ESMO2014摘要汇总

costa_na · 发表于 2014-9-26 15:41:05

本帖最后由 costa_na 于 2014-9-29 12:26 编辑

1225O - Overall and intracranial (IC) efficacy results and time to symptom deterioration in PROFILE 1014: 1st-line crizotinib vs pemetrexed - platinum chemotherapy (PPC) in patients (pts) with advanced ALK-positive non-squamous non-small cell lung cancer (NSCLC)

Aim
Clinical outcomes (overall and IC efficacy, lung cancer symptoms) with crizotinib (criz) vs standard chemotherapy as 1st-line treatment for advanced ALK-positive NSCLC were compared in the ongoing randomized open-label phase III study PROFILE 1014 in the whole pt population and in pt subgroups.

Methods
Pts with previously untreated advanced non-squamous ALK-positive NSCLC (N = 343) were randomized 1:1 to criz 250 mg PO BID (n = 172) or PPC (pemetrexed 500 mg/m2 + cisplatin 75 mg/m2 or carboplatin AUC 5–6; all IV q3w for ≤6 cycles; n = 171). Continuation of/crossover to criz after PD (per independent radiology review [IRR]) was allowed for pts randomized to criz or PPC, respectively. The primary endpoint was PFS per IRR. Secondary endpoints included OS, IC TTP, time to deterioration in symptoms of chest pain, dyspnea, or cough (TTDS), and safety.

Results
171 pts received criz, 91 pem − cis, 78 pem-carbo, and 3 no treatment. The study met its primary objective: criz was superior to PPC in prolonging PFS (median 10.9 vs 7.0 mo; HR: 0.45; 95% CI: 0.35 − 0.60; P < 0.0001). PFS benefit with criz was observed in most pt subgroups analysed. Median PFS was 6.9 mo with pem − cis (HR: 0.49; P < 0.0001) and 7.0 mo with pem − carbo (HR: 0.44; P < 0.0001). At time of data cutoff 120 pts had received criz after PPC; with 68% of pts in follow-up, OS differences between criz and PPC were not statistically significant (NS). The IC TTP HR for criz vs PPC was 0.60 (95% CI: 0.34 − 1.05; NS; only ～15% of pts had IC events) and 0.45 in the 79-pt subgroup with baseline brain metastases (95% CI: 0.19 − 1.07; NS). TTDS was significantly longer with criz (median 2.1 vs 0.5 mo; HR: 0.62; P = 0.0004). The most common AEs of any cause with criz were vision disorder and GI symptoms. AEs with PPC were consistent with those previously reported in unselected NSCLC.

Conclusions
Crizotinib treatment showed significant improvements in PFS and TTDS vs PPC, a numerical improvement in IC TTP, and an acceptable safety profile, establishing crizotinib as the standard of care for pts with treatment-naïve advanced ALK-positive non-squamous NSCLC.

costa_na · 发表于 2014-9-26 15:42:07

454P - Pre-clinical and clinical evaluation of AZD9291, a mutation-specific inhibitor, in treatment-naïve EGFR mutated NSCLCAim

AZD9291 is an oral, irreversible EGFR-TKI effective against EGFR-TKI-sensitising (EGFRm+) and resistance T790M mutations. It is efficacious in EGFRm+ advanced NSCLC patients with acquired resistance to EGFR-TKIs. We report on the evaluation of AZD9291 in the first-line setting.

Methods

In vitro and in vivo xenograft studies were performed utilising PC-9 (EGFR exon 19 del) and H3255 (EGFR L858R) cells. The efficacy of AZD9291 was compared with known EGFR inhibitors: gefitinib, afatinib and WZ4002. Transgenic mice with lung tumours driven by EGFR L858R or exon 19 del were also dosed with AZD9291. In the clinic, AZD9291 was given to patients with advanced stage NSCLC with a documented EGFR-TKI-sensitising mutation as first-line therapy (treatment-naïve), in an ongoing Phase I trial (NCT01802632).

