Presentation is loading. Please wait.

Presentation is loading. Please wait.

Harry H. Yoon, MD MHS Mayo Clinic Rochester, MN, USA

Published byEthelbert Reynolds Modified over 6 years ago

Similar presentations

Presentation on theme: "Harry H. Yoon, MD MHS Mayo Clinic Rochester, MN, USA"— Presentation transcript:

1 Harry H. Yoon, MD MHS Mayo Clinic Rochester, MN, USA
Debate: What is appropriate 2nd-line therapy in metastatic gastric cancer? Chemo alone Harry H. Yoon, MD MHS Mayo Clinic Rochester, MN, USA Great Debates in GI Malignancies March 2015

2 Disclosure Relevant Financial Relationship(s)
Roche/Genentech: Advisory, Research Funding Lilly Oncology: Advisory, Research Funding FivePrime: Advisory Off Label Usage apatinib, regorafenib

3 TCGA identifies 4 molecular subtypes of gastric cancer
Nature 2014 Array-based somatic copy no. analysis, whole exome sequencing, array-based DNA methylation profiling, mRNA sequencing, miRNA sequencing, reverse-phase protein array

4 Monthly cost in U.S. of branded oncology drugs (inflation-adjusted)
Biologics have doubled in price Monthly cost in U.S. of branded oncology drugs (inflation-adjusted) $5,000 2003 2013 2008 $10,000 Adapted from Bach PB. NEJM 2009 and IMS Institute for Health Informatics Monthly cost of 1 drug Average monthly cost over 5 y Health spending $2.8 trillion current 5.8% annual growth

5 [T]he growth rate in health spending is unsustainable …
[I]f no one else will act, leading cancer centers … should.

6 Health outcomes achieved
2014 Value = Health outcomes achieved Dollar spent Porter ME 2010 NEJM

7 RAM is the only biologic shown to improve OS in Western population 2nd-line gastric cancer
Positive Phase 3 RAM + paclitaxel (RAINBOW) RAM (REGARD) Apatinib (only China) Null or Not Tested in Phase 3 Everolimus Gefitinib Sunitinib Regorafenib ImmunoRx MET HER2/HER3 cancer stem cell Results are null in phase 2 or phase 3 Phase 2 only No published randomized data in 2nd-line RAM = ramucirumab Anti-VEGFR2 Ab

8 My Position: RAM is not appropriate as 2nd-line Rx in gastric cancer, because it lacks value.
Chemo alone improves OS RAM + chemo adds minimal efficacy to chemo alone RAM monoRx has similar efficacy as chemo RAM has not been proven to improve QOL Value = Health outcomes Dollar spent Cost of RAM is high

9 My Position: RAM is not appropriate as 2nd-line Rx in gastric cancer, because it lacks value.
Chemo alone improves OS RAM + chemo adds minimal efficacy to chemo alone RAM monoRx has similar efficacy as chemo RAM has not been proven to improve QOL Value = Health outcomes Dollar spent Cost of RAM is high

10 Chemo improves OS (v BSC alone) Consistent results across three phase 3 trials (N = 410)
Gastric cancer, 2nd-line COUGAR-2 (N = 168, U.K.) Kang et al. (N = 202, Korean) HR 0.67 (P =.01) ∆OS = 1.6 m HR 0.66 (P =.007*) ∆OS = 1.5 m irinotecan or docetaxel 5.3 m docetaxel 5.2 m BSC 3.6 m BSC 3.8 m BSC = best supportive care * 1-sided P AIO 2011 (N = 40): irinotecan vs BSC. Results: HR 0.48 for OS (4 vs 2.4 m [∆1.6m]; P =.01)

11 Discontinue due to toxicity
Chemo is reasonably tolerated Mostly heme toxicity Study Grade 3+ Toxicity a Discontinue due to toxicity Rx duration weeks irinotecan or docetaxel vs BSC neutropenia ≤18% anemia ≤32% 13% ~17 Docetaxel vs BSC (COUGAR) neutropenia 15% infection 15% febrile neutropenia 7% 31% 9.5 Paclitaxel arm (RAINBOW) Non-Heme, each ≤5% Neutropenia 19% Anemia 10% 12% 12 a For COUGAR and Korean studies, shown are G3+ events in >5% of chemo arm with ∆>2% compared to BSC arm. COUGAR had G3+ anemia in 6%. Irinotecan had G3+ diarrhea in 8% (v 5% in BSC) BSC, best supportive care (active symptom control) 12 % paclitaxel arm (RAINBOW)

