Clive Mulatero

Phase III Trial of Vandetanib Compared With Erlotinib in Patients With Previously Treated Advanced Non–Small-Cell Lung Cancer

PURPOSE Vandetanib is a once-daily oral inhibitor of vascular endothelial growth factor receptor and epidermal growth factor receptor signaling. This phase III study assessed the efficacy of vandetanib versus erlotinib in unselected patients with advanced non-small-cell lung cancer (NSCLC) after treatment failure with one to two prior cytotoxic chemotherapy regimens. PATIENTS AND METHODS One thousand two hundred forty patients were randomly assigned to receive vandetanib 300 mg/d (n = 623) or erlotinib 150 mg/d (n = 617). The primary objective was to show superiority in progression-free survival (PFS) for vandetanib versus erlotinib. If the difference did not reach statistical significance for superiority, a noninferiority analysis was conducted. RESULTS There was no significant improvement in PFS for patients treated with vandetanib versus erlotinib (hazard ratio [HR], 0.98; 95.22% CI, 0.87 to 1.10; P = .721); median PFS was 2.6 months for vandetanib and 2.0 months for erlotinib. There was also no significant difference for the secondary end points of overall survival (HR, 1.01; P = .830), objective response rate (both 12%), and time to deterioration of symptoms for pain (HR, 0.92; P = .289), dyspnea (HR, 1.07; P = .407), and cough (HR, 0.94; P = .455). Both agents showed equivalent PFS and overall survival in a preplanned noninferiority analysis. Adverse events (AEs; any grade) more frequent with vandetanib than erlotinib included diarrhea (50% v 38%, respectively) and hypertension (16% v 2%, respectively); rash was more frequent with erlotinib than vandetanib (38% v 28%, respectively). The overall incidence of grade ≥ 3 AEs was also higher with vandetanib than erlotinib (50% v 40%, respectively). CONCLUSION In patients with previously treated advanced NSCLC, vandetanib showed antitumor activity but did not demonstrate an efficacy advantage compared with erlotinib. There was a higher incidence of some AEs with vandetanib.

Outcome and Biomarker Analysis from a Multicenter Phase 2 Study of Ipilimumab in Combination with Carboplatin and Etoposide as First-Line Therapy for Extensive-Stage SCLC

Objectives: Our aim was to evaluate the safety and efficacy of ipilimumab combined with standard first‐line chemotherapy for patients with extensive‐stage SCLC. Methods: Patients with chemotherapy‐naive extensive‐stage SCLC were treated with carboplatin and etoposide for up to six cycles. Ipilimumab, 10 mg/kg, was given on day 1 of cycles 3 to 6 and every 12 weeks. Response was assessed by the Response Evaluation Criteria in Solid Tumors (RECIST), version 1.0, and immune‐related response criteria. The primary end point was 1‐year progression‐free survival (PFS) according to RECIST. Secondary end points included PFS according to immune‐related PFS and overall survival. Autoantibody serum levels were evaluated and correlated with clinical outcomes. Results: A total of 42 patients were enrolled between September 2011 and April 2014; 39 were evaluable for safety and 38 for efficacy. Six of 38 patients (15.8% [95% confidence interval (CI): 7.4–30.4]) were alive and progression‐free at 1‐year by RECIST. Median PFS was 6.9 months (95% CI: 5.5–7.9). Median immune‐related PFS was 7.3 months (95% CI: 5.5–8.8). Median overall survival was 17.0 months (95% CI: 7.9–24.3). Of the patients evaluable for response, 21 of 29 (72.4%) achieved an objective response by RECIST and 28 of 33 (84.8%) achieved an objective response by the immune‐related response criteria. All patients experienced at least one adverse event; at least one grade 3 or higher toxicity developed in 35 of 39 patients (89.7%); in 27 patients (69.2%) this was related to ipilimumab. Five deaths were reported to be related to ipilimumab. Positivity of an autoimmune profile at baseline was associated with improved outcomes and severe neurological toxicity. Conclusions: Ipilimumab in combination with carboplatin and etoposide might benefit a subgroup of patients with advanced SCLC. Autoantibody analysis correlates with treatment benefit and toxicity and warrants further investigation.