Results

In vitro, compared to afatinib at 0.8nM, resistance to AZD9291 at 10nM was delayed by an average of 43 days in PC9 cells. Notably, 73% (8/11) of cell populations exposed to gefitinib or afatinib developed T790M mutation compared to none (0/14) with AZD9291. In PC9 and H3255 xenograft studies, AZD9291 demonstrated strong efficacy, evidenced by profound and sustained tumour reduction. Robust tumour shrinkage was also noted in exon 19 del and L858R in vivo transgenic models. These lines of evidence prompted the clinical investigation of AZD9291 in treatment-naïve patients with advanced NSCLC. As of 2 April 2014, 22 patients ( 7 males; median age 61 yrs; WHO PS 0/1, 14/6; Asian ethnicity 18; EGFR-TKI-sensitising mutation exon 19del 6, L858R 8, other 1, unknown 7) were treated with AZD9291 at 80 mg/day. Safety and efficacy data from all evaluable patients will be presented.

Conclusions

AZD9291 is a novel, mutation-specific EGFR inhibitor which demonstrates good activity in pre-clinical EGFR mutant xenograft models. Early clinical data with AZD9291 in treatment-naïve patients with advanced NSCLC supports further evaluation in first-line therapy of EGFRm+ NSCLC.

costa_na · 发表于 2014-9-26 15:42:37

456P - Preclinical evidence and clinical cases of AZD9291 activity in EGFR-mutant non-small cell lung cancer (NSCLC) brain metastases (BM)Aim

AZD9291 is a potent, selective, oral irreversible EGFR-TKI effective against the EGFR-TKI-sensitising (EGFRm+) and resistance T790M mutations. We researched the potential efficacy of AZD9291 against EGFRm+ NSCLC BM.

Methods

Preclinical brain exposure of AZD9291 and an active circulating metabolite (AZ5104) were evaluated in mouse models. In vivo efficacy of AZD9291 was assessed in a mouse EGFRm+ (exon 19 deletion) BM xenograft (PC9) model. Human doses that could potentially deliver BM efficacy were predicted using a preclinical pharmacokinetic/pharmacodynamic (PK/PD) mathematical model, adapted to account for the differential exposure and binding of AZD9291 and AZ5104 in brain compared with plasma. Selected case reports of clinical activity in EGFRm+ NSCLC BM were available from a Phase I, open-label, dose-escalation study of AZD9291 (AURA; NCT01802632). Collection of cerebrospinal fluid and plasma PK samples are ongoing.

Results

In preclinical studies, AZD9291 showed significant exposure in the brain. Concentrations in mouse brain tissue compared with plasma were 5–25-fold higher for AZD9291 and approximately equivalent for AZ5104. At clinically relevant doses, AZD9291 distribution to the brain is ～10-fold higher than gefitinib. In the PC9 BM model, AZD9291 5 mg/kg/day showed tumour growth inhibition of BM. Using an adapted preclinical PK/PD model, simulations with clinical AZD9291/AZ5104 PK data predicted that a human dose of 80 mg would be sufficient to target EGFRm+ BM. In AURA, extracranial objective responses according to RECIST were observed at all dose levels (20–240 mg) and for some patients shrinkage in BM was reported. Clinical cases will be presented.

Conclusions

Preclinical studies indicate AZD9291 has significant exposure in the brain and activity against EGFRm+ BM. In light of early clinical evidence of AZD9291 activity in patients with EGFRm+ NSCLC BM, further investigation into the potential benefit of AZD9291 in patients with EGFRm+ NSCLC and BM is warranted.

costa_na · 发表于 2014-9-26 15:44:59

471P - Effect of nintedanib (BIBF 1120) combined with standard 2nd-line docetaxel in NSCLC patients who received prior pemetrexed in LUME-Lung 1: A randomised, placebo-controlled phase III trialAim

Nintedanib (N) is an oral, triple angiokinase inhibitor of VEGF, PDGF and FGF signalling. Primary analysis of the LUME-Lung 1 trial (NCT00805194; 1199.13) showed a significant improvement in PFS with N + docetaxel (D) in NSCLC patients (pts) regardless of histology; OS was also significantly improved in adenocarcinoma (adeno) pts. Pemetrexed (PEM) is a standard 1st-line and maintenance treatment for nonsquamous NSCLC pts. To determine whether prior PEM would influence outcomes of pts in LUME-Lung 1, we evaluated the efficacy and safety of N + D in pts who received 1st-line and maintenance PEM.

Methods

1314 pts with Stage IIIB/IV recurrent NSCLC were randomised to receive either N 200 mg bid + D 75 mg/m2 q21d (n = 655) or placebo (Pl) + D (n = 659) in LUME-Lung 1. Retrospective subgroup analyses according to prior PEM treatment (1st line or maintenance) were performed to determine OS and safety.

