ESMO 2018: News in Oncology - Ovarian Cancer

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LBA36 - Association of PD-L1 expression and gene expression profiling with clinical response to pembrolizumab in patients with advanced recurrent ovarian cancer: results from the phase 2 KEYNOTE-100 study

Speaker:
Jonathan A. Ledermann (London, GB)

Results from the KEYNOTE-100 trial (NCT02674061) suggest that pembrolizumab (pembro) has clinical activity in patients (pts) with advanced ovarian cancer (AOC), and also suggests that PD-L1 expression (combined positive score [CPS] ≥10) was associated with response. This abstract explored other biomarkers that could be associated with response. In addition to PD-L1 CPS, T-cell-GEP (T-cell-inflamed 18-gene expression profile) was associated with a response to pembro monotherapy for treatment of AOC in a single-arm setting, while HRD (homologous recombination deficiency) biomarkers (like HRD genomic scar and BRCA 1/2 mutations) were not found to be associated with response.

937PD - A phase 2 trial of combination nivolumab and bevacizumab in recurrent ovarian cancer

Speaker:
Joyce F. Liu (Boston, US)

Single agent trials of immune checkpoint inhibitors that target PD1 or PDL1 have shown modest effect in ovarian Cancer.  VEGF (vascular endothelial growth factor) has demonstrated immune-suppressive functions through mechanisms such as impairment of dendritic cell function and maturation. As a result, anti-VEGF therapy may enhance immunotherapeutic responses when combined with immune checkpoint inhibitors. This abstract presents results from a trial to investigate the combination of the anti-VEGF agent bevacizumab and the PD1 inhibitor nivolumab in women with recurrent ovarian cancer.  Combination nivolumab + bevacizumab demonstrated clinical activity in women with recurrent ovarian cancer, with an overall confirmed response rate of 21% and a median PFS of 9.4 months. Further studies of anti-angiogenic and immune checkpoint blockade combinations in ovarian cancer are warranted.

LBA35 - TROPHIMMUN, a 2 cohort phase II trial of the anti-PD-L1 monoclonal antibody avelumab in chemo-resistant gestational trophoblastic neoplasia (GTN) patients: preliminary outcomes in cohort A

Speaker:
Benoit M. You (Lyon, FR)

PD-L1 is constitutively expressed in all GTN subtypes (Bolze et al. Int J Gynecol Cancer 2017).  The objective of the TROPHIMMUN trial is to assess the efficacy of the anti-PD-L1 monoclonal antibody avelumab in patients with chemoresistant GTN.  Preliminary TROPHIMMUN trial outcomes suggest that avelumab might be effective, and better tolerated than standard chemotherapy in patients with resistance to single chemotherapy. This is the first clinical trial reporting potential cures with a non-chemotherapy agent in patients with this rare cancer.

ESMO 2018: News in Oncology - Metastatic Breast Cancer

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290O - Patient-reported outcomes (PROs) in advanced breast cancer (ABC) treated with ribociclib + fulvestrant: results from MONALEESA-3

Speaker:
Peter A. Fasching (Erlangen, DE)

In the MONALEESA-3 trial (NCT02422615), ribociclib + fulvestrant significantly improved progression-free survival (PFS) vs placebo + fulvestrant in patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative BC who had received no prior therapy or only 1 line of prior endocrine therapy for ABC.  This abstract presents PROs from the MONALEESA-3 trial including health-related quality of life (HRQoL).  According to the trial results, mean GHS/QLS (global health status/quality of life scale score of the EORTC QLQ-C30 questionnaire) was maintained or improved during every cycle of treatment in both arms.  Ribociclib + fluvestrant significantly prolonged PFS compared to placebo + fluvestrant while maintaining QoL.  