Ipilimumab-induced colitis: experience from a tertiary referral center

Background: Ipilimumab is an anticytotoxic T-lymphocyte antigen-4 (CTLA-4) monoclonal antibody used for the treatment of malignant melanoma. It can cause immune-mediated inflammatory adverse events, including diarrhoea and even intestinal perforation or death in clinical trials but there is a dearth of data on postmarketing outcomes. Methods: A total of 546 patients attending for treatment of metastatic melanoma between 1 January 2009 and 31 August 2015 were identified by interrogation of the oncology database. A total of 83 of these patients received ipilimumab. Clinical information was extracted from chart reviews, endoscopy and radiology reports, and prescription data. Results: A total of 83 patients received ipilimumab. Only 19.3% (n = 16) of patients developed a diarrhoeal illness not attributable to other causes. The median grade of diarrhoea among included patients was 2 (range 1–4). In two cases, diarrhoea settled spontaneously without any specific treatment. A total of 87.5% of patients received antidiarrhoeal agents such as loperamide or codeine. These resolved symptoms in all patients with grade 1 diarrhoea. For other treatment, 50% patients received systemic glucocorticosteroids and 31.3% required infliximab. Infliximab resolved symptoms in 100% of cases compared with 50% for systemic glucocorticosteroids. Conclusions: The rate of diarrhoea related to ipilimumab in real-world practice is substantial, but below the range observed in data from RCTs. Grade 1 colitis can usually be managed symptomatically, without recourse to stopping ipilimumab. When diarrhoea was grade 2 or above, results from glucocorticosteroids use proved disappointing; but infliximab has been shown to work well. Further research is required into the earlier use of infliximab as an effective treatment for ipilimumab-induced diarrhoea.

Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH) masquerading as metastatic carcinoma with multiple pulmonary deposits

Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH) is a rare pulmonary disorder presenting with multiple pulmonary nodules in association with a typical mosaic perfusion pattern on computed tomography. In this case, the absence of mosaic perfusion led to an erroneous initial diagnosis of pulmonary metastases from an unknown primary malignancy. This illustrates the importance of considering differential diagnoses when presented with imaging findings compatible with pulmonary metastases from an unknown primary, and highlights the importance of histopathologic confirmation in such cases.

Abstract CT106: A phase I/IIa study of IMCgp100: Partial and complete durable responses with a novel first-in-class immunotherapy for advanced melanoma

