable au pembrolizumab, inhibiteur de Programmed Cell Death protéine-1 (PD-1).
Un homme de 74 ans, aux antécédents d’hypertension et en cours de traitement pour un adénocarcinome œsophagien T3N1, se présentait avec des lésions nécrotiques pulpaires des 2e et 3e doigts de la main droite et 4e doigt de la main gauche.
Les premiers symptômes avaient commencé 6 mois auparavant, à 1 mois de l’initiation du pembrolizumab à 2mg/kg administrée selon une périodicité de 3 semaines et consistaient en des paresthésies des extrémités des membres supérieurs s’aggravant progressivement.
L’examen physique identifiait des lésions pulpaires nécrotiques, douloureuses, mal limitées sans autre signe cutané en dehors d’un phénomène de Raynaud bilatéral. La manœuvre d’Allen était pathologique de manière bilatérale mais les pouls périphériques étaient conservés. Il n’y avait ni fièvre, douleur thoracique, souffle cardiaque ou arythmie.
L’angioscanner aortique et l’échocardiographie étaient normaux. L’échographie-doppler artérielle retrouvait des thromboses de l’artère ulnaire droite et des artères digitales des 2e et 3e doigts de la main droite et du 4e doigt de la main gauche.
Biologiquement, le syndrome inflammatoire était peu marqué avec une CRP à 9,2mg/L. La fonction rénale n’était pas altérée et l’hémogramme normal. Les explorations microbiologiques n’étaient pas contributives. Les facteurs antinucléaires étaient positifs à 1/640, sans spécificité et les ANCA négatifs. L’exploration du complément était normale sans argument pour une cryoglobulinémie. Le bilan de thrombophilie comprenant le dosage plasmatique d’homocystéine, recherche d’anti-phospholipides et les mutations usuelles de syndrome myéloprolifératif était négatif.
Le patient a été traité par une anticoagulation curative, une antiagrégation plaquettaire et un traitement vasodilatateur adjuvant par ilomédine puis inhibiteur calcique. L’évolution à 1 mois était favorable mais le patient a été par la suite perdu de vue. Sur les critères de la pharmacovigilance, on a retenu l’imputabilité du pembrolizumab.
Les EILI liés à l’immunothérapie sont progressivement mieux décrits. Ils résultent de la levée d’inhibition des lymphocytes T CD8+ par la destruction de la liaison avec la cellule tumorale (liaison PD-1/PD-L1) induisant la prolifération de lymphocytes polyclonaux antitumoraux au prix d’une réponse lymphocytaire systémique de cellules T CD8+ autoréactives.
Les EILI secondaires aux anti-PD-1 touchent environ 70 % des patients traités, avec une toxicité majoritairement de grades 1–2 1. Ils apparaissent comme un bon marqueur de l’activité antitumorale du traitement. L’atteinte cutanée est fréquente mais on décrit aussi des manifestations digestives, endocriniennes, musculo-squelettique, immunohématologiques et une atteinte pulmonaire pouvant engager le pronostic vital 2.
Le traitement de ces effets indésirables est adapté au grade des EILI et consiste avant tout en une corticothérapie systémique. L’éviction de l’immunothérapie peut être proposée en cas d’EILI grave mais expose au risque de rechute néoplasique. Enfin, certains auteurs rapportent l’efficacité de traitements immunosuppresseurs tels que le mycophénolate mofétil ou l’azathioprine 2.
À notre connaissance, il s’agit du deuxième cas rapporté de thrombose artérielle imputable au pembrolizumab 3. Les évènements thrombotiques, bien que non mis en évidence dans les essais de phase I/II, peuvent être expliqués par un effet pro-inflammatoire et pro-athérogène des anti-PD1. Cependant, on ne peut pas exclure une toxicité vasculaire secondaire à des chimiothérapies (i.e. sels de platine) antérieures. Leur traitement est symptomatique et antithrombotique.
La thrombose artérielle est une manifestation peu décrite sous immunothérapie anti-PD1 et doit amener à discuter son interruption. Cela amène à une plus grande vigilance dans le contexte d’accumulation de facteurs de risque cardiovasculaires qu’il convient de contrôler lors de l’initiation de l’immunothérapie.
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