asco 2016 sarcoma review

The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute

2016 ASCO Update: Sarcoma David A Liebner, MD June 18, 2016

Ewing Sarcoma

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EURO-E.W.I.N.G. 99 § Large, multicenter study of Ewing Sarcoma open to all newly

diagnosed patients with Ewing Sarcoma <50 yrs §  Initial study design 1997 § Stratified by risk-category at presentation:

§ R1: Standard-risk localized disease (Le Deley et al., JCO 2014) § R2Loc: High-risk localized disease § R2Pulm: Metastatic to lung only § R3: Disseminated multifocal disease (Ladenstein et al., JCO

2010)

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EURO-E.W.I.N.G. 99 R2Loc

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EURO-E.W.I.N.G 99: High-Risk Localized Dz

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EURO-E.W.I.N.G 99: R2Loc Treatment Randomization

EURO-E.W.I.N.G 99: R2Loc

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Subset analyses § Suggests benefit may be

greatest in patients <25 yrs § Not statistically significant

(p=0.12) § Similar to other studies of dose-

intensification in EwS

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EURO-E.W.I.N.G 99: R2Loc Acute Toxicites

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EURO-E.W.I.N.G. 99: Rationale R2Loc

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Take Home: EURO-E.W.I.N.G. 99 (R2Loc) § Consolidation with BuMel x1 is associated with

improvements in EFS (HR = 0.64) and OS (HR = 0.60) in patients with: 1.  High-risk localized disease (R2Loc) 2.  Treated with induction chemotherapy with VIDE x 6 cycles 3.  Who are candidates for high-dose chemotherapy with

stem-cell rescue

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Discussion § Challenges to generalization of EURO-E.W.I.N.G. 99 results:

1.  VIDE induction chemotherapy is not the standard backbone for EwS in the United States

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AEWS0031: Dose-Dense Therapy in Localized Ewing Sarcoma

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AEWS0031: Impact on EFS and OS

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5-yr EFS: 73% vs 65% HR = 0.74 (p = 0.048)

5-yr OS: 83% vs 77% HR = 0.69 (p = 0.056)



2.  Among patients eligible for treatment on the R2Loc protocol, only 216 of 477 were randomized (45%)

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EURO-E.W.I.N.G. 99 R2Loc: Challenges to Accrual

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2.  Among patients eligible for treatment on the R2Loc protocol, only 216 of 477 were randomized (45%)

3.  Patients > 25 yrs did not clearly benefit

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Take Home: EURO-E.W.I.N.G. 99 (R2Loc) §  Impact of BuMel x 1 on EFS and OS is NOT clear for:

1.  Patients treated with an alternative induction regimen (e.g., VDC/IE), particularly dose-dense therapy

2.  The subset of patients with R2Loc disease who did not meet study criteria or who elected not to enroll (~55% of eligible subjects)

3.  Patients >25 yrs did not clearly benefit

§  Standard-of-care in the U.S. will likely remain dose-dense VDC/IE

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EURO-E.W.I.N.G. 99 R2Pulm

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EURO-E.W.I.N.G 99: Pulmonary Metastases

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EURO-E.W.I.N.G 99: R2Pulm Treatment Randomization

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Discussion: Challenges to Generalization

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EURO-E.W.I.N.G 99: R2Pulm

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Subset analyses § Suggests possible impact of

histologic response on optimal consolidation regimen: § VAI + WLI better in patients

with a suboptimal response to induction therapy with VIDE

§ BuMel better for patients with a good response to induction therapy

§ Possible association with patient age as well

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EURO-E.W.I.N.G 99: R2Pulm Acute Toxicites

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Take Home: EURO-E.W.I.N.G. 99 (R2Pulm) § Consolidation with BuMel x1 is NOT associated with

improvements in EFS or OS in patients with: 1.  Pulmonary metastatic disease (R2Pulm) 2.  Treated with induction chemotherapy with VIDE x 6 cycles 3.  Who are candidates for high-dose chemotherapy with

stem-cell rescue § Subset analyses suggest:

1.  A possible benefit to BuMel x 1 in patients with the best responses to induction chemotherapy (<10% viable cells)

2.  A possible benefit to VAI + WLI in patients with the worst responses to induction chemotherapy (>30% viable cells)

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Take Home: EURO-E.W.I.N.G. 99 (R2Pulm) §  Impact of BuMel x 1 on EFS and OS is difficult to generalize

to: 1.  Patients treated with an alternative induction regimen (e.g.,

VDC/IE) 2.  The subset of patients with R2Pulm disease who did not

meet study criteria or who elected not to enroll (~54% of eligible subjects)

§  Long-term follow-up will be needed given concerns for potential long-term toxicities of WLI and BuMel with stem-cell rescue

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Immunotherapy in Sarcoma

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An Ode to Coley!

