On target: Rational approaches to KRAS inhibition for treatment of non-small cell lung carcinoma

Non-small cell lung carcinoma (NSCLC) is a leading cause of cancer death. Approximately one-third of patients with NSCLC have a KRAS mutation. KRASG12C, the most common mutation, is found in ~13% of patients. While KRAS was long considered 'undruggable', several novel direct KRASG12C inhibitors have shown encouraging signs of efficacy in phase I/II trials and one of these (sotorasib) has recently been approved by the US Food and Drug Administration. This review examines the role of KRAS mutations in NSCLC and the challenges in targeting KRAS. Based on specific KRAS biology, it reports exciting progress, exploring the use of novel direct KRAS inhibitors as monotherapy or in combination with other targeted therapies, chemotherapy, and immunotherapy

Pain outcomes in patients with bone metastases from advanced cancer: assessment and management with bone-targeting agents

Bone metastases in advanced cancer frequently cause painful complications that impair patient physical activity and negatively affect quality of life. Pain is often underreported and poorly managed in these patients. The most commonly used pain assessment instruments are visual analogue scales, a single-item measure, and the Brief Pain Inventory Questionnaire-Short Form. The World Health Organization analgesic ladder and the Analgesic Quantification Algorithm are used to evaluate analgesic use. Bone-targeting agents, such as denosumab or bisphosphonates, prevent skeletal complications (i.e., radiation to bone, pathologic fractures, surgery to bone, and spinal cord compression) and can also improve pain outcomes in patients with metastatic bone disease. We have reviewed pain outcomes and analgesic use and reported pain data from an integrated analysis of randomized controlled studies of denosumab versus the bisphosphonate zoledronic acid (ZA) in patients with bone metastases from advanced solid tumors. Intravenous bisphosphonates improved pain outcomes in patients with bone metastases from solid tumors. Compared with ZA, denosumab further prevented pain worsening and delayed the need for treatment with strong opioids. In patients with no or mild pain at baseline, denosumab reduced the risk of increasing pain severity and delayed pain worsening along with the time to increased pain interference compared with ZA, suggesting that use of denosumab (with appropriate calcium and vitamin D supplementation) before patients develop bone pain may improve outcomes. These data also support the use of validated pain assessments to optimize treatment and reduce the burden of pain associated with metastatic bone disease

Thymidylate synthase expression and mismatch repair protein expression in colorectal cancer

The tumour, node, metastasis (TNM) system, with the current staging and risk stratification methods for prognostication in colorectal cancer (CRC) has its limitations. The need for additional validated prognostic and predictive markers is particularly important in CRC stage II and III as some of these patients can be cured by surgery alone. In international tumour marker guidelines there is still not enough evidence to recommend the routine use of any tissue-based tumour markers in the treatment or surveillance of CRC. The problems are that the majority of studies evaluating tumour markers lack standardized methods for assessment, are non-randomized and involve a limited number of patients. Another main concern is the intrapatient heterogeneity of a certain tumour marker between the primary tumour and the corresponding metastases and even between different metastatic sites. Two potential prognostic and predictive markers are: 1) Thymidylate synthase (TS), a rate-limiting enzyme involved in DNA synthesis and the target enzyme for 5-Fluorouracil (5-FU), which is the standard treatment used in CRC. 2) Microsatellite instability (MSI), the hallmark of a defective DNA mismatch repair (MMR) that occurs in about 15 % of sporadic colorectal cancer (CRC). In this thesis we have compared the expression of TS assessed with immunohistochemistry (IHC) in lymph node metastases as well as lung- and liver metastases of CRC with TS expression in matched primary tumours. Furthermore, we have evaluated the prognostic and predictive role of TS expression and MMR protein expression using IHC in stage II and III CRC. A significant correlation was found between expression of TS in lymph node metastases and TS expression in their matched primary tumours. TS expression assessed in lymph node metastases did significantly improve the prognostic precision compared with TS expression in primary tumours but did not predict response to 5-FU-based adjuvant chemotherapy. A low TS expression in lymph node metastases was associated with a longer OS and DFS. TS expression was analyzed in liver metastases (n=38) and lung metastases (n=10) as well as in their matched primary tumours (n=45) There was no significant correlation between TS expression in distant metastases and their matched primary tumours. A tendency to a higher TS expression was seen in liver metastases (84%) compared to lung metastases (70%). TS expression was a significant prognostic marker in patients treated with surgery alone where an improved survival was found in patients with a low TS. Patients with the highest TS expression (grade 3) had a significantly improved survival when treated with adjuvant 5-FUbased chemotherapy independently of the dose of 5-FU. MMR protein expression was found to be a significant prognostic marker for survival in univariate analysis as well as in multivariate analysis adjusted for gender, age, grade of differentiation, stage of disease and numbers of analyzed lymph nodes. Patients with MMR protein negative tumours had an improved survival compared to patients with MMR protein positive tumours. MMR protein expression did not predict benefit of adjuvant 5-FU-based chemotherapy with respect to survival. In a combined analysis no significant correlation was revealed between MMR protein expression and TS expression in colon cancer. There was a significantly improved survival in stage III patients with MMR protein positive colon tumours expressing high TS when receiving adjuvant 5-FU-based chemotherapy compared to treatment with surgery alone. It is questionable whether a single molecular marker may play a relevant prognostic and predictive role in a complex and heterogenous disease such as CRC. In the future we rather have to define different subtypes of CRC based on molecular, clinical and morphological features in order to tailor the optimal treatment for each individual patient maximizing the therapeutic effects whilst minimizing toxicity