291O - Ribociclib (RIB) + tamoxifen (TAM) or a non-steroidal aromatase inhibitor (NSAI) in premenopausal patients (pts) with hormone receptor-positive (HR+), HER2-negative (HER2–) advanced breast cancer (ABC): MONALEESA-7 patient-reported outcomes (PROs)

Speaker:
Nadia Harbeck (Munich, DE)

In the Phase III MONALEESA-7 trial (NCT02278120), RIB + TAM/NSAI + goserelin (GOS) significantly improved progression-free survival vs placebo (PBO) + TAM/NSAI + GOS in premenopausal pts with HR+, HER2– ABC.  This abstract features PRO updates from the MONALEESA-7 trial.  According to PROs, RIB + TAM/NSAI + GOS improves HRQoL and maintains functioning, work productivity, and activity in premenopausal pts with HR+, HER2– ABC. RIB + TAM/NSAI + GOS is also associated with a clinically meaningful reduction in pain vs PBO + TAM/NSAI + GOS.

292O - Patient-reported outcomes (PRO) in patients (pts) with advanced breast cancer and a germline BRCA1/2 mutation (gBRCAm) receiving talazoparib (TALA) vs physician’s choice chemotherapy treatment (PCT): a focus on the EMBRACA triple negative (TNBC) subpopulation

Speaker:
Hope S. Rugo (San Francisco, US)

One of the key subgroup analyses of the EMBRACA trial (a randomized 2:1 open-label phase 3 study) revealed a statistically significant improvement in progression-free survival (PFS) with TALA vs PCT in pts with advanced TNBC and gBRCAm.  This abstract reports on a post hoc analysis of PROs from the EMBRACA trial. In pts with gBRCAm advanced TNBC, TALA resulted in significantly greater improvement from baseline and delayed TTD (time to deterioration) in GHS/QoL (global health status/quality of life) and pain symptoms vs PCT.

ESMO 2018: News in Oncology - Early Stage Breast Cancer

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LBA12_PR - PERSEPHONE: 6 versus 12 months (m) of adjuvant trastuzumab in patients (pts) with HER2 positive (+) early breast cancer (EBC): cost effectiveness analysis results

Speakers:
Claire Hulme (Leeds, GB) and Peter Hall (Edinburgh, GB)

Adjuvant trastuzumab has significantly improved outcomes for HER2+ EBC, using the 12m (month) duration empirically adopted from pivotal registration trials. Given the annual per patient cost of trastuzumab treatment, a shorter duration has the potential to improve cost-effectiveness if efficacy is maintained.  According to results from the PERSEPHONE trial, 6m of trastuzumab treatment was shown to be cost effective compared to 12m of trastuzumab treatment with no evidence of a detriment to quality of life. 

185O_PR - Serum assessment of non-adherence to adjuvant endocrine therapy (ET) among premenopausal patients in the prospective multicenter CANTO cohort

Speaker:
Barbara Pistilli (Villejuif, FR)

Previous studies have demonstrated that younger patients (pts) with breast cancer (BC) are more likely to be non-adherent to adjuvant ET, leading to impaired prognosis.  According to the results of this CANTO cohort study, at one year from initiation of TAM (tamoxifen), plasma measurements show that a substantial proportion of premenopausal pts are not adequately adherent to this treatment. Poorly-adherent pts could benefit from metabolic and pharmacogenetic investigations. Identification of pts at risk of non-adherence allows early targeted interventions to promote adherence in this unique population.

186O - Tumor-infiltrating lymphocytes (TILs) as an independent prognostic factor for early HER2+ breast cancer patients treated with adjuvant chemotherapy and trastuzumab in the randomized ShortHER trial

Speaker:
Maria Vittoria Dieci (Padova, IT)

TILs are an established prognostic factor for triple negative breast cancer and the ShortHER trial investigated the prognostic role of TILs for HER2+ early breast cancer patients.  According to the trial results, TILs are an independent prognostic factor for HER2+ early breast cancer patients treated with adjuvant chemotherapy and trastuzumab. Integration of TILs in prognostic algorithms could help refine risk stratification and guide therapeutic de-escalation.

ESMO 2018: News in Oncology - Metastatic Non-Small Cell Lung Cancer (NSCLC)

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LBA50 - Mechanisms of acquired resistance to first-line osimertinib: preliminary data from the phase III FLAURA study

Speaker:
Suresh S. Ramalingam (Atlanta, US)

In the phase 3 FLAURA study, osimertinib showed efficacy in patients (pts) with previously untreated EGFRm (epidermal growth factor receptor mutant) advanced NSCLC compared to standard of care (SoC).  This abstract reports on the mechanisms of acquired resistance to osimertinib experienced by pts who progressed on the FLAURA study. In line with previous analyses, T790M was acquired in approximately 50% of SoC-treated pts, and none of the osimertinib‑treated pts; no unexpected resistance mechanisms were observed in osimertinib-treated pts. Exploration into novel acquired mutations is ongoing.