Proceedings: AACR 106th Annual Meeting 2015; April 18-22, 2015; Philadelphia, PA Background: IMCgp100 is an affinity-enhanced T cell receptor (TCR) specific for the HLA-A2 restricted melanoma gp100 peptide (YLEPGPVTA) fused to an anti-CD3 antibody fragment. Binding of IMCgp100 to melanoma cells redirects T cell cytotoxicity even in the presence of significant levels of PD-1 and PD-L1. Due to its high affinity, IMCgp100 enables T cells to kill HLA down-regulated melanoma cells otherwise invisible to natural T cell recognition. During phase I dose escalation of a weekly schedule, the Maximum Tolerated Dose (MTD) was 600ng/kg or 50mcg absolute dose. An expanded cohort is accruing at the MTD, and a second dose escalation was initiated to determine the MTD, toxicity and potential activity of a daily x 4 q3w schedule. Methods: Patients enrolled are HLA A2 positive, stage IV or unresectable stage III melanoma, with an ECOG Performance Status (PS) ≤1 and a lymphocyte count of ≥0.5×109/L. The phase II expansion of weekly dosing has a target of 10 patients; accrual will continue until a trio of evaluable biopsies are available from at least six patients. Dose escalation for the daily x 4 q3w regimen began at 10mcg/daily. One cycle is 6 weeks. Results: 16 patients have been treated weekly at MTD (600ng/kg or 50mcg). 63% were male, median age 58 yrs, ECOG PS 0 in 56%. All but one patient had stage IV disease. 63% of patients received ≥2 prior systemic therapies; some patients had prior ipilimumab (56%), RAFi (31%) and anti-PD1 or other immunotherapies (13%). Two patients were subsequently shown to be gp100 negative by IHC. Common toxicities included transient grade 3 pruritic rash and grade 2 pyrexia/edema. Lymphocytes migrated to skin and tumor as evidenced by biopsy analysis, accompanied by chemokine/cytokine release. Three partial responses (PR) and one complete response (CR) were observed and are still ongoing. Two PRs continue after >12 months, one, in an ipilimumab refractory patient continues after >3 months and a CR continues after >4 months; these include responses in the two ocular melanoma patients enrolled (long term PR and CR). Sites of response include lung, liver, lymphatic system and various soft tissues. For the daily x 4 regimen, the 20mcg daily dose is complete, toxicities are tolerable and escalation continues. Conclusions: Toxicities of IMCgp100 were consistent with the mode of action of the drug i.e. IMCgp100 mediated T cell mobilisation, activation and tumor killing. Objective durable responses were observed including in ocular melanoma patients. Additional patients are being accrued at 50mcg weekly. For the daily x 4 regimen, the 20mcg dose was completed, which equates to 80mcg every 3 weeks, or just over half the dose achievable in this period with weekly dosing. Dose escalation in the d x 4 regimen continues. Citation Format: Mark R. Middleton, Pippa Corrie, Mario Sznol, Jeffrey Infante, Clive Mulatero, Jeff Evans, Neil Steven, David Krige, William H. Shingler, Yvonne McGrath, Namir J. Hassan, Bent K. Jakobsen. A phase I/IIa study of IMCgp100: Partial and complete durable responses with a novel first-in-class immunotherapy for advanced melanoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr CT106. doi:10.1158/1538-7445.AM2015-CT106

Targeting gp100 and TRP-2 with a DNA vaccine: Incorporating T cell epitopes with a human IgG1 antibody induces potent T cell responses that are associated with favourable clinical outcome in a phase I/II trial

ABSTRACT A DNA vaccine, SCIB1, incorporating two CD8 and two CD4 epitopes from TRP-2/gp100 was evaluated in patients with metastatic melanoma. Each patient received SCIB1 via intramuscular injection with electroporation. The trial was designed to find the safest dose of SCIB1 which induced immune/clinical responses in patients with or without tumour. Fifteen patients with tumor received SCIB1 doses of 0.4-8 mg whilst 20 fully-resected patients received 2–8 mg doses. Twelve patients elected to continue immunization every 3 months for up to 39 months. SCIB1 induced dose-dependent T cell responses in 88% of patients with no serious adverse effects or dose limiting toxicities. The intensity of the T cell responses was significantly higher in patients receiving 4 mg doses without tumor when compared to those with tumor (p < 0.01). In contrast, patients with tumor showed a significantly higher response to the 8 mg dose than the 4 mg dose (p < 0.03) but there was no significant difference in the patients without tumor. One of 15 patients with measurable disease showed an objective tumor response and 7/15 showed stable disease. 5/20 fully-resected patients have experienced disease recurrence but all remained alive at the cut-off date with a median observation time of 37 months. A positive clinical outcome was associated with MHC-I and MHC-II expression on tumors prior to therapy (p = 0.027). We conclude that SCIB1 is well tolerated and stimulates potent T cell responses in melanoma patients. It deserves further evaluation as a single agent adjuvant therapy or in combination with checkpoint inhibitors in advanced disease.

