Date: 2015-06-01
Type of information: Presentation of results at a congress
phase: 3
Announcement: presentation of results at the 51st ASCO Annual Meeting underway in Chicago (IL, USA) from May 29th to June 2nd
Company: MolMed (Italy)
Product: NGR-hTNF
Action
mechanism: fusion protein. NGR-hTNF is a vascular targeting agent with unique mode of action, and a first-in-class compound in the class of peptide/cytokine complexes able to selectively target the tumour vasculature. It consists of a tumour homing peptide (NGR) that selectively binds tumour blood vessels, fused to the human cytokine TNF. NGRhTNF is undergoing clinical development both as monotherapy and in combination therapy, in a total of seven indications.
Disease: malignant pleural mesothelioma
Therapeutic area: Cancer - Oncology - Rare diseases
Country: European Union (including Poland, Germany, UK, Austria and Ireland), USA and Canada
Trial
details: NGR015 is a pivotal randomised, double-blind, placebo-controlled, international, multicentre Phase III trial on 390 malignant pleural mesothelioma patients, whose disease progressed after a pemetrexed-based chemotherapy. The trial is powered to detect a survival benefit for NGR-hTNF, when combined with best investigator’s choice (BIC), where BIC includes either best supportive care alone or in combination with chemotherapy (either doxorubicin, or gemcitabine, or vinorelbine). NGR-hTNF is administered according to the dose and schedule that were confirmed as the most efficacious in Phase II trials: 0.8 microg/m2 weekly, until disease progression. NGR019 is a randomised, double-blind, placebo-controlled, international, multicentre Phase II trial on 100 adult pleural mesothelioma patients with non-progressive disease after a pemetrexed-based chemotherapy. The trial is powered to detect a progression-free survival benefit for NGR-hTNF, when combined with best supportive care (BSC). NGR-hTNF is administered according to the dose and schedule that were confirmed as the most efficacious in Phase II trials: 0.8 µg/m2 weekly, until disease progression. Secondary endpoints include overall survival, tumour response, safety and quality of life.
The NGR015 trial was based on NGR010 Phase II trial results in 57 chemo-pre-treated patients with malignant pleural mesothelioma who received NGR-hTNF as monotherapy - either every three weeks or weekly. The overall results showed a disease control rate of 46%, a median progression-free time of 4.7 months and a median survival time of 12.1 months, while the median survival time historically reported in this setting is approximately 6 months (Krug LM et al., European Multidisciplinary Cancer Congress 2011). The comparison of the 3-year overall survival rates between the weekly and every-three-week cohorts showed a clear advantage of the dose intensification approach.
Latest
news: * On June 1, 2015, MolMed announced that the complete results of the Phase III trial with its investigational therapeutic NGR-hTNF in mesothelioma were presented and discussed orally in the “Lung Cancer-NSCLC local-regional/SCLC/Other Thoracic Cancers” session at the 51st ASCO Annual Meeting underway in Chicago (IL, USA) from May 29th to June 2nd. The international phase III trial, which started in 2010 and whose top line results were released in 2014, showed a statistically significant 45% improvement in overall survival in patients who progressed more rapidly after first-line treatment. This outcome was observed in the 50% of patients with a poorer prognosis, while the primary endpoint was not met for the entire population. In this poor prognosis patient population, the robustness of the benefit induced by NGR-hTNF in combination with chemotherapy, over chemotherapy alone, has been confirmed by the efficacy consistently reported across all patient subgroups, defined on the basis of well-established risk factors (e.g. histology, performance status, age, sex, etc.), and across all the other study endpoints, with NGR-hTNF able to prolong progressionfree survival time by 45%, to reduce early progression rate by 45% and to increase the survival duration in patients with disease control by 65%. The meaningfulness of results achieved in mesothelioma patients has been further endorsed by additional analyses related to the phase III trial data that were also presented at the ASCO conference in two poster presentations. The first analysis highlighted the value of the clinical parameter - the treatment-free interval after first-line therapy - in easily identifying patients who benefited most from NGR-hTNF treatment and in defining the