LBA52 - Results of the GEOMETRY mono-1 phase II study for evaluation of the MET inhibitor capmatinib (INC280) in patients (pts) with METΔex14 mutated advanced non-small cell lung cancer (NSCLC)

Speaker:
Juergen Wolf (Cologne, DE)

MET mutations leading to exon 14 deletion (METΔex14) occur in 3-4% of NSCLCs.  Capmatinib is a highly potent and selective MET inhibitor and GEOMETRY mono-1 is a multi-cohort, multicenter study (NCT02414139), evaluating capmatinib in pts with METΔex14 mutated or MET amplified advanced NSCLC. In this study, Capmatinib has demonstrated a clinically meaningful response rate and a manageable toxicity profile in pts with METΔex14 mutated NSCLC, particularly in treatment naive pts where the ORR by BIRC (blinded imaging review committee) is 72%.

1377O - Phase 2 study of tepotinib + gefitinib (TEP+GEF) in MET-positive (MET+)/epidermal growth factor receptor (EGFR)-mutant (MT) non-small cell lung cancer (NSCLC)

Speaker:
Yi-Long Wu (Guangzhou, CN)

Patients with NSCLC can acquire resistance to EGFR tyrosine kinase inhibitors (EGFR TKIs) via MET activation, therefore dual MET/EGFR inhibition may have potential in EGFR TKI-resistant NSCLC. Tepotinib (TEP) is a potent, selective MET TKI and gefitinib (GEF) is an EGFR inhibitor. According to the results of this phase 2 study, the tepotinib + gefitinib combination (TEP+GEF) shows promising antitumor activity in pts with MET protein overexpression (IHC3+) and gene amplification EGFR-MT NSCLC.  TEP + GEF was well-tolerated in this study.   

ESMO 2018: News in Oncology - Sarcoma

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LBA67 - Cabozantinib in patients with advanced osteosarcomas and Ewing sarcomas: a French Sarcoma Group (FSG)/ US National Cancer Institute phase II collaborative study

Speaker:
Antoine Italiano (Bordeaux, FR)

Patients with relapsed and unresectable high-grade osteosarcoma (OS) and Ewing sarcoma (ES) have had a dismal and unchanging prognosis over the last decades.  There are currently no approved drugs for this challenging setting but pharmacologic inhibition of MET signaling and of aberrant angiogenesis has shown promise in pre-clinical OS and ES models.  This late-breaking abstract suggests that carbozantinib has shown meaningful clinical activity in OS and ES patients with heavily pre-treated advanced disease and reached the primary efficacy endpoints in both the OS and ES cohorts. 

1603O - Initial results of phase 1 study of DCC-2618, a broad-spectrum KIT and PDGFRa inhibitor, in patients (pts) with gastrointestinal stromal tumor (GIST) by number of prior regimens

Speaker:
Suzanne George (Boston, US)

DCC-2618 is a switch control inhibitor which broadly inhibits mutations in the KIT exons 9,11,13, 14, 17 and 18.  Results presented at ESMO 2018 suggest that DCC-2618 demonstrated encouraging clinical benefit and a favorable tolerability profile in GIST pts treated in the 2nd line or later.  Initiation of a second Phase 3 study for this agent in 2nd line GIST pts is anticipated by the end of 2018.

Press Release: CARE National Congress 2018

The second National CARE Congress: Update on Biosimilars and Access to Innovation will be held at the Shangri-La Hotel in Toronto on April 6th, 2018. This year’s meeting seeks to address questions and considerations regarding biosimilars in Canada and how they build towards a larger discussion on access to innovative medicine. The CARE Congress will involve stakeholder representation from leading Canadian specialists (gastroenterology, hematology, oncology, respiratory medicine, dermatology, and rheumatology); allied health care (nurses, pharmacists); government, legal, ethical, associations, health economists, advocacy groups, industry, and public and private payers.