Abstract CT331: Phase I/II trial of a novel antibody DNA immunotherapy, targeting CD64, in the treatment of Melanoma

SCIB1 is a novel DNA immunotherapy that has epitopes from gp100 and TRP-2 melanoma antigens, engineered into a human IgG1 antibody. The therapy works by direct transfection and cross presentation via CD64 of dendritic cells. Vaccination results in high avidity T cells and tumour elimination in preclinical models. (1,2) A clinical trial was conducted to determine its safety and its ability to induce cellular immune responses. Patients and Methods: The vaccine was administered via Intramuscular injection with electroporation at 3 weekly intervals for 3 vaccinations then at 3 and 6 months. In part 1 of the study, nine patients with Stage III/IV melanoma were given escalating doses of SCIB1. Due to lack of toxicity the 2mg cohort were allowed to receive 4mg doses in their booster immunisations and the 4mg cohorts were allowed to continue with 3-6 monthly immunisations for 5 years. The 4mg dose was selected for an expansion cohort (part 2). To date 8 patients with fully resected stage III and 6 with fully resected stage IV melanoma have been treated and 7/14 patients are receiving ongoing vaccination. Results: No systemic dose-limiting toxicities were observed. The most common adverse event was injection site pain. 4/6 patients in the 2mg/4mg cohorts who received >3 doses of SCIB1, are still alive with a median survival time of 24 months. One patient had multiple tumour lesions (several in her lungs). All decreased in size or disappeared following treatment except for one lesion which was resected. Immunohistochemistry demonstrated strong expression of PD.L1 on the tumour cells. All patients in part 2 remain alive and only three have progressed. The median survival time in Part 2 is 15 months from study entry and 19 months from diagnosis of metastatic disease. In part 1, one patient in the 0.4mg cohort, all three patients in the 2mg/4mg dose cohort and two patients in the 4mg dose cohort mounted a measurable immune response to the vaccine-encoded antigens. In part 2, all 14 patients responded immunologically. 12/14 patients in the proliferation assay, 13/14 patients responded after T cell expansion in-vitro followed by ELISPOT assay and 11/14 patients responded in both assays. Responses were seen against both the CD8 epitopes and against the CD4+ epitopes. Six patients responded to all four epitopes, five patients responded to three epitopes and three patients responded to two epitopes. Significant responses (p>0.0001) were seen after three, four or five immunisations, indicating that at least three doses are required for a strong immune response to develop. Conclusion: We demonstrate that SCIB1 is safe in melanoma patients. 19/20 patients showed immune responses to repeat dosing at 2 or 4 mg. Detection of an objective clinical response and overall survival times are encouraging. 1. Pudney et al (2010). Eur J Immunol 40: 899. 2. Brentville et al (2012). Plos one 7:e4111 Citation Format: Lindy G. Durrant, Christian H. Ottensmeier, Paul Lorigan, Clive Mulatero, Ruth Plummer, Michelle Cunell, Rachael Metheringham, Victoria Brentville, Lee Machado, Poulam Patel. Phase I/II trial of a novel antibody DNA immunotherapy, targeting CD64, in the treatment of Melanoma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr CT331. doi:10.1158/1538-7445.AM2014-CT331

Abstract CT329: A Phase I study of IMCgp100: durable responses with a novel first-in-class immunotherapy for advanced melanoma

Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CA Background: IMCgp100 comprises an affinity-enhanced T cell receptor (TCR) specific for the HLA-A2 restricted melanoma gp100 peptide (YLEPGPVTA) fused to an anti-CD3 antibody fragment. Binding of IMCgp100 to melanoma cells redirects T cell cytotoxicity even in the presence of significant levels of PD-1 and PD-L1. Importantly, IMCgp100 enables T cells to kill HLA down-regulated melanoma cells otherwise invisible to cancer specific T cells. A Phase I study was conducted to determine the Maximum Tolerated Dose (MTD) and toxicity of IMCgp100 in patients with metastatic melanoma. Methods: HLA A2 positive patients with Stage IV or unresectable Stage III melanoma, with an ECOG Performance Status (PS) ≤1 and a lymphocyte count of ≥0.5x109/L were enrolled. Those with symptomatic, unstable brain metastases requiring steroids and those who might benefit from immediate vemurafenib treatment were excluded. IMCgp100 was administered on day 1 and patients followed to day 30. Those who tolerated the first dose received repeated cycles of six weekly doses. The dose of IMCgp100 was escalated in cohorts of 3 (+3) patients until criteria for MTD were met. MTD was defined as the highest dose level with an observed incidence of Dose Limiting Toxicity (DLT) in fewer than 33% of patients enrolled at that level. Transient Grade 3 lymphopenia and Grade 3 skin toxicity were excluded from the definition of a DLT. Results: 31 patients were enrolled in 8 cohorts (doses from 5 to 900ng/Kg). 58% were male, median age was 61, ECOG PS 0 in 52% and 1 in 48%. All but 1 patient had stage IV disease. 60% of patients had received systemic treatment with DTIC (29%), ipilimumab (6%), vemurafenib (3%) or one or more experimental therapies (22%) prior to enrolment. At dose 900ng/Kg, 2/4 patients developed Grade 3 hypotension, therefore the MTD was defined at 600ng/Kg. Common toxicities included transient grade 3 pruritic rash and grade 2 pyrexia. Patients experienced profound lymphocyte trafficking to skin as evidenced by immunohistochemical analysis of skin biopsies, accompanied by chemokine/cytokine release. Rash was initially observed at dose level 45ng/Kg. Tumor flare was observed in patients with cutaneous or subcutaneous disease. Four partial responses (PR) and multiple lesser responses (not meeting RECIST PR) have been documented to date. One PR was achieved after a single dose. Two PRs continue after >9 months of continued treatment. One patient continues with stable disease for >10 months. Sites of response included the lung, the liver, the lymphatic system and various soft tissues. Conclusions: Toxicities of IMCgp100 were consistent with the mode of action of the drug i.e. IMCgp100 mediated T cell mobilisation, activation and tumor killing. Objective durable responses were observed. The study has been expanded to accrue additional patients at 600ng/Kg and to explore potentially superior dosing regimens. Citation Format: Mark Middleton, Jeff Evans, Neil Steven, Pippa Corrie, Clive Mulatero, Mario Sznol, William H. Shingler, Dominic Smethurst, Namir Hassan, Yvonne McGrath, Bent Jakobsen. A Phase I study of IMCgp100: durable responses with a novel first-in-class immunotherapy for advanced melanoma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr CT329. doi:10.1158/1538-7445.AM2014-CT329

Pneumocystis jirovecii pneumonia in a patient with melanoma treated with infliximab and corticosteroids for ipilimumab-associated colitis

Immunotherapy has been successfully used in the management of malignancies including metastatic melanoma but is associated with autoimmune complications that may require corticosteroids and other immunosuppressive therapies to manage. We describe a case of a woman with metastatic melanoma treated with ipilimumab who developed severe Pneumocystis jirovecci pneumonia (PCP) following treatment for ipilimumab-associated colitis with corticosteroids and infliximab. We outline the approach to diagnosis and management of this opportunistic infection. PCP is an important infection to consider in the differential diagnosis for patients who are immunosuppressed and have an acute respiratory presentation. Early diagnosis and treatment is important especially since mortality is high in patients with cancer. Bronchoalveolar lavage and polymerase chain reaction is a useful diagnostic tool. First line therapy for PCP is trimethoprim/sulfamethoxazole. Patients with melanoma treated with immunomodulating therapies are at risk of autoimmune-related adverse events that may require powerful immunosuppressive treatments with the threat of subsequent opportunistic infection. Consideration should be given to PCP prophylaxis in these patients. Correspondence to: Dr. Finbar Slevin, Specialty Registrar in Clinical Oncology, St James’s Institute of Oncology, Leeds, United Kingdom, E-mail: finbarslevin@nhs.net