Nephrotic syndrome induced by cetuximab in a patient with metastatic colorectal cancer

Introduction Cetuximab, an anti-EGFR monoclonal antibody, often cause skin toxicity, most commonly acneiform rash. We present a rare case of glomerulonephritis associated with cetuximab therapy. Case Report A 58-year-old male patient recently completed cetuximab-based chemotherapy for metastatic colorectal adenocarcinoma. He presented with acute renal failure, anasarca edema and nephrotic proteinuria. The amount of protein in the 24-h urine test was over 15.6 grams. Management & Outcome The patient showed a dramatic improvement in renal function shortly after terminated of cetuximab therapy without immunosuppressive therapy. Discussion Therefore, drugs targeting epidermal growth factor receptor (EGFR) monoclonal antibody were thought to trigger nephrotic syndrome by causing glomerular damage. As a result, physicians using EGFR monoclonal inhibitors should be very careful about renal functions and proteinuria in patients.

Management of acneiform rash associated with anti-EGFR monoclonal antibody treatment

Introduction. Dermatologic adverse events (DAEs) occur in 50-90% of cases during anti-EGFR monoclonal antibody treatment. Positive correlation between the severity of acneiform rash (AR) and the effectiveness of anti-EGFR management is established. Low effectiveness of traditional treatment for AR impairs patients’ compliance, leads to dose reduction or drug discontinuation, affecting treatment results.Objective. To assess the effectiveness of traditional and proposed combined treatment for AR associated with anti-EGFR monoclonal antibody therapy.Materials and methods. 44 patients with grade I-II acneiform rash were included in a 12-week study. Patients were divided into 3 equal groups and received different treatment: group 1a – traditional therapy, group 1b – combined continuous therapy, and group 1c – combined intermittent therapy. Assessment of clinical outcomes was performed with DLQI, IGA score, and the NCI CTCAE v. 4.03.Results. The severity of AR in groups 1b and 1c improved by the end of week 1, and this trend was kept until the end of the study. The improvement was more prominent in group 1c comparing to group 1b. The severity of AR in group 1a improved by the end of week 1. During weeks 2 and 3 there was no significant change. At week 4 a deterioration of the evaluated parameters was registered, and the treatment regimen in group 1a was changed according to the treatment protocols of group 1c with rapid improvement of AR.Conclusion. Combined intermittent therapy with systemic doxycycline and topical therapy with metronidazole 1% gel and cream with hydrocortisone acetate 1% and fusidic acid 2% showed the best effectiveness and tolerability in patients with anti-EGFR monoclonal antibody-related AR.

Prevention and therapy of acne-like rash in cancer patients receiving therapy with EGFR receptor inhibitors

Cancer chemotherapy advanced dramatically. The success in the management of a broad spectrum of malignancies was achieved due to the development of targeted chemotherapeutic drugs, such as inhibitors of the epidermal growth factor receptor (iEGFR). The most common dermatologic side effect of iEGFR therapy is an acneiform rash that occurs in 60–80 % of patients. This adverse event develops during the first 2 weeks of treatment with iEGFR. Diagnostics of acneiform rash may be complicated because of different interpretations by oncologists and dermatologists. Acneiform rash is frequently associated with pain and itch. Skin toxicity affects a patient’s quality of life, including physical and psychological well-being, emotional and social adaptation, may lead to dose reduction and iEGFR discontinuation. The degree of acneiform rash correlates with an iEGFR effectiveness, which is currently confirmed by different data. Thus, the prevention and prompt management of dermatologic adverse events is a pressing issue because they influence the anti-cancer treatment prognosis. This article reviews the current recommendations on the prevention and management of iEGFR associated acneiform rash. The authors present their own clinical case of a patient with acneiform rash during panitumumab (monoclonal antibody against EGFR) therapy.

LGG-04. A PHASE II RE-TREATMENT STUDY OF SELUMETINIB FOR RECURRENT OR PROGRESSIVE PEDIATRIC LOW-GRADE GLIOMA (pLGG): A PEDIATRIC BRAIN TUMOR CONSORTIUM (PBTC) STUDY