This meeting will include discussion and will provide a platform for key stakeholders across multiple fields to meet, collaborate, and discuss concepts that have a practical impact on the Canadian healthcare landscape.

Biosimilars are drugs that may replace expensive biologic drugs that are going off patent. The CARE faculty has been looking at the impact of biosimilars since 2015, given the significance of this topic across both chronic and disease entities. This meeting will consider the evolving impact biosimilars will have in the Canadian landscape both clinically and systemically. It will also consider how the adoption of biosimilars can support access to innovation, asking the questions “how do we incorporate/afford innovative drugs and ensure access to improve patient outcomes”?

The Aim of the CARE Congress is to allow assembled faculty and panelists to consider the use of biosimilars and align on the importance of access to innovation.

Meeting Format – the meeting will be divided into two distinct sessions:

Section 1 – Update on biosimilars

The meeting will open with an update on where CARE Faculty and assembled stakeholders sit on a continuum of understanding, as well as information and data needed to increase comfort levels and adoption of biosimilars.

Section 2 – Access to innovation

The second part of the meeting will focus on access to innovation. A series of speakers will:

  • Review impact of innovative medicine
  • Project where innovation is heading and the costs associated
  • Review approval process for innovation at federal level and access considerations by both public and private payers
  • Reflect on systemic challenges to access innovative medicine
  • Consider the ethical, legal and economic challenges with access to innovation

CARE Faculty believes in:

  • Developing clinical practice through optimization of current therapies
  • Improving patient outcomes by developing innovative therapeutics
  • Ensuring access to quality care for all Canadians by the responsible and evidence-based use of treatment
  • Welcoming competition to improve efficiency and access to innovation

For more information on the steering faculty, assembled CARE Faculty, speaker list, or for questions/information needs regarding CARE, please contact Erica Duncan.

NACF 2017: News in Respirology

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CYSTIC FIBROSIS

NACF 2017. P247. Efficacy and Safety of Tezacaftor/Ivacaftor in Patients Aged ≥12 Years with CF Homozygous for F508del-CFTR: A Randomized Placebo-Controlled Phase 3 Trial

 J. Taylor-Cousar, et al.

Results:

509 pts received ≥1 dose of tezacaftor (VX-661; TEZ)/ivacaftor (IVA) (n=251) or placebo (PBO) (n=258). Baseline (BL) characteristics were well balanced between groups. There was a significant treatment effect favouring TEZ/IVA in absolute change in ppFEV1 (4.0 percentage points; 95% CI 3.1, 4.8; P<0.0001); a similar effect was seen in pts with ppFEV1 <40 at BL (TEZ/IVA [n=23] vs PBO [n=24]: 3.5 percentage points; 95% CI 1.0, 6.1; P=0.0070). Treatment differences for relative change in ppFEV1 and pulmonary exacerbations (Pex) (event rate, 0.64 vs 0.99; P=0.0054 [negative binomial regression]) met statistical significance while the comparison for change in BMI did not. Effects favouring TEZ/ IVA in CFQ-R and sweat chloride were nominally significant. In pts who had treatment-emergent adverse events (AEs), the majority were mild (TEZ/IVA 45.4% vs PBO 38.4%) or moderate (TEZ/IVA 36.3% vs PBO 45.3%); the most common were infective PEx (TEZ/IVA 29.9% vs PBO 37.2%), cough (26.3% vs 32.6%), headache (17.5% vs 14.3%), nasopharyngitis (16.7% vs 15.1%), and sputum increased (14.3% vs 16.3%). Predefined respiratory events occurred in 13.1% of pts in the TEZ/IVA arm and 15.9% in the PBO arm. Discontinuations due to AEs occurred in 2.8% (TEZ/IVA) and 3.1% (PBO) of pts; none were due to respiratory events. Serious AEs were reported in 12.4% (TEZ/IVA) and 18.2% (PBO) of pts, and no deaths were reported.

Conclusions:

Significant improvements in ppFEV1, PEx rate, CFQ-R score (nominal), and sweat chloride (nominal) were observed with 24 wks of TEZ/IVA vs PBO. Treatment was well tolerated with few discontinuations due to AEs. Incidence of respiratory events was similar between PBO and TEZ/IVA, and none resulted in treatment discontinuation. These study results support the safety and efficacy of TEZ/IVA in pts with CF homozygous for F508del-CFTR.

