Clinical Trial Insights

The annual European meeting offers insights into new data from ongoing clinical trials as well as a chance to discuss the implications of recently reported trial outcomes presented a few short months ago at ASCO. Pennside has reviewed the program in detail and we offer our assessment of key presentations at the meeting for drug developers and biotech.

 

Our Assessment of ESMO Key Presentations:

CRC

  • Analysis of KRAS/NRAS and BRAF mutations in FIRE-3:A randomized phase III study of FOLFIRI plus cetuximab or bevacizumab as first-line treatment for WT KRAS (exon 2) mCRC(abst#17, embargoed)
    • Data at ASCO this past June showed that there was no benefit from Vectibix for patients with NRAS mutations—it will be interesting to see if this also holds true for Erbitux in this biomarker analysis from the FIRE-3 trial.
  • ASPECCT: a randomized, multicenter, open-label, phase 3 study of panitumumab (pmab) vs cetuximab (cmab) for previously treated WT KRAS mCRC (abst#18, embargoed)

    • This is a head to head trial of Vectibix vs. Erbitux in the 3rd line setting—maybe one agent will come out ahead of the other, but most likely they will report similar data, possibly with some differences in safety.
  • Effects of regorafenib therapy on health-related quality of life in patients with metastatic colorectal cancer in the phase III CORRECT study (abst#2156)

    • TKIs have a history of poor tolerability in CRC, and Stivarga in particular was concerning because of its use in the 3/4th line palliative setting. However, this analysis appears to show that Stivarga is not detrimental to QOL, and any AEs are manageable with dose modifications.
  • Aflibercept in combination with FOLFIRI for the second-line treatment of patients with metastatic colorectal cancer: Interim safety data from the global Aflibercept Safety and Quality-of-Life Program (ASQoP and AFEQT studies) (abst#2276)
    • There is growing concern within the CRC community that while Zaltrap’s efficacy is similar to Avastin in 2nd line CRC, the tolerability is poor. The data from this study suggests that Zaltrap’s AEs are manageable and may even be lower in the real-world setting vs. the VELOUR trial. 

NSCLC

  • A phase III study of belagenpumatucel-L therapeutic tumor cell vaccine for non-small cell lung cancer (NSCLC). (LBA2, embargoed)
    • Given the recent vaccine trial failure by GSK in melanoma, we eagerly await the results of the STOP trial for belagenpumatucel-L (aka Lucanix).
  • Clinical activity, safety and biomarkers of PD-L1 blockade in non-small cell lung cancer (NSCLC): Additional analyses from a clinical study of the engineered antibody MPDL3280A (anti-PDL1). (3408, embargoed)
    • Key question for followers of PD-1/PD-L1: is there an efficacy/safety differences between inhibiting either target? If not – then it is a race to “first to market”
  • Prognostic and predictive role of kras mutations in patients with advanced non small cell lung cancer treated with docetaxel or erlotinib as second line treatment in the TAILOR trial. (LBA32, embargoed)
    • Anything new to learn regarding Kras status in NSCLC? What does a positive Kras status mean for ~20%+ of patients with adenocarcinoma? Hopefully the data will shed new light on this area rather than just casting an intriguing shadow of continued confusion for those who follow NSCLC.

BrCa

  • T-DM1 for HER2-positive metastatic breast cancer (MBC): Primary results from TH3RESA, a phase 3 study of T-DM1 vs. treatment of physician’s choice (15, embargoed)
    • The TH3RESA trial may provide rationale for the use of Kadcyla in the 3rd line setting for patients who have progressed on Herceptin and Tykerb.  This trial could provide Roche with even more of a stronghold on the HER2+ disease state.
  • PARP inhibition with BMN 673 in ovarian and breast cancer patients with deleterious mutations of BRCA1 and BRCA2 (29, embargoed)
    • This data release will provide evidence of the potency of next generation PARPs and will, if successful provide quicker enrollment in the Phase III trial. 

PnCa

  • Additional data from the MPACT trial of Abraxane + gemcitabine vs. gemcitabine in metastatic PnCa (PET response, 2577; peripheral neuropathy, 2583; dosing, 2586)
    • Abraxane was recently approved in the US for the treatment of pancreatic cancer. These three studies will give us more information on response, side effects, and dosing.
  • GVAX/CRS207 (2590)
    • This is a new immunotherapy approach for the treatment of pancreatic cancer.  The Ph II study was stopped early due to positive OS results for the combination of GVAX/CRS207 vs. GVAX alone.

Melanoma

  • As it was at ASCO, Melanoma and immunotherapy will be on the hot seat again at this meeting with key presentations in the opening session: Mobilizing the Immune System to Treat Cancer (S, Topalian)
    • With hundreds of mutations extant in patients with advanced cancer, the only way to address the disease is systemically. Immunotherapies are an excellent approach, and research is bearing fruit.
  • Vemurafenib and MEK inhibitor, cobimetinib , in advanced BRAFV600-mutated melanoma : Dose-escalation and expansion results of a phase IB study (3703)
    • This MEK/BRAF combination is a very fast follower  of the recently approved GSK agents trametinib and dabrafenib.  Although the two GSK drugs were approved separately, data from ASCO suggests that the combo is better, and KOLs seem to agree that this will become the new standard of care. The two drugs in this study are from Roche who aims to take market share from GSK as quickly as they can. 

