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.

EHA 2017: News in Hematology

Chronic Lymphocytic Leukemia: Ibrutinib Monotherapy

EHA 2017. S769. Long-term Efficacy and Safety with Ibrutinib in Previously Treated CLL: Up to Four Years Follow-up of the RESONATE Study

Byrd, John C et al.

Results: A total of 391 patients were randomized to receive ibrutinib (n=195) or ofatumumab (n=196). The median age was 67 years, with 40% age ≥70 years, and Rai stage III/IV in 57% of patients. At a median follow-up of 44 months (maximum 53 months) for the ibrutinib arm, PFS was significantly longer for ibrutinib vs ofatumumab (median NR vs 8 months, [HR 0.133; P<0.0001]). The 3-year PFS was 59% for ibrutinib vs 3% for ofatumumab. A significant PFS benefit was observed across baseline subgroups. In the ibrutinib arm, PFS for the del11q subgroup trended to have the most favorable outcome; however, PFS outcomes were not statistically different for patients with del17p or del11q or patients without these FISH abnormalities. At time of analysis, with the majority of patients randomized to ofatumumab (68%) crossing over to receive ibrutinib therapy, OS was longer for ibrutinib vs ofatumumab (median OS NR for either arm). The 3-year OS rate for ibrutinib was 74%. The ORR for ibrutinib was 91% with a CR/CRi rate that increased over time (currently 9%). Baseline cytopenias improved with extended ibrutinib therapy for hemoglobin (85% of patients), platelet (95% of patients), and absolute neutrophil counts (95% of patients). The adverse event (AE) profile of ibrutinib was consistent with previous reports. During a follow-up of up to 4 years, major hemorrhage occurred in 6%, grade ≥3 atrial fibrillation occurred in 6%, and grade ≥3 hypertension occurred in 8% of patients. The incidence of most grade ≥3 AEs decreased from year 1 vs year 2-3: neutropenia: 18% vs 8%; pneumonia: 11% vs 4%; atrial fibrillation: 4% vs 2%, respectively. The most frequent reasons for treatment discontinuation were progressive disease (27%) and AEs (12%). At analysis, 90 patients randomized to ibrutinib (46%) continue to receive ibrutinib.

Conclusion: In this international phase 3 RESONATE study with median follow-up of up to 4 years, long-term treatment with ibrutinib showed a favorable tolerability profile with sustained PFS and OS benefit regardless of high-risk cytogenetics. The results in relapsed del17p and del11q patients compared favorably to those previously reported in phase 2 studies.

Clinical trial information: NCT01578707

CARE Faculty Perspective: Ibrutinib improves long-term survival outcomes, especially in patients with relapsed/refractory CLL who are not eligible for chemotherapy approaches.

This phase 3 RESONATE trial confirmed these positive survival effects in terms of PFS and OS, while maintaining a favourable tolerability profile.  Furthermore, at the recent International Workshop on Chronic Lymphocytic Leukemia, pooled data from the RESONATE, RESONATE-2, and HELIOS trials were presented. Ibrutinib achieved higher CR rates, ORR rates, PFS, and OS when compared with other agents. This pooled analysis confirms the data from the original studies and highlights the efficacy of ibrutinib as monotherapy or as part of a combination.

Access & Innovation Considerations - The main concerns with ibrutinib use relate to toxicities that may limit its use or lead to the introduction of alternative therapies. Ibrutinib resistance is another clinical challenge. A better understanding of the mechanisms of resistance to monotherapy and combination strategies as well more in depth understanding of the effects of ibrutinib on immune effectors will be of benefit for practicing clinicians.

ASCO 2017: News in Genitourinary Cancer - High Risk Prostate Cancer

ASCO 2017. LBA 3. LATITUDE: A phase III, double-blind, randomized trial of androgen deprivation therapy with abiraterone acetate plus prednisone or placebos in newly diagnosed high-risk metastatic hormone-naive prostate cancer.

Karim Fizazi et al.

Results:

 

Conclusions: Early use of AA+P added to ADT in pts with high-risk mHNPC yielded significantly improved OS, rPFS, and all secondary end points vs ADT+PBOs alone. ADT+AA+P had a favorable risk/benefit ratio and supports early intervention with AA+P in newly diagnosed, high-risk mHNPC. 