 

NACF 2017. P273. Efficacy and Safety of Tezacaftor/Ivacaftor and Ivacaftor in Patients Aged ≥12 Years with CF Heterozygous for F508del and a Residual Function Mutation: A Randomized, Double blind, Placebo-Controlled, Crossover Phase 3 Study

 S. Rowe, et al.

Results:

Pts received tezacaftor (VX-661; TEZ)/ivacaftor (IVA) (TEZ/ IVA) (n=161), IVA monotherapy (n=156), or placebo (PBO) (n=161). Study baseline characteristics were balanced between groups (mean [SD] ages (y), 35.6 [13.5], 36.3 [15.2], and 32.6 [13.9] and mean [SD] baseline ppFEV1, 61.8 [14.9], 62.8 [14.6], and 62.1 [14.0] percentage points for TEZ/IVA, IVA, and PBO). Significant treatment effects were observed for TEZ/IVA and IVA in absolute ppFEV1 and CFQ-R respiratory domain score vs PBO. In addition, the treatment difference of absolute ppFEV1 between TEZ/IVA and IVA was statistically significant in favour of TEZ/ IVA. The majority of adverse events (AEs) were mild (TEZ/IVA 35.8%; IVA 35.0%; PBO 38.9%) or moderate (34.0%; 32.5%; 33.3%). The most common AEs (>10%) were infective pulmonary exacerbation of CF, cough, headache, and haemoptysis. No increase in respiration abnormal with TEZ/IVA was observed. No treatment discontinuations due to AEs were reported in the TEZ/IVA group vs 1.3% IVA and 0.6% PBO. Serious AEs were reported (TEZ/IVA 4.9%; IVA 6.4%; PBO 8.6%). No deaths occurred during the study.

Conclusions:

Significant improvements in ppFEV1 and CFQ-R respiratory domain were seen with TEZ/IVA and IVA treatment vs PBO. Significant improvement in ppFEV1 was also seen with TEZ/IVA vs IVA. Treatments were well tolerated with no (TEZ/IVA) or few (IVA) discontinuations due to AEs. These findings support safety and efficacy of TEZ/IVA and IVA in pts with CF heterozygous for F508del and a second mutation resulting in CFTR residual function.

CARE FACULTY PERSPECTIVE:

The two studies on tezacaftor-ivacaftor show that this combination therapy improves lung function (FEV1) and reduces exacerbation rate in CF patients with the most common genotype (Phe508del/ Phe508del) similar to lumacaftor-ivacaftor (OrkambiTM) but with better tolerability, and also improves lung function in patients with a residual function mutation, to a similar degree as ivacaftor monotherapy. Whether the combination of improved FEV1 and reduced exacerbation rate will result in greater treatment effects over time is unclear at this point though conceivable, as exacerbations contribute to a more rapid pulmonary function decline. Results from the open-label extension studies in which the majority of the study subjects were enrolled, may help clarify this in the near future.

While these studies demonstrate that CFTR modulating therapies have beneficial effects on some aspects of the disease, the clinical benefit of the current combination therapies for CF patients with the most common CFTR genotype (Phe508del/ Phe508del) falls within the range of established symptomatic therapies such as nebulized inhaled hypertonic saline or recombinant human DNAse. There is still an unmet need for truly effective new therapies to be developed for all individuals with CF. The complete study results on tezacaftor-ivacaftor combination therapy were recently published in the New England Journal of Medicine (Taylor-Cousar JL, et al., and Rowe SM, et al., N Engl J Med. 2017 Nov 3. [Epub ahead of print]), with an accompanying Editorial (Grasemann H, N Engl J Med. 2017 Nov 3. [Epub ahead of print]).

Whether new CFTR targeting combination therapies that are in the drug development pipeline, will ultimately result in clinically meaningful improvement of lung function and clinical status needs to be seen. Preliminary results presented by Dr. E. Tullis from Toronto suggest that the addition of a second corrector to corrector/potentiator combination regimens can result in improved efficacy of CFTR modulator therapy.