Results

The percentage of pts with adeno tumour histology who were treated 1st line with PEM along with platinum was approximately 19% (N arm, n = 61; Pl arm, n = 65). Pt characteristics were balanced across groups. OS results according to receipt of any PEM 1st-line and maintenance therapy for adeno pts are shown in the table. For all pts and those with adeno histology in particular, no significant difference in OS was noted between those who did or did not receive PEM; no significant interaction between treatment groups and any PEM treatment was observed. Further, slightly more pts in the N arms across all subgroups experienced grade ≥3 adverse events; diarrhoea and reversible increases in liver enzymes occurred more frequently in pts in both N arms.

OS results in NSCLC pts with adeno histology who received 1st-line and/or maintenance PEM

[table=98%]

No PEM 1st-line

PEM 1st-line

No maintenance PEM 1st-line

Maintenance PEM 1st-line

N n = 261

Pl n = 271

N n = 61

Pl n = 65

N n = 309

Pl n = 322

N n = 13

Pl n = 14

Median OS, months13.410.812.08.012.610.018.912.8
HR (95% CI); p-value0.83 (0.68–1.00); p = 0.050.79 (0.53–1.18); p = 0.250.84 (0.70–1.00); p = 0.050.78 (0.30–2.07); p = 0.62
Interaction between treatment & subgroup variable, p-valuep = 0.9026p = 0.7162

Conclusions

On-study treatment with N + D resulted in a comparably favourable improvement in OS regardless of whether pts with adeno tumours were treated 1st line with a PEM- or non-PEM-containing platinum doublet.

costa_na · 发表于 2014-9-26 15:45:29

473P - Prior taxane use in the LUME-Lung 1 phase III trial and the effect on outcome following 2nd-line treatment with nintedanib (BIBF 1120) and docetaxel in patients with advanced NSCLCAim

Several Phase III studies confirm the efficacy of standard 2nd-line docetaxel (D) in advanced non-small cell lung cancer (NSCLC) patients (pts) previously treated with 1st-line paclitaxel-based therapy irrespective of tumour histology. In LUME-Lung 1, nintedanib (N)—an oral, triple angiokinase inhibitor of VEGF, PDGF and FGF signalling—has demonstrated clinically meaningful efficacy along with 2nd-line chemotherapy (NCT00805194; 1199.13). Here we report the efficacy and safety of N + D in pts previously treated with taxanes as part of a preplanned analysis.

Methods

Stage IIIB/IV recurrent NSCLC pts (N = 1314) progressing after 1st-line chemotherapy were randomised 1:1 to receive either N 200 mg bid + D 75 mg/m2 q21d (n = 655) or placebo (Pl) + D (n = 659). Endpoints evaluated included progression-free survival (PFS) by central independent review, overall survival (OS) and safety. Chemotherapy with 1st-line D was an exclusion criterion; subgroup analyses according to the pt's use of 1st-line taxane therapy and NSCLC histology were also performed.

Results

Pt characteristics were balanced across all groups. For all pts and those with adenocarcinoma (Ad) in particular, no significant difference in survival benefit was noted regardless of the use of 1st-line taxane therapy (Table). Comparison of N + D and Pl + D showed that the percentage of all pts with grade ≥3 adverse events (AEs) was slightly higher for pts in the N arm (no 1st-line taxane = 71.6% vs 65.5%; prior 1st-line taxane = 70.3% vs 59.4%). Consistent with overall findings in LUME-Lung 1, reversible increases in alanine and aspartate aminotransferases as well as diarrhoea were the AEs that were more common among all pts in the N arm.

OS results for LUME-Lung 1 in NSCLC pts who received 1st-line taxane therapy

[table=98%]

All pts

Pts with Ad

No taxane 1st-line

Taxane 1st-line

No taxane 1st-line

Taxane 1st-line

N, n = 510

Pl, n = 519

N, n = 145

Pl, n = 140

N, n = 245

Pl, n = 271

N, n = 77

Pl, n = 65

Median OS, months10.09.111.59.012.210.315.111.6
HR (95% CI); p-value

0.97 (0.85–1.11); p = 0.67

0.81 (0.62–1.06); p = 0.13

0.86 (0.71–1.05); p = 0.13

0.75 (0.51–1.11); p = 0.15

Interaction between treatment & subgroup variable, p-value

p = 0.2562

p = 0.6135

Conclusions

On-study treatment with N + D resulted in a comparably favourable OS improvement regardless of whether pts with tumours of Ad histology were treated 1st line with a taxane- or non-taxane-containing platinum doublet.