The PBTC conducted a re-treatment study (NCT01089101) evaluating selumetinib (AZD6244, ARRY-142886), a MEK I/II inhibitor, in children with recurrent/progressive pLGG. Eligible patients must have previously enrolled on PBTC-029 or PBTC-029B and progressed after coming off treatment with selumetinib. Patients must have maintained stable disease (SD) for ≥12 courses or had a sustained radiographic response (partial or complete) during their first exposure to selumetinib. Thirty-five eligible patients (median age: 13.11 years [range 7.96–25.33]) were enrolled, 57% of whom had optic pathway or hypothalamic target lesions. At the time of submission, median duration of treatment was 18 courses (range 2–48) and 21 subjects remained on therapy. Best responses reported to date are 6/35 (17%) partial response, 22/35 (63%) SD and 7/35 (20%) progressive disease with a 2-year progression-free survival of 75.7 + 8.3%, which met the design parameters for success. The most common attributable toxicities were grade 1 diarrhea, elevated AST, hypoalbuminemia, elevated CPK, maculo-papular rash, fatigue, paronychia, ALT elevation, acneiform rash and grade 2 CPK elevation. Rare grade 3 toxicities included CPK elevation (3), lymphopenia (2), paronychia (2) and ALT elevation (2). There was only one grade 4 CPK elevation. Five patients (14%) required dose reductions due to toxicity. There does not appear to be a notable difference in toxicities observed during initial selumetinib therapy versus re-treatment. In pLGG that has recurred/progressed following treatment with selumetinib, re-treatment with selumetinib appears to be effective with 80% of patients again achieving response or prolonged stable disease. Long-term follow-up is ongoing.

Results of the non-small cell lung cancer part of a phase III, open-label, randomized trial evaluating topical corticosteroid therapy for facial acneiform dermatitis induced by EGFR inhibitors: stepwise rank down from potent corticosteroid (FAEISS study, NCCH-1512)

Purpose This FAEISS study was designed to confirm the superior efficacy of reactive topical corticosteroid strategies employing serially ranking-DOWN from very strong steroid levels for the treatment of facial acneiform rash induced by epidermal growth factor receptor (EGFR) inhibitors (EGFRIs), in comparison with strategies employing serially ranking-UP from weak steroid levels. This article reports the primary results of the non-small cell lung cancer (NSCLC) part of the trial. Methods Patients with EGFR-mutated advanced NSCLC treated with erlotinib or afatinib were enrolled in the first registration. All patients received preemptive therapy with oral minocycline and heparinoid moisturizer from the initiation of an EGFR inhibitor. Enrolled patients who developed facial acneiform rash within 2 weeks were randomized at second registration to either a ranking-UP (WEAK) group or a ranking-DOWN group. The primary endpoint was incidence of grade ≥ 2 facial acneiform rash over 8 weeks. Results Fifty-one patients were enrolled at the first registration and received EGFRIs (n = 30 for afatinib, n = 21 for erlotinib). However, 35 patients did not develop facial acneiform rash within 2 weeks; one patient discontinued preemptive treatment. Fifteen patients (29.4%) were enrolled in the second registration; nine were assigned to the WEAK group and six to the DOWN group. There was no significant difference in the incidence of grade ≥ 2 facial acneiform rash between the WEAK group (one patient, twice) and the DOWN group (one patient, twice; p = 0.8417). No patients developed severe facial acneiform rash within 10 weeks. Conclusion In NSCLC patients who received EGFRIs, preemptive therapy of oral minocycline and heparinoid moisturizer reduced facial acneiform rash incidence. Trial registration UMIN000024113

Topical aloe vera for the treatment of cetuximab-related acneiform rash in colorectal cancer: A case report

Introduction Colorectal cancer is one of the most common cancers in the world. Cetuximab is an epidermal growth factor receptor (EGFR) inhibitor which provides survival benefit when combined with chemotherapy in RAS wild type metastatic colorectal cancer. Cutaneous toxicities associated with cetuximab have a significant impact on patient quality of life, treatment continuation and healthcare resource utilization. Case report A 60-year-old male patient presented with fatigue, weight loss and abdominal pain. Two closely located malignant polypoid lesions were detected in the sigmoid colon, and pathological examination revealed colonic adenocarcinoma. Management and outcome: Thorax, abdominal and pelvic computed tomography showed metastases. FOLFOX chemotherapy and cetuximab were started. The patient developed acneiform rash firstly in his face, although prophylactic vitamin K1 0.1% containing cream was given. He was given mild potency topical corticosteroid and doxycycline. The lesions progressed to his front and back body. He did not want to use topical vitamin K1 cream, topical steroid and doxycycline tablets. Instead, he wanted to use aloe vera extract which he produced from the leaves of the plant. Patient’s lesions were regressed significantly. Discussion The most common and earliest skin toxicity is acneiform rash which affects 60 to 80% of the patients. In this case, cetuximab-related severe acneiform rash was effectively treated by topical aloe vera. Topical aloe vera may be used in the management of cetuximab-related cutaneous toxicities without any side effect.