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Nature Reviews Cancer 9, 361-371 (May 2009)

Ongoing Trials of Immunotherapy in Sarcoma

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SARC 028 Pembrolizumab

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SARC 028: Pembrolizumab in Sarcoma

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SARC 028: Pembrolizumab in Sarcoma

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SARC 028: Pembrolizumab (STS)

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SARC 028: Pembrolizumab (Bone Sarcoma)

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NCI-2014-02403 Nivolumab in uLMS

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Nivolumab in Uterine Leiomyosarcoma (uLMS)

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§  ≥1 response (RECIST 1.1) in stage 1 (n=12) required to open Stage 2

Nivolumab in uLMS

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• No objective responses noted: (ORR = 0%)

• Median PFS = 1.8 mo

Take Home: PD-1 inhibitors in Sarcoma § PD-1 inhibitor therapy in bone and soft-tissue sarcoma was

well-tolerated with no unexpected toxicities § Response rates (RECIST) appear to vary by histology

though sample sizes are small and definitive conclusions are not possible at this phase: § Soft-tissue sarcoma (SARC 028): 19% (7/37) § Bone sarcoma (SARC 028): 5% (2/38) § Uterine leiomyosarcoma: 0% (0/12)

§ Ongoing assessment of efficacy on trial is strongly preferred

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Promising Signal of PD-1 Inhibition in STS

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KEYNOTE-001 (NSCLC) SARC 028 (STS)

ORR = 19% Median PFS = 4.2 mo

ORR = 19.4% Median PFS = 3.7 mo

TKIs in Soft-Tissue Sarcoma

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Regorafenib in non-GIST Sarcoma

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Regorafenib in non-GIST Sarcoma

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• Placebo-controlled cross-over study of regorafenib in doxorubicin pre-treated STS (4 cohorts) conducted in France/Austria

Regorafenib in non-GIST Sarcoma § Relatively few patients had received a prior TKI (pazopanib)

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Regorafenib in non-GIST Sarcoma: PFS

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Regorafenib in non-GIST Sarcoma: PFS

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Take Home § Regorafenib is associated with improved PFS (HR = 0.36)

compared to placebo in patients with non-adipocytic soft-tissue sarcoma § Median PFS improved by 3 months (4.0 mo vs 1.0 mo) which

is comparable to the results seen in the phase 3 PALETTE study which led to the approval of pazopanib for non-adipocytic STS

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Take Home

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PALETTE trial (Lancet. 2012 May 19;379(9829):1879-86.)

Take Home § Regorafenib is associated with improved PFS (HR = 0.36)

compared to placebo in patients with non-adipocytic soft-tissue sarcoma § Median PFS improved by 3 months (4.0 mo vs 1.0 mo) which

is comparable to the results seen in the phase 3 PALETTE study which led to the approval of pazopanib

§ The study was not designed to detect any improvement in OS

§ Efficacy of regorafenib in patients with pazopanib-refractory disease is unknown due to small sample size

§ Pazopanib remains the preferred 1st line TKI in non-adipocytic STS

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PAPAGEMO: Pazopanib ± Gemcitabine

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PAPAGEMO: Pazopanib +/- Gemcitabine in STS

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PAPAGEMO: Pazopanib +/- Gemcitabine in STS

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PAPAGEMO: Primary Endpoint (PFS)

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PAPAGEMO: Secondary Endpoint (OS)

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PAPAGEMO: Toxicity

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Take Home: PAPAGEMO § Combination therapy with pazopanib + gemcitabine is

associated with improved PFS compared to pazopanib alone (HR = 0.58)

§ There is no impact on OS § Combination therapy was more toxic (SAE 54% vs 16.3%)

and potentially associated with 2 toxic deaths

§ Combination therapy cannot be recommended at this time

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asco 2016 sarcoma review

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