costa_na · 发表于 2014-9-26 15:46:01

1288P - A phase IB dose-escalation study of the HSP90 inhibitor SNX-5422 and erlotinib in patients with EGFR-mutant lung cancer and acquired resistance to EGFR tyrosine kinase inhibitorsAim

SNX-5422 is a pro-drug of SNX-2112, a highly potent, non-geldanamycin analogue, HSP90 inhibitor with preclinical anti-tumor activity in multiple tumour models including models of acquired resistance (AR) in EGFR-mutant lung cancer. To prevent disease flare after stopping EGFR tyrosine kinase inhibitors (TKIs) in patients (pts) with EGFR mutant lung cancer, erlotinib (E) is often continued with subsequent lines of treatment for AR. This phase IB study will determine the maximally tolerated dose (MTD) of SNX-5422 and E for pts with mutated EGFR and RECIST progression on EGFR TKIs.

Methods

All pts had EGFR mutant lung cancer, with development of AR (per Jackman, JCO 2010) after treatment with an EGFR TKI. Pts underwent repeat tumour biopsies after development of AR and prior to study entry. Pts received SNX-5422 qod, 3 wks on/1 wk off, and E 150mg daily P.O. in 28-day cycles, with dose escalation using a standard 3 + 3 design. Safety and tolerability were evaluated also to determine the MTD and blood samples were obtained for pharmacokinetics.

Results

Since May 2013, 17 pts were enrolled. No dose-limiting toxicities (DLTs) were reported in the first cohort (SNX-5422 50 mg/m2 + E), but DLTs (diarrhoea) were reported by 2 pts in the second cohort (SNX-5422 75 mg/m2 + E). Adverse events possibly related to the combination in ≥ 4 of 17 pts in were diarrhoea, nausea, fatigue, dry eyes, paronychia, and rash, all graded 1 or 2; except for 2 cases of grade 3 diarrhoea. No cardiovascular, renal or hepatic toxicities have been observed. 1 Pt reported mild, reversible nictalopia at the DLT level of SNX-5422 75 mg/m2 + E. Pts received a median of two cycles (range 1-6), and 3 remain on study. No partial responses have been seen in 15 evaluable pts; 1 ongoing pt had an 18% decrease from baseline in target lesions in Cycle 4. Stable disease was the best response in 4 pts at 8 wks, 3 pts at 16 weeks and 1 pt at 24 weeks.

Conclusions

SNX-5422 and E is a well-tolerated combination at dose levels up to SNX-5422 50 mg/m2 qod + E 150 mg. The MTD was declared SNX-5422 50 mg/m2 + E.

costa_na · 发表于 2014-9-26 15:50:35

1256P - A phase II trial of first-line nab-paclitaxel/carboplatin versus gemcitabine/carboplatin in advanced squamous cell carcinoma of the lung (CTONG1002)Aim

The administration of nab-paclitaxel/carboplatin (nab-PC) as first-line therapy in patients with advanced non-small-cell lung cancer was efficacious and resulted in a significantly improved objective overall response rate (ORR) versus solvent-based PC in a phase ||| trial. Subgroup analysis showed the squamous histology appeared to be a predictive factor to nab-paclitaxel treatment. This phase || trial (NCT01236716; CTONG1002) compared the eficacy and safety of first-line nab-PC wih gemcitabine/carboplatin (GC) in advanced squamous cell carcinoma of the lung.

Methods

From November 2010 to June 2013, 127 untreated patients with locally advanced and metastatic squamous cell carcinoma of the lung were randomly assigned 1:1 to receive first-line nab-PC (nab-P, 135mg/m2, d1,d8, q3w; C, AUC = 5, d1, q3w) or GC (G, 1250mg/m2, d1, d8, q3w; C, AUC = 5, d1, q3w ). The primary endpoint was ORR. The secondary endpoints were progression-free survival (PFS), overall survival (OS), safety and quality of life (QoL).

