Niels Reinmuth

Diagnosis, monitoring and management of immune-related adverse drug reactions of anti-PD-1 antibody therapy.

PD-1 checkpoint inhibitors are associated with a specific spectrum of immune-related adverse events. This spectrum is different from toxicities known for kinase inhibitors or cytotoxic drugs. Since PD-1 directed therapies show effectivity in an increasing number of malignant diseases, their clinical usage will increase rapidly. Therefore clinicians from different specialities such as medical oncology, internal medicine, family doctors and emergency unit staff should be aware of the adverse effects of PD-1 checkpoint inhibitors to avoid delays in diagnosis and treatment. Based on pooled data from pivotal trials as reported by the European Medicines Agency, the present paper reviews incidences and kinetics of onset and resolution of immune-mediated adverse events of specific interest (AEOSI) of both approved PD-1 inhibitors nivolumab and pembrolizumab. In general, the severity of AEOSI is mild to moderate (grade 1-2); the frequency of immune-mediated but also idiopathic grade 3-4 adverse drug reactions is ⩽2% for any event term. Recommendations for the diagnosis, monitoring and management of the relevant dermatological, gastrointestinal, pulmonary, endocrine, renal and hepatic toxicities are convened by an expert panel that consolidated and clarified treatment recommendations after the onset of AEOSI. Although the time of onset is not predictable - the medians range from 1 to 6months - the huge majority of events is reversible, with no impact of the time of onset. By the systemic use of glucocorticoids, notably methylprednisolone or equivalents, most AEOSI are well manageable. Non-steroidal immunosuppressants may be used in certain cases of refractory/recalcitrant, long-lasting immune toxicities. With regard to the outstanding clinical activity of the anti-PD-1 antibodies, therapy restart is the principal therapeutic option after recovery of grade 2 AEOSI, or diminution of higher grade skin or endocrine events to mild severity. Early diagnosis and close clinical monitoring are essential for successful management of immune-related adverse events.

Combined immune checkpoint blockade (anti-PD-1/anti-CTLA-4): Evaluation and management of adverse drug reactions

BACKGROUNDnCombined immune checkpoint blockade (ICB) provides unprecedented efficacy gains in numerous cancer indications, with PD-1 inhibitor nivolumab plus CTLA-4 inhibitor ipilimumab in advanced melanoma as first-ever approved therapies for combined ICB. However, gains in efficacy must be balanced against a higher frequency and severity of adverse drug reactions (ADR). Because delays in diagnosis and management might result in symptom worsening and further complications, clinicians shall be well trained to identify ADR promptly and monitor patients adequately. This paper reviews safety data assessed by the European Medicines Agency for the anti-PD-1/CTLA-4 combination and provides a literature overview on published case reports for rare ADR with suspected potential underreporting. Incidences and kinetics of immune-related ADR are described. Recommendations for the evaluation and management of ADR are convened by an interdisciplinary expert panel focusing on rare but clinically important side effects arising from combined ICB. Pooled safety data from 1551 patients with advanced melanoma, treated either with 3mg/kg ipilimumab plus 1mg/kg nivolumab (N=407), or nivolumab alone (N=787), or ipilimumab alone (N=357) demonstrate that immune-related ADR occur more frequently for the combination, with a shorter time-to-onset, and tend to be more severe. The majority of events is reversible after systemic use of glucocorticoids, notably methylprednisolone or equivalents; in certain cases of long-lasting and refractory immune toxicities, non-steroidal immunosuppressants may be used, once ICB is interrupted or terminated. Combined ICB has considerable toxicities, therefore close monitoring and high experience in diagnosis and treatment of ADR is necessary.

Correlation of EGFR mutations with chromosomal alterations and expression of EGFR, ErbB3 and VEGF in tumor samples of lung adenocarcinoma patients

INTRODUCTIONnMutations in the tyrosine kinase domain of the epidermal growth factor receptor (EGFR) are frequently detected in lung adenocarcinomas with bronchioloalveolar (BAC) differentiation and have been associated with increased response to small molecule EGFR inhibitors in some clinical studies. However, further molecular characterization of tumor cells carrying EGFR mutations (EGFR-mut) is warranted.nnnMETHODSnBy DNA sequencing, 120 patients with lung adenocarcinomas (70 tumors with BAC components) were screened for EGFR mutations within exons 18-21. Performing comparative genomic hybridization (CGH) and immunohistochemistry, chromosomal imbalances and protein expression levels of EGFR, ErbB3 and VEGF (vascular endothelial growth factor) were analyzed, respectively.nnnRESULTSnEGFR mutations were detected in 20/120 tumors. Tumors with BAC components carried more frequently EGFR mutations compared to adenocarcinomas without BAC histology (17/70=24% vs 3/50=6.0%; p=0.012). In a subsequent matched-pair analysis, CGH-analysis demonstrated similar mean numbers of chromosomal imbalances for EGFR mutated and wild-type tumors (8.6 vs 7.8 gains; 2.4 vs 2.7 losses), respectively. Furthermore, tumors with mutated EGFR demonstrated gains in chromosomes 7p, 16p and 20q and losses in chromosome 8p. Interestingly, EGFR mutated tumors showed higher VEGF expression (p=0.03) while differences in EGFR expression were not statistically significant.nnnCONCLUSIONnEGFR gene mutations are frequently seen in lung adenocarcinomas with BAC differentiation and can be linked to chromosomal imbalances and increased VEGF expression.