HCC

  • Sorafenib alone versus Sorafenib combined with Gemcitabine and Oxaliplatin (GEMOX) in the first-line treatment of advanced hepatocellular carcinoma: Final analysis of the randomized phase II GoNext trial (a UNICANCER / FFCD / PRODIGE 10 study) (2467)
    • This is an update of the previous positive data that was presented at ASCO 2013 this past June—the regimen of Nexavar and GEMOX chemo appears to be active in this population of first line HCC.
  • Efficacy and safety of nintedanib vs sorafenib in Asian patients with advanced hepatocellular carcinoma (HCC): A randomised Phase II trial (2580)
    • This study demonstrated that nintedanib has similar efficacy to Nexavar, but with improved tolerability.  As toxicity is a major issue in HCC due to poor patient condition, any agents with improved safety and at least equal efficacy to standard of care would be a welcome addition to the treatment algorithm.
  • Subgroup analysis of prognostic factors for overall survival in the SHELTER trial evaluating resminostat in advanced hepatocellular carcinoma (HCC) – the SHELTER Study Group (2601)
    • Data released earlier this month at ILCA showed the potential for a biomarker to select patients most likely to respond to resminostat, and this analysis of subpopulations from the Ph I/II SHELTER study of resminostat alone or in combination with sorafenib may help further define the ideal patient population for this developmental HDAC inhibitor. In particular, the combination of resminostat and sorafenib shows encouraging activity in second line patients who progressed on prior sorafenib.

ThyCa

  • Progressive, metastatic medullary thyroid cancer: Baseline symptoms and disease characteristics among patients enrolled in the EXAM trial (3154)
    • The results from this analysis of the EXAM trial of cabozantinib in medullary thyroid cancer suggest that, despite the common perception that this is an indolent tumor, many patients that present with radiologic findings of progressive disease actually have high disease burden and related symptoms. This justifies approval of two targeted agents in MTC (cabozantinib and vandetanib), as many patients will inevitably need an efficacious therapy once they reach the point of high disease burden.
  • Association between tumor BRAF and RAS mutation status and clinical outcomes in patients with radioactive iodine (RAI)-refractory differentiated thyroid cancer (DTC) randomized to sorafenib or placebo: Sub-analysis of the phase III DECISION trial (3155)
    • This biomarker analysis of the DECISION explored the effect of RAS and BRAF mutations on benefit from Nexavar. While all patients, regardless of mutational status, appeared to benefit from therapy, those with RAS mutations had lowered PFS, while patients with BRAF mutations had improved PFS. Since all patients benefitted from Nexavar, it is unlikely that these biomarkers would be used to select patients for therapy, but important to know that the benefit exists regardless of mutational status.
  • An open-label, multi-center phase 2 study of the BRAF inhibitor vemurafenib in patients with metastatic or unresectable papillary thyroid cancer positive for the BRAF V600 mutation and resistant to radioactive iodine (28, embargoed)
    • There is a lot of excitement surrounding the use of BRAF inhibitors in patients with BRAF V600 mutated thyroid tumors. This late-breaking abstract for vemurafenib will be a first look at the potential promise of these agents in RAI-refractory thyroid cancer. 

GBM

  • Bevacizumab, irinotecan and radiotherapy versus standard temozolomide and radiotherapy in newly diagnosed, MGMT-non-methylated glioblastoma patients: Updated results from the randomized multicenter GLARIUS trial (3300)
    • This is an update of the data presented at ASCO 2013 this past June. Again, it appears that Avastin/irinotecan therapy prolong PFS in patients with MGMT non-methlyated GBM, where SOC TMZ therapy is ineffective and an active regimen is needed.
  • Efficacy and safety of bevacizumab (Bv) plus standard combination temozolomide (T) and radiotherapy (RT) in newly diagnosed glioblastoma: Final results from AVAglio (3301)
    • An update of the AVAglio data presented at ASCO—final OS data will be presented at the meeting. The additional data coming at ESMO may help clarify the role of Avastin in GBM, where data has been inconsistent. 

STS

  • PICASSO 3: A phase 3 international, randomized, double-blind, placebo-controlled study of doxorubicin (dox) plus palifosfamide (pali) vs. dox plus placebo for patients (pts) in first-line for metastatic soft tissue sarcoma (mSTS) (3802)
    • The failure of the PICASSO trial once again shows the need for more targeted trial designs in Soft Tissue Sarcoma.  KOLs continue to press for better targeted trials in this difficult group of diseases.
  • Final results of sequential phase 2 studies of palbociclib
    (PD0332991) in CDK4-amplified liposarcoma  (3826)

    • The use of CDK4 amplification as a biomarker may provide palbociclib with a targeted approach in Sarcoma that will prove effective.  The Phase III trial is being planned. 

NET

  • A randomized, double-blind, placebo-Controlled study of Lanreotide Antiproliferative Response in patients with gastroenteropancreatic  NeuroEndocrine Tumors (CLARINET). (LBA3, embargoed)
    • IPSEN has announced that lanreotide has meet it’s primary endpoint in the CLARINET and ELACT trials.  The presentation on Saturday should give us insights into the robustness of the data and an expectation for ELECT at ASCO GI in January, 2014.