The potential of altering the tumor ECM to improve drug response remains fairly unexplored. To identify targets for modification of the ECM aiming to improve drug response and overcome resistance, we analyzed expression data sets from pre-treatment patient cohorts. Cross-evaluation identified a subset of chemoresistant tumors characterized by increased expression of collagens and collagen-stabilizing enzymes. We demonstrate that strong collagen expression and stabilization sets off a vicious circle of self-propagating hypoxia, malignant signaling, and aberrant angiogenesis that can be broken by an appropriate auxiliary intervention: Interfering with collagen stabilization by inhibition of lysyl oxidases significantly enhanced response to chemotherapy in various tumor models, even in metastatic disease. Inhibition of collagen stabilization by itself can reduce or enhance tumor growth depending on the tumor type. The mechanistical basis for this behavior is the dependence of the individual tumor on nutritional supply on one hand and on high tissue stiffness for FAK signaling on the other.

Tumors are characterized by a rigid, highly cross-linked extracellular matrix (ECM), which impedes homogeneous drug distribution and potentially protects malignant cells from exposure to therapeutics. Lysyl oxidases are major contributors to tissue stiffness and the elevated expression of these enzymes observed in most cancers might influence drug distribution and efficacy. We examined the effect of lysyl oxidases on drug distribution and efficacy in 3D in vitro assay systems. In our experiments elevated lysyl oxidase activity was responsible for reduced drug diffusion under hypoxic conditions and consequently impaired cytotoxicity of various chemotherapeutics. This effect was only observed in 3D settings but not in 2D-cell culture, confirming that lysyl oxidases affect drug efficacy by modification of the ECM and do not confer a direct desensitizing effect. Both drug diffusion and efficacy were strongly enhanced by inhibition of lysyl oxidases. The results from the in vitro experiments correlated with tumor drug distribution in vivo, and predicted response to therapeutics in murine tumor models. Our results demonstrate that lysyl oxidase activity modulates the physical barrier function of ECM for small molecule drugs influencing their therapeutic efficacy. Targeting this process has the potential to significantly enhance therapeutic efficacy in the treatment of malignant diseases.

550 Background: Pmab monotherapy significantly improves progression-free survival versus best supportive care in pts with chemorefractory KRAS wild-type (WT) mCRC. This study evaluated the efficacy and safety of pmab in routine clinical practice in Germany. Methods: To ensure a representative sample, eligibility criteria were largely unrestricted. Consenting pts were >18 years old, had histologically confirmed KRAS WT mCRC, >4 weeks pmab therapy, failure of fluoropyrimidine-, oxaliplatin- and irinotecan-containing chemotherapy (CTx) regimens, and women of child-bearing age received contraception. Predefined endpoints were overall response rate (ORR; investigator`s assessment) and skin toxicity (NCI Common Terminology Criteria for Adverse Events v3.0). Results: A total of 428 pts were included in the full analysis set. At the start of pmab therapy, median age was 69 (range 22-89) years, 268 pts (63%) were male and 343 (80%) had an ECOG performance status of 0-1. Overall, 400 pts (93%) had undergone prior surgery and 154 (36%) had received ≥1 cycle of adjuvant CTx. Pts had received a median of 3 cycles (range: 1‑12) of prior CTx for mCRC. The most common regimens were FOLFOX/FOLFIRI ±antibody therapy; 65% of regimens were given with palliative, 32% with curative/palliative and 3% with curative intent. The median pmab dose was 6 mg/kg (range 2.4-7.2) q2w for a median of 8 (range 2‑45) cycles, with 143 pts (33%) receiving >10 cycles. The ORR during pmab therapy was 20% (complete response: n=7 [2%]; partial response: n=77 [18%]); disease control (including stable disease) was achieved in 261 pts (61%). Skin reactions occurred in 324 pts (67%) with 52% experiencing a maximum grade ≥2. Most pts had some type of rash (48% acne, 5% desquamation, 4% hand-foot skin reaction, 1% erythema multiforme). Overall, 21% of pts had other toxicities. Three serious adverse drug reactions (infection/fever; thrombosis/embolism; erythema multiforme) and two grade 1 infusion reactions were reported. Conclusions: In this observational study, pmab monotherapy had efficacy at least as good as was seen in the randomised pmab trial and safety was also similar.

IntroductionThis study aimed to better understand panitumumab use in real-life clinical practice in first- and second-line treatment of metastatic colorectal cancer in five European countries.MethodsThis is a combined analysis of two observational, non-interventional prospective cohort studies, one of which was conducted in Germany and France, the other in Bulgaria, Czech Republic, and Hungary. The studies observed patients with wild-type [Kirsten] rat sarcoma viral oncogene homolog ([K]RAS/RAS) metastatic colorectal cancer (mCRC), who had been treated with panitumumab in combination with fluorouracil, leucovorin, and oxaliplatin (FOLFOX) in the first line or with panitumumab combined with fluorouracil, leucovorin, and irinotecan (FOLFIRI) in the second line following fluoropyrimidine-based chemotherapy. The planned duration of observation was 12 months from the first dose of panitumumab.ResultsA total of 332 patients treated with panitumumab + FOLFOX in the first line and 94 patients treated with panitumumab + FOLFIRI in the second line were analyzed. The median number of panitumumab infusions was 10.0 in first-line FOLFOX patients and 11.5 in second-line FOLFIRI patients; the median duration of panitumumab exposure was 5.7 and 6.9 months, respectively. The unadjusted overall response rate (complete or partial response) in patients with available post-baseline response assessment (n = 290) was 51.7% in first-line FOLFOX and 44.9% in second-line FOLFIRI patients. In the first-line setting, resectability was achieved in 9.3%. Reported hospitalizations were mostly cancer-related visits such as scheduled anticancer treatment administrations, tumor assessment visits, or interventions. The majority of adverse drug reactions were skin disorders, with 75.3% in first-line FOLFOX patients and 72.3% in second-line FOLFIRI patients.ConclusionOverall, the study results show that treatment patterns, clinical efficacy, and the safety profile of panitumumab in routine clinical practice were comparable to those in randomized controlled trials. The relatively low skin toxicity rate could be attributed to increasing experience in managing panitumumab-associated rash and some degree of underreporting.FundingAmgen.Electronic supplementary materialThe online version of this article (10.1007/s12325-019-0874-6) contains supplementary material, which is available to authorized users.

Patients treated with DA in routine clinical practice had increases in Hb and reported improvement in QoL. Due to the uncontrolled design, no conclusions can be made regarding causality to treatment and the clinical relevance of the improvement.