Combined anti-PDGFRα and PDGFRβ targeting in non-small cell lung cancer

Activation of the platelet‐derived growth factor (PDGF)‐receptors is critically involved into various stromal cell functions including recruitment of stromal cells and vascular endothelial growth factor (VEGF) induction in tumor and perivascular cells. To evaluate the effects of combined PDGFRα and ‐β inhibition in a non‐small cell lung cancer model, we stably transfected A549 lung cancer cells with the PDGF‐A mutant PDGF‐0. PDGF‐0 has been generated by substituting amino acids in the binding region of PDGF‐A with the corresponding VEGF‐A region, leading to a decreased receptor‐binding affinity and activation. Compared with control vector transfected cells, transfection with PDGF‐0 had no impact on monolayer growth and apoptosis in vitro, but significantly impaired the number of colony formation in soft agar. After subcutaneous injections, all mice developed tumors within 5 days. While control vector transfected A549 cells were characterized by constant tumor growth, PDGF‐0 transfected A549 revealed a reduced tumor mass (p < 0.001) with no further growth beyond 14 days (2 months observation time) and complete regressions in 7 of 13 cases. Immunohistochemical analyses revealed that PDGF‐0 transfected tumors demonstrated decreased recruitment of periendothelial cells, while the tumor invasion zone was similar to control vector transfectants. Similarly, conditioned medium from PDGF‐0 transfected cells induced significantly less migration of smooth muscle cells and fibroblasts in vitro. Interestingly, in PDGF‐0 transfectants, neither total vessel count nor VEGF expression were significantly altered. These studies demonstrate that combined inhibition of PDGFRα and ‐β results in markedly decreased tumor growth in vivo because of impaired recruitment of periendothelial cells.

Current data on predictive markers for anti-angiogenic therapy in thoracic tumours

The fact that growth and spread of tumours are dependent on angiogenesis has led to the investigation of the role of anti-angiogenic agents in the therapeutic strategies for thoracic tumours such as nonsmall cell lung cancer or mesotheliomas. Since various angiogenic factors may contribute to the regulation of angiogenesis in the individual tumour, in the era of increasing amounts of clinically tested agents it is of utmost importance to properly select patients that may benefit from a specific therapy. Due to the complex nature of tumour angiogenesis, various biomarkers may be applicable. For example, the profile of activated angiogenic pathways in endothelial cells may be determined in order to make conclusions about the relevance of inhibiting a given pathway by a selected agent. Moreover, changes in protein expression in stromal and tumour cells, as well as structural alterations in the vasculature, may be used for predicting and monitoring the clinical effects of such a therapy. In this review, the current data from clinical studies evaluating predictive markers for anti-angiogenic agents in thoracic cancers are summarised. Besides giving clinical examples, the rationales for investigating various parameters based on pre-clinical studies are described.

Treatment and outcome of patients with metastatic NSCLC: a retrospective institution analysis of 493 patients

BackgroundMost patients with metastatic non-small cell lung cancer (NSCLC) will face treatment with systemic therapy. Current clinical studies are demonstrating improvements in chemotherapy and overall survival. However, it remains unclear whether these results are translated into clinical practice.MethodsWe reviewed all stage IV NSCLC patients without second malignancies that were diagnosed from 2004 to 2006 at our institution. 493 consecutive patients were included into this retrospective analysis and were followed-up until end of 2011.Results352 patients (71.4%) received systemic therapy for up to 7 lines. For most patients, adjustments of dosages or applications had to be made at some point of the treatment, but the total applied dose remained generally close to the intended dose. The best disease control (BDC) rate decreased with increasing therapy lines from 59.7% to about 35%. Patients with palliative local therapy but no systemic treatment demonstrated inferior survival (median 2.9 versus 8.7xa0months, pu2009<u20090.001). The median interval between last treatment and death was 50xa0days and 15xa0days for chemotherapy and anti-EGFR therapy, respectively. BDC to the previous therapy lines was predictive for improved BDC to third- but not second-line therapy. Performing multivariate analysis, BDC to previous therapy, never-/ former-smoking status, and ageu2009>u200970xa0years were associated with improved survival performing third-line therapy.ConclusionsStage IV NSCLC patients may receive substantial systemic therapy resulting in response and median survival rates that are comparable to data from clinical studies. However, preselection factors are increasingly important to improve therapy outcome and life quality.