Results

There were 110 cases evaluable for ORR (nab-PC, 54; GC, 56), 119 evaluable for survival (nab-PC, 57; GC, 62) and 124 evaluable for safety (nab-PC, 59; GC, 65), respectively. ORR was 46.3% (25/54) for the nab-PC arm and 30.4% (17/56) for the GC arm respectively, p = 0.085. There was an approximately 18.8% improvement in PFS (median, 5.7 v 4.8 months; hazard ratio [HR], 0.907; 95%CI, 0.588 to 1.399; p = 0.657) in the nab-PC arm versus the GC arm. OS was not significantly different between the two arms (median, 11.9 v 14.4 months; HR, 1.010; 95%CI, 0.640 to 1.590; p = 0.970). Significant grade ≥3 leucopenia (41.7% v 17.2%, p<0.010) and neutropenia (70.0% v 42.2, p<0.010) occurred in the nab-PC arm. Improvement of QoL favored the nab-PC arm, but there was no significant difference between the two arms (Total FACT-L, 72.9% v 58.1%, p = 0.160; LCS, 76.7% v 75.0%, p = 0.870; TOI, 75.0% v 57.8%, p = 0.050).

Conclusions

First-line nab-PC in advanced squamous cell carcinoma of the lung was efficacious and resulted in a marginally improved ORR versus GC, but not achieving the primary endpoint. There was no significant difference in terms of survival and QoL between the two arms. The overall adverse events of nab-PC were manageable though more leucopenia and neutropenia were observed in nab-PC arm than with GC.

costa_na · 发表于 2014-9-26 15:51:34

1278P - BE-POSITIVE: Beyond progression after tyrosine kinase inhibitor in EGFR-Positive non-small cell lung cancer (NSCLC) patients. Preliminary results from a multicenter Italian observational studyAim

Patients (pts) with advanced lung adenocarcinoma harbouring EGFR mutations mainly experience tumour regressions when treated with EGFR Tyrosine Kinase inhibitors (TKis) but they always develop drug resistance causing progressive disease. Aim of this study is to evaluate therapeutic outcomes of first and second line treatment in different Italian centers.

Methods

Caucasian EGFR-mutated pts with stage IV NSCLC, receiving 1st-line reversible EGFR TKi were evaluated from June 2009 until May 2013 in 23 Italian institutions. Primary end-points were objective response rate (ORR) to 1st- and 2nd-line treatment, together with: duration of treatment, progression-free survival (PFS), overall survival (OS) and safety for both therapies. Secondary end-point was the assessment of therapeutic approaches beyond EGFR TKis progression.

Results

299 pts (median age 65,6 years old; range: 32-87) were included. Most of them were females (196, 65,6%), never smokers (192, 64,2%), with adenocarcinoma histology (278, 93%) and received gefitinib (278, 93%). The most common mutations were EGFR exon 19 deletion and L858R, detected in 182 and 93 cases (60,9% and 31,1%, respectively). Pts who progressed after first line treatment at the time of data lock were 262: 261 evaluable for ORR and 260 for duration of treatment. The ORR was 48.7% (95% CI 42.6-54.7): 6 (2.3%, 95% CI 0.4-4.1) complete responses, 121 (46.4%, 95% CI 40.3-52.4) partial responses and 77 (29.5%, 95% CI 24.0-35.0) stable diseases (around 75% received the EGFR TKi for more than 6 months). Median duration of first line treatment was 42,9 weeks; 15 pts (5,7%) stopped early due to inacceptable toxicity and 156 pts (59,5%) received a second-line treatment (39% a platinum based doublet, 18% a monotherapy, in 13 cases a rechallenge with EGFR TKi was done).

Conclusions

BE-Positive is the first multicenter observational study reporting outcomes of first-line EGFR TKi and second line approach in a large "real life population" of Caucasian patients.

costa_na · 发表于 2014-9-26 15:52:19

1240P - A phase 1b study of the anti-cancer stem cell agent demcizumab (DEM), pemetrexed (PEM) & carboplatin (CARBO) in pts with 1st line non-squamous NSCLCAim

Delta-like ligand 4 (DLL4) activates the Notch pathway and is important for cancer stem cell (CSC) survival. DEM is a humanized IgG2 anti-DLL4 antibody that has been shown to inhibit tumor growth, decrease CSC frequency & cause dysfunctional sprouting of new vessels resulting in an antiangiogenic effect in human tumor xenograft models.

Methods

Pts received DEM (2.5 or 5 mg/kg), PEM 500 mg/m2 & CARBO (AUC = 6) every 3 wks X 6 cycles followed by maintenance DEM (cohorts 1-4) or truncated DEM (5 or 7.5 mg/kg), PEM 500 mg/m2 & CARBO (AUC = 6) every 3 wks X 4 cycles followed by maintenance PEM (cohorts 5 & 6). The objectives were to determine the MTD, safety, efficacy, immunogenicity, pharmacokinetics & biomarkers of Notch signaling.