increased aggressiveness and poor prognosis of disease. The second analysis indicated the rationale underlying the increased NGR-hTNF effects observed in the patient population presenting with disease characterized by an augmented tumor angiogenesis (as assessed by high circulating lactate dehydrogenase levels), and the key role of patient immune status in predicting NGR-hTNF efficacy. Indeed, in those patients who presented with elevated blood markers of angiogenesis and of the immune response, overall survival improved by 72% and progression-free survival by 89% with NGR-hTNF plus chemotherapy compared with chemotherapy alone. * On June 3, 2014, Molmed announced it has reported a statistically significant 40% improvement of both overall survival and progression-free survival in a large population of patients, identified by a pre-specified analysis on the prior treatment-free interval, and who presented a very dismal prognosis at the 50th ASCO annual meeting. These efficacy results were observed in an international randomized Phase III study evaluating the investigational drug NGR-hTNF in combination with best investigator choice in 400 patients with malignant pleural mesothelioma (MPM) who had previously failed a first-line chemotherapy. The magnitude of treatment effect increased with NGR-hTNF duration and was particularly marked in patients receiving at least three months of therapy, with a median survival time nearly doubled in patients treated with NGR-hTNF compared to control patients: 16.5 vs 9.8 months, respectively. The data reported at ASCO, mainly obtained in combination with either gemcitabine or vinorelbine in a very aggressive and chemo-resistant disease, assume particular relevance as they are confirmatory of the efficacy previously shown by NGR-hTNF plus gemcitabine in the first-line Phase II study in squamous lung cancer patients. Furthermore, NGR-hTNF confirmed in this large patient population its very favourable tolerability profile in combination with the three different chemotherapeutic agents administered in this study (gemcitabine, vinorelbine and doxorubicin). An additional two randomized Phase II studies reported at ASCO meeting clearly established the effect of NGR-hTNF on survival. In the four-arm randomized Phase II study in sarcoma patients, the low-dose weekly NGR-hTNF plus doxorubicin regimen induced a statistically significant doubled survival time, as compared with the other schedules given at high dose in combination with doxorubicin or as monotherapy at low or high dose. The 3-year survival rate with this schedule exceeded 40% and, notably, similar results were reported for both chemo-naïve and pretreated patients, thus confirming the elevated NGR-hTNF efficacy in more aggressive, chemo-resistant disease. In the randomized Phase II study in resistant / refractory ovarian cancer patients, NGR-hTNF in combination with an anthracycline improved overall survival in patients with normal or high baseline lymphocyte counts, as compared to patients receiving an anthracycline alone. Taken together, these clinical evidences are also consistent with the drug mechanism of action, based on both an increased intratumoral chemotherapy uptake and interaction with host immune system. * On May 5, 2014, MolMed has announced the results of the double-blinded, placebo-controlled Phase III trial of NGR-hTNF versus best investigator choice in 400 patients with malignant pleural mesothelioma who had previously failed a first-line chemotherapy. Despite not meeting its primary endpoint of improving overall survival (OS) in the entire population, the study showed a statistically significant (unstratified p=0.02; stratified p=0.01) 40% improvement of OS in patients with poorer prognosis who had progressed during or shortly after first-line chemotherapy. These patients represent 50% of the entire patient population and were identified by a pre-specified analysis based on prior treatment-free interval. This clinical parameter will allow to easily identifying patients who derive most clinical benefit from NGR- hTNF in combination with the chemotherapy of choice. Consistent with the overall survival improvement in this patient population, a 40% percent longer progression-free survival (PFS) was also reported for the NGR-hTNF treated arm in those patients who presented a more aggressive, chemo-resistant disease. In addition to the efficacy data, NGR-hTNF confirmed in this large patient population its very favourable tolerability profile also in combination with the three chemotherapeutic agents administered in this study (gemcitabine, vinorelbine