Characteristics and outcome of patients with second primary lung cancer.

Patients with lung cancer are at risk of developing a second primary lung cancer (SPLC). However, the characteristics of patients at risk remain largely speculative. We reviewed 2816 lung cancer patients from our institution for the occurrence of SPLC. Any SPLC was categorised as synchronous when diagnosed within 2 years of the first primary lung cancer (FPLC) and after direct histological comparison of both tumours. All other SPLCs were considered as metachronous. 139 patients developed a second malignancy including 69 nonsmall cell lung cancer (NSCLC) and 9 small cell lung cancer. The median interval for diagnosis of metachronous SPLC (n=59) after FPLC occurrence was 72 months. SPLC detected within 5 years of FPLC diagnosis had a more favourable stage distribution (p=0.02). After diagnosis of SPLC, patients had a superior median overall survival compared to controls (57.7 versus 18.1 months; p<0.0001). Interestingly, comparing only stage IV NSCLC patients, a history of FPLC was also associated with a favourable survival (median 27.4 versus 8.97 months; p=0.007). In summary, previous lung cancer treatment does not lead to impaired prognosis after diagnosis of SPLC. Improved surveillance programmes beyond 5 years after FPLC treatment may result in more favourable disease stages for detected SPLC. Previous lung cancer treatment does not lead to impaired prognosis after diagnosis of secondary primary lung cancer http://ow.ly/oW5h6

Targeting the Epidermal Growth Factor Receptor in Non-Small Cell Lung Cancer

The epidermal growth factor receptor (EGFR) has been implicated in a multiplicity of cancer-related signal transduction pathways like cellular proliferation, adhesion, migration, neoangiogenesis and apoptosis inhibition, all of them important features of cancerogenesis and tumour progression. The inhibition of this receptor has been discovered as a suitable pharmaceutical intervention aimed at interrupting tumour activity. In cancer, both monoclonal antibodies and small molecules with anti-tyrosine kinase activity have been assessed in several trials with significant efficacy in clinical applications. The current review focuses in particular on the clinical data of EGFR inhibition in non-small cell lung cancer with emphasis on tyrosine kinase inhibition.

Insulin-like growth factor 1 pathway mutations and protein expression in resected non–small cell lung cancer

The purpose of this study was to characterize the prevalence of insulin-like growth factor 1 receptor (IGF1R) mutations, single nucleotide polymorphisms (SNP), and protein overexpression in surgically resected non-small cell lung cancers in relation to patient characteristics and prognosis. This retrospective study was conducted on 304 patients with non-small cell lung cancers who underwent curative pulmonary resection (median follow-up for surviving patients, 3.6 years). IGF1R gene alterations (n = 304) and protein expression (n = 181) were evaluated by polymerase chain reaction-based assays and immunohistochemistry, respectively. Membranous and cytoplasmic staining were analyzed separately. In an exploratory analysis, 1 silent mutation in exon 16 and 3 mutations in introns of the IGF1R gene comprising the tyrosine kinase domain were detected. Moreover, evaluating selected IGF1R SNPs, patients with adenocarcinomas and homozygous for the rs8038415 T-allele had a significantly better survival (P = .025) but no different disease-free survival. Regarding expression, membranous but not cytoplasmic IGF1R staining was higher in squamous cell carcinomas versus other histologies (P < .0001) and showed a trend to longer survival (P = .08). No association between SNP variations and protein expression was found. Membranous IGF1R protein expression is higher in squamous cell versus other histologies but does not correlate with prognosis. SNPs and mutations can be detected and may harbor prognostic value. These alterations may be of interest when evaluating the IGF1R as potential therapeutic target and should receive further research.

Characteristics of lung cancer after a previous malignancy.

BACKGROUNDnIn the era of improving overall survival rates of malignant diseases, the impact of a previous malignancy (PM) on treatment and outcome of lung cancer (LC) remains unclear.nnnMETHODSnWe reviewed all LC patients from our institution that were treated from 2004 to 2006 for the occurrence of LC with PM excluding patients with multiple primary LC.nnnRESULTSnA total of 444 and 2698 LC patients with and without a history of a PM were identified (prevalence of 14.1%). PM were most often located in breast (15.5%), prostate (14.9%), bladder (9.0%) and kidney (8.8%). Compared to never smokers, patients with nicotine consumption had more often a cancer history of prostate, gastrointestinal, and the head-neck region. The median interval until diagnosis of LC was 72.2 months (range 0-537 months) with most LC diagnosed 5 years after PM diagnosis. With a similar distribution of histology, stage and localization compared to controls, NSCLC patients with PM and stage IV disease showed a favorable overall survival (p < 0.0001). In contrast, SCLC patients had similar survival curves (n.s.).nnnCONCLUSIONSnA considerable subgroup of LC patients has a history of PM that may indicate a favorable prognostic factor. However, these patients should be treated similar to other LC patients.