ASCO 2017. LBA 5003. Adding abiraterone for men with high-risk prostate cancer (PCa) starting long-term androgen deprivation therapy (ADT): Survival results from STAMPEDE

Nicholas D. James et al.

Results: 1,917 pts were contemporaneously randomized to these arms (Nov 2011- Jan 2014). Groups were balanced: median age 67yrs; 52% metastatic, 20% N+/X M0, 28% N0M0; 95% newly-diagnosed; median PSA 53ng/ml. Median follow-up was 40m. There were 262 control arm deaths (82% PCa). The adjusted HR = 0.63 (95% CI 0.52-0.76; p=0.115x10-7; 184 deaths) for SOC+Abi vs SOC, with 3yr OS improved from 76% to 83%. There were 535 control arm FFS events; the adjusted HR = 0.29 (95% CI 0.25-0.34; p = 0.377x10-63, 248 FFS events) for SOC+Abi vs SOC. Grade 3 & 4 adverse events were seen in 29% & 3% SOC, 41% & 5% SOC+Abi; Grade 5: 3 & 9 (1 & 2 related). 

Conclusions: The results show a clinically & statistically significant effect on overall survival & failure-free survival from adding abiraterone at start of ADT with a manageable increase in toxicity. ADT (+/- RT) + abiraterone is a new standard of care for this group. Clinical trial information: NCT00268476

CARE Faculty Perspective:

Abiraterone has established a survival benefit for patients with advanced prostate cancer. The combination of abiraterone, prednisone, and androgen deprivation therapy (ADT) is able to stop the production of hormones directly at the testicular level and through inhibition of CYP17, an enzyme that convers cholesterol in androgens.

The STAMPEDE and LATITUDE trials support the use of upfront treatment of abiraterone with prednisone and ADT for advanced prostate cancer. The STAMPEDE trial investigated almost 2000 patients.  Patients were eligible if they had metastatic disease, or if they had local/locoregional disease with high risk features.  For all comers, the 3-year survival rate when adding abiraterone and prednisone to ADT was 83% compared to 76% when using ADT alone. The LATITUDE trial concluded that when abiraterone (with prednisone) is added to ADT therapy, a 38% improvement in OS was noted and PFS was 33 months compared with 14.8 months with ADT alone. These results could change the treatment paradigm of patients with advanced but castrate sensitive disease moving forward.

There is still much to be learned about the optimal treatment combination or sequence. We still do not know how abiraterone compares to docetaxel, and whether combination of the two is better than either agent alone. It will be interesting to see the results of trials looking at these types of combinations that are currently underway, such as the PEACE 1 & 2 trials and the ENZAMET study (although patients were randomized to enzalutamide or bicalutamide, roughly 50% of patients in either arms also received docetaxel as part of standard of care). This will give us an idea of the impact of abiraterone and docetaxel with ADT, and how the standard-of-care may be impacted.

Whether abiraterone is better than docetaxel, at least in patients with metastatic disease, remains untested in head to head randomized trials.  However, as eloquently shown by Eric Small during his discussion of the two studies, the results observed in LATITUDE seem to quite closely mirror the results of CHAARTED – given the cost and toxicity differences in these two treatment approaches, deciding on an optimal regimen in these patients may require a personalized approach and payers may potentially end up taking some the decisions away from the prescriber and patient. 

Treatment efforts do not end with this combination. It is also important to consider treatment sequencing after a patient [inevitably] progresses. Recent retrospective trials focused on sequencing have suggested that post- ADT, chemotherapeutic options (docetaxel followed by cabazitaxel) may extend OS. It is therefore important to monitor patients closely with PSA and regular imaging and not wait until symptomatic progression to consider further treatment. Otherwise, the opportunity to maximize subsequent lines of therapy may be less effective and/or not valid.

With the number of specialists involved in the management of prostate cancer (i.e. medical oncologists, urologists, radiation oncologists), collaboration and education on the entire course of therapy is of value, along with considerations for referral to another specialist if the patient’s current management approach is no longer working.