and doxorubicin). Claudio Bordignon, Chairman and CEO of MolMed, commented: "The results obtained in a pre-specified population of high-risk patients represent an important reward for the Company's mission and effort in improving survival and quality of life of cancer patients, even if the primary endpoint was not reached in the entire population. For the first time in malignant pleural mesothelioma a highly significant clinical benefit was achieved in a large subpopulation with the worst prognosis, represented by patients refractory or rapidly progressing after first line treatment. In addition, these data provide confirmation of NGR-hTNF effect on survival already observed in Phase II studies in other indications. Pending a more in depth evaluation, these top line results already provide potential to pursue conditional marketing authorisation and further clinical development in mesothelioma and other indications." For the same pathology the Company is running a randomised Phase II study on NGR-hTNF as maintenance therapy after completion of first line chemotherapy (NGR019). The study aims at extending t he treatment-free interval of those patients who did not progress after first line, providing them with a long term therapy with a high tolerability profile. * On December 13, 2012, MolMed has announced completion of enrolment in the pivotal NGR015 Phase III trial of its investigational drug NGR-hTNF in relapsed malignant pleural mesothelioma. Primary efficacy results are expected in the third quarter of 2013. Currently, NGR-hTNF is the only drug in Phase III development for relapsed mesothelioma. Concomitantly with the Phase III study in the second-line setting, the Company is conducting a randomised Phase II trial with NGR-hTNF given as first-line maintenance therapy to assess whether earlier drug administration is able to increase the clinical benefit. The efficacy of NGR-hTNF is also being tested in three additional randomised Phase II trials in non-small cell lung cancer, soft tissue sarcomas and ovarian cancer. * On October 25, 2011, MolMed has announced the expansion in the United States of a pivotal Phase III trial of its investigational anticancer drug NGR-hTNF in malignant pleural mesothelioma, with treatment of the first patient at one of the most prestigious US Universities in New York. The trial is already ongoing in in Europe and plans to involve more than 40 centres worldwide. Results from the trial are expected in 2013. The start of Phase III in the US follows IND clearance from the FDA. * On February 24, 2011, MolMed has announced the international expansion of Phase III trial NGR015 of its investigational anticancer drug NGR-hTNF for the treatment of malignant pleural mesothelioma, with the recruitment of the first patient in a clinical centre in Poland. The trial, already ongoing in 10 centres across Italy, will be further expanded to involve up to 45 centres in the European Union (including Germany, UK, Austria and Ireland), the United States and Canada. Top line results are expected in 2013. NGR-hTNF has already been granted Orphan Drug designation for the treatment of mesothelioma in both the EU (03-06-2008) and the US (22-08-2008).
These clinical results are also in line with the drug’s hypothesized mechanism of action, which is based on an improved intratumoral penetration of chemotherapeutic agents and increased tumor lymphocyte infiltration, thanks to NGR-hTNF’s activity on newly formed tumor vasculature. MolMed’s global effort in the treatment of mesothelioma is further reinforced by the currently ongoing randomized Phase II trial with NGR-hTNF given as a maintenance approach after completion of first-line therapy.
Claudio Bordignon, Chairman and CEO of MolMed, commented: “The oral presentation of the data discussed at the ASCO meeting acknowledges the value of the results achieved by NGR-hTNF in those patients who suffer from a resistant disease and are most in need of treatment options, and significantly confirms the therapeutic potential of the molecule already observed in other tumor indications evaluated in Phase II trials. The identification of patients who benefit most from NGR-hTNF, their extended survival time, and the consistently reported efficacy represent three key results of the study and, more importantly, offer the perspective of a relevant and appropriate treatment choice for patients with poorer prognosis”. These results represent the basis for the Company to pursue the next steps, including initiation of the registration process, and the further clinical development of NGR-hTNF.