Real-world use of talimogene laherparepvec in Germany: a retrospective observational study using a prescription database

Aim: There is a growing body of data on real-world use of talimogene laherparepvec (T-VEC). We aimed to characterize real-world T-VEC use using a nationally representative German prescription database covering 60% of prescriptions reimbursed. Patients & methods: A retrospective analysis was conducted using the German IMS (R) LRx prescription database, analyzing patients aged >= 18 years with an initial T-VEC prescription at 10(6) plaque-forming units (PFU)/ml and >= 1 subsequent prescription at 10(8) PFU/ml. Median time on T-VEC treatment, patient characteristics and patterns of T-VEC use were described. Results: Of 127 patients prescribed T-VEC, 72 patients (57%) met study criteria. About two-thirds of these patients initiated T-VEC in 2017. Median age at T-VEC initiation was 74 years (range: 44 to 91). Most prescriptions (88%) were dispensed from hospitals. At study end, 26 (36%) patients remained on T-VEC; 46 (64%) had ended treatment. Median duration of T-VEC treatment for all patients was 18.7 weeks (95% CI: 15.3-26.9) and was longer among those who initiated treatment in 2017 versus 2016 (26.7 vs 15.6 weeks, respectively). Median volume administered for the first 10(6) PFU/ml and second 10(8) PFU/ml was 4 ml; the volume decreased for subsequent administrations (2 ml by the eighth administration and 1 ml by the 16th administration). Conclusion: This real-world prescription database study showed that patients who initiated treatment in 2017 had a treatment duration in clinical practice that corresponded with the European Summary of Product Characteristics guideline of continuing T-VEC for >= 6 months. Additional long-term data linking drug use with clinical outcomes are needed

Practical clinical guide on the use of talimogene laherparepvec monotherapy in patients with unresectable melanoma in Europe

Talimogene laherparepvec, a herpes simplex virus type 1-based intralesional oncolytic immunotherapy, is approved in Europe for the treatment of adults with unresectable stage IIIB-IVM1a melanoma, with no bone, brain, lung or other visceral disease. It has direct oncolytic effects in injected lesions, leading to the release of tumour-derived antigens and systemic immune effects mediated by the induction of anti-tumour immunity, which is enhanced by the production of granulocyte macrophage colony-stimulating factor. Responses (which occur in >40% of stage IIIB-IVM1a patients) are often durable (>50% last ≥6 months) and occur in injected and uninjected lesions (in stage IIIB-IVM1c patients, 64%/34% of evaluable injected/uninjected non-visceral lesions, respectively, decreased in size by ≥50%). As with other immunotherapies, responses may be delayed or can arise after pseudoprogression. The pattern of treatment-emergent adverse events is distinct, being mostly grade 1/2, easy to manage, and rarely leading to treatment discontinuation. Systemic therapy represents the backbone of care for many metastatic melanoma patients. Nonetheless, the potential for durable locoregional control with a locally injected agent may make talimogene laherparepvec suitable for selected patients with stage IIIB/C disease, for whom surgery is not possible (e.g. with in-transit metastases, multiple melanoma lesions at different body sites, or those relapsing rapidly after repeated rounds of surgery) and slowly progressing disease. Here, we discuss which patients could be suitable for talimogene laherparepvec monotherapy based on the European indication, review the patterns/timing of response, and discuss the incidence/management of adverse events. Its potential use combined with immune checkpoint inhibitors is also discussed

Pain outcomes in patients with bone metastases from advanced cancer: assessment and management with bone-targeting agents

Bone metastases in advanced cancer frequently cause painful complications that impair patient physical activity and negatively affect quality of life. Pain is often underreported and poorly managed in these patients. The most commonly used pain assessment instruments are visual analogue scales, a single-item measure, and the Brief Pain Inventory Questionnaire-Short Form. The World Health Organization analgesic ladder and the Analgesic Quantification Algorithm are used to evaluate analgesic use. Bone-targeting agents, such as denosumab or bisphosphonates, prevent skeletal complications (i.e., radiation to bone, pathologic fractures, surgery to bone, and spinal cord compression) and can also improve pain outcomes in patients with metastatic bone disease. We have reviewed pain outcomes and analgesic use and reported pain data from an integrated analysis of randomized controlled studies of denosumab versus the bisphosphonate zoledronic acid (ZA) in patients with bone metastases from advanced solid tumors. Intravenous bisphosphonates improved pain outcomes in patients with bone metastases from solid tumors. Compared with ZA, denosumab further prevented pain worsening and delayed the need for treatment with strong opioids. In patients with no or mild pain at baseline, denosumab reduced the risk of increasing pain severity and delayed pain worsening along with the time to increased pain interference compared with ZA, suggesting that use of denosumab (with appropriate calcium and vitamin D supplementation) before patients develop bone pain may improve outcomes. These data also support the use of validated pain assessments to optimize treatment and reduce the burden of pain associated with metastatic bone disease