The skin types closely related to development of the facial acneiform rash and the therapeutic effects of EGFR inhibitors in RAS wild-type metastatic colorectal cancer: Ancillary analysis of FAEISS study.

3637 Background: At ESMO2019, we reported the primary results of a randomized controlled trial (FAEISS study) investigating the efficacy of topical corticosteroid treatment to facial acneiform rash (AR) by EGFR inhibitors comparing groups starting with a very strong topical corticosteroid and the standard weak topical corticosteroid. As an ancillary analysis, we investigated the association between AR and the pre-treatment skin types, as well as between the skin types and therapeutic effects of EGFR inhibitors on the primary disease. Methods: Utilizing pre-treatment clinical photos of the face taken according to the method determined by FAEISS study protocol, we divided the skin types into categories including enlarged pore, oiliness, xerosis, wrinkles, skin color/redness, and allocated the score (1-3) by central review. The severity of AR occurred during the study was graded and was evaluated the association with the specific skin type by Fisher’s exact test. We also investigated the association between the skin types and the best overall response (RECISTv1.1) to EGFR inhibitor therapy on the primary disease using the Cochran-Armitage trend test. Results: Of the registered 172 cases of RAS wild-type metastatic colorectal cancer [104 men and 68 women, median age = 68 (26-79)], omitting the cases with unevaluable data, finally we analyzed 146 cases for associations between the skin types and AR and 147 cases for best overall response. Interestingly, AR developed 13.6% of enlarged pore score 1, 29% of score 2 and 45.8% of score 3, and patients with enlarged pore tended to have more AR (p = 0.058). Surprisingly, the response(CR/PR/SD) of the primary disease were 59.1% of the enlarged pore score 1, 70.6% of score 2 and 87.0% of score 3, and showed statistically significant trend(p < 0.038). Conclusions: This study suggested that a skin type (enlarged pore) is a possible marker predicting AR risk in EGFR inhibitor therapy for RAS wild-type metastatic colorectal cancer, and better therapeutic effects of EGFR inhibitors.

A phase II study of durvalumab (MEDI4736) (anti-PD-L1) and trametinib (MEKi) in microsatellite stable (MSS) metastatic colorectal cancer (mCRC).

152 Background: Monotherapy with immune checkpoint blockade (ICB) is ineffective for patients (pts) with MSS mCRC. Novel approaches to modulate the tumor microenvironment (TME) are needed. Here, we investigate whether the combination of trametinib (T) with durvalumab (D) can alter the immune TME by successfully priming and activating T-cells. Methods: An open-label, single center phase II trial with primary endpoint of immune-related response rate for T+D in refractory MSS mCRC pts (NCT03428126). T is 2mg/day orally starting 1 week prior to D, which is given 1500mg intravenously every 4 weeks. Dose de-escalation strategy performed to identify maximum tolerated dose (MTD). Simon 2-stage design utilized with plans to enroll 29 pts into the first stage, requiring response in 2 or more pts to proceed to stage 2 (n = 15). Results: Demographics for 29 treated pts: 48% female, median age 48 years (range 28-75), and median prior therapies was 2 (range 1-5). No grade (G) 4 treatment-related adverse events (TRAE). The most common G3 TRAE included autoimmune hepatitis (14%) and acneiform rash (10%). G1/2 TRAE included acneiform rash (69%), fatigue (24%) and anemia (21%). No fatal TRAE and 4 pts discontinued treatment due to TRAE. 1 of 29 pts had confirmed partial response (PR) lasting 9.3 months (mo) for an ORR of 3.4%. This pt had an ATM E221fs*14 mutation. 7 pts had stable disease (SD) with median time to progression (TTP) of 5.4 mo (range 3.9-9.3 mo). 1 pt remains on active therapy with SD ( > 10 mo). 5 pts (1 PR, 4 SD) demonstrated decrease in total CEA ng/mL (best percentage reduction: 94%, 95%, 42%, 34% and 21.6% respectively). Median TTP for the entire cohort was 3.2 mo (range 1.1-9.3 mo). Consensus molecular subtypes (CMS) were performed on the primary CRC in 23 pts: 12 CMS2, 2 CMS3, and 9 CMS4. 4 SD pts were CMS2, 1 SD pt was CMS4 and the CMS status of the pt with a PR was unknown. Conclusions: The combination of T+D did not meet efficacy criteria to proceed to the second stage of the study. Analysis of 15 paired on-treatment biopsies is ongoing and will be presented. Utilization of CMS characterization in mCRC clinical trials is feasible and may provide an improved biological understanding of treatment activity. Clinical trial information: NCT03428126.