Results

Thirty-nine pts were enrolled; 6 received 2.5 mg/kg, 20 received 5 mg/kg, 6 received 7.5 mg/kg of truncated DEM & 7 received 5 mg/kg of truncated DEM. Related AEs in > 20% of pts were: nausea (49%), fatigue (44%), hypertension (41%), vomiting (31%), edema (26%), neutropenia (26%), & increased B-type natriuretic peptide (BNP) (23%). Increased BNP values are an early indicator of the cardiac effects of DEM & mildly elevated values are being used to initiate cardioprotective therapy with an ACE inhibitor or carvedilol. Two pts receiving 5 mg/kg developed reversible pulmonary hypertension & heart failure on days 167 & 183, respectively. As a result, DEM treatment was limited to 63 days in cohorts 5 & 6. One of 32 (3%) evaluable pts had a RECIST CR, 13 (41%) had a PR and 14 had SD. The Kaplan Meier estimated median progression free survivals for the 2.5, 5, truncated 5 & truncated 7.5 mg/kg pts were 4.3, 5.3, not yet reached & 4.4 months, respectively. Five pts who discontinued the study for a reason other than progression (3 continued to receive CARBO & PEM off-study) were progression-free through Days 223 + , 243 + , 457 + , 497 + , 680+ and a sixth pt (who continued to receive CARBO & PEM off-study) progressed at Day 850.

Conclusions

This therapy was generally well tolerated with nausea, fatigue & hypertension being the most common drug related toxicities. Encouraging early clinical activity has been observed. Additional data with truncated DEM will be presented.

costa_na · 发表于 2014-9-26 16:24:50

1327P - A Phase I open-label study to evaluate the safety and tolerability of MEDI4736, an anti-programmed cell death-ligand 1(PD-L1) antibody, in combination with tremelimumab in patients with advanced non-small cell lung cancer (NSCLC)Aim

Programmed cell death-1 (PD-1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) are inhibitory regulators of T cell activation. MEDI4736 (M) is a human IgG1 mAb, engineered to prevent ADCC activity, that blocks PD-L1 binding to PD-1 and CD-80. Tremelimumab (T) is a human IgG2 monoclonal antibody directed against CTLA-4. M + T in NSCLC may have greater antitumor activity compared with each agent alone.

Methods

A Phase 1 study (NCT02000947) is evaluating the safety/tolerability, pharmacokinetics, immunogenicity and antitumor activity of M + T in patients (pts) with NSCLC. The study has dose-escalation phase and dose-expansion phase (immunotherapy-naïve and -pretreated cohorts). The study will assess pharmacokinetic, pharmacodynamic parameters, including serum/tissue PDL1, immune cell phenotypes and cytokine profiling. Pharmacogenomic analysis of blood/tumor samples may be performed to examine gene expression patterns at baseline versus changes in response to treatment.

Results

As of April 23, 2014, 12 pts were treated: 3 pts each in Cohort 1a (3 mg/kg M + 1 mg/kg T), Cohort 2a (10 mg/kg M + 1 mg/kg T); Cohort 3a (15 mg/kg M + 1 mg/kg T), Cohort 3b (10 mg/kg M + 3 mg/kg T). Pts had 2–5 lines of prior therapy (Median = 3). ECOG PS ranged from 0–1. The most frequent drug-related AEs (reported in ≥ 2 pts) included increased amylase, abdominal pain, arthralgia, colitis, diarrhea, epigastric discomfort, fatigue and nausea. ≥Grade (Gr) 3 drug-related AEs: 2 pts with Gr 3 (Cohort 2a: increased AST/ALT, 3b: diarrhea/colitis), 1 pt with Gr 4 (Cohort 3a: increased amylase), and 1 pt with Gr 5 (Cohort 2a: myasthenia gravis resulting in respiratory failure). Drug-related AEs leading to treatment discontinuation: 2 pts (Cohort 2a: increased ALT, myasthenia gravis, 3b: colitis). On first assessment at 8 weeks for 12 subjects: 2 unconfirmed PRs, 3 additional pts with tumor shrinkage not meeting PR, and 5 pts (Cohort 1a: 3; Cohort 3b: 2) with PD. 10 pts remain on study.

Conclusions

The current safety profile and early anti-tumor activity of M + T supports continued clinical assessment.