12 My Position: RAM is not appropriate as 2nd-line Rx in gastric cancer, because it lacks value.
Chemo alone improves OS RAM + chemo adds minimal efficacy to chemo alone RAM monoRx has similar efficacy as chemo RAM has not been proven to improve QOL Value = Health outcomes Dollar spent Cost of RAM is high

13 RAM adds only 2.2 m OS to chemo alone
RAINBOW: RAM + paclitaxel vs paclitaxel OS (primary) HR 0.81 [0.68 to 0.96] P =.02 Curves merge at 13 months: Benefit is transient. RAM + paclitaxel 9.6 m Placebo + paclitaxel 7.4 m Wilke et al, 2014, Lancet Oncology

14 Subgroup analysis: RAM has greater benefit in West?
RAINBOW: RAM + paclitaxel vs paclitaxel Median OS OS But … No interaction reported: Interesting but exploratory Only 2.7 m increase in OS in West HR 0.99 Non-sig Asia n=223 West n=398 HR 0.73 P =.005 ∆2.7 m Wilke et al, 2014, Lancet Oncology and World GI 2014

15 RAM + paclitaxel has less efficacy compared with recent “positive” gastric trials
Trials that showed OS benefit when agent was added to chemo Hazard ratios for OS Median OS ToGA: EMA † trastuzumab + CF vs trastuzumab 16.0 v 11.8 (∆ 4.2) ToGa: All trastuzumab + CF vs CF 13.8 v 11.1 (∆ 2.7) V325 DCF vs CF 9.2 v 8.6 (∆ 0.6) RAINBOW RAM + paclitaxel vs paclitaxel 9.6 v 7.4 (∆ 2.2) † HER2-positive per European Medicines Agency (IHC3+ or IHC2+ with FISH+)

16 RAM has increased G3+ bleeding
RAINBOW: RAM + paclitaxel vs paclitaxel RAM arm Placebo Any 81% 63% Neutropenia 41% 19% Special Interest Hypertension 15% 3% Bleeding 4% 2% GI bleed Wilke et al, 2014, Lancet Oncology

17 My Position: RAM is not appropriate as 2nd-line Rx in gastric cancer, because it lacks value.
Chemo alone improves OS RAM + chemo adds minimal efficacy to chemo alone RAM monoRx has similar efficacy as chemo RAM has not been proven to improve QOL Value = Health outcomes Dollar spent Cost of RAM is high

18 Almost ½ patients had PFS event at first scan
RAM monoRx adds 1.4m OS REGARD: RAM vs BSC alone OS (primary) PFS HR 0.48 [0.38 to 0.62] P <.001 HR 0.78 [0.603 to 0.998] P =.047 RAM 5.2 m RAM 2.1 m Placebo 3.8 m 1.3 m Almost ½ patients had PFS event at first scan Fuchs et al, 2013, Lancet

19 Efficacy of RAM monoRx is not better than chemo
Trials that showed OS benefit for anticancer Rx vs BSC alone Overall survival HR Median Korean irinotecan or docetaxel vs BSC 5.3 vs (∆1.5) COUGAR docetaxel vs BSC 5.2 vs (∆1.6) REGARD RAM vs BSC 5.2 vs (∆1.4)

20 Treatment duration median
RAM monoRx seems well-tolerated, but treatment duration was very short … REGARD: RAM vs BSC alone Treatment duration median RAM: 8 weeks [IQR 6 to 16] vs Placebo: 6 weeks [IQR 4 to 8] G3+ Toxicity RAM placebo Hypertension 8% 3% Abdominal pain 6% Bleeding 3% vs 3%; and <1% for arterial TE, proteinuria, GI perforation, fistula … so we would not expect a great deal of toxicity. Fuchs et al, 2013, Lancet

21 My Position: RAM is not appropriate as 2nd-line Rx in gastric cancer, because it lacks value.
Chemo alone improves OS RAM + chemo adds minimal efficacy to chemo alone RAM monoRx has similar efficacy as chemo RAM has not been proven to improve QOL Value = Health outcomes Dollar spent Cost of RAM is high

22 REGARD: No evidence that RAM monoRx significantly improves QOL or symptoms
RAM vs BSC alone Global QOL at 6 weeks RAM placebo Conclusion of investigators: “RAM conferred no worse effect than placebo …” 78% 54% No data Improved 10% v 4% P =.23 Fuchs et al, 2013, Lancet

23 Conclusion of investigators
RAINBOW: No peer-reviewed evidence that RAM + paclitaxel improves QOL or symptoms RAM + paclitaxel vs paclitaxel 2 QOL surveys used RAM arm Placebo arm Global 49 48 Health 0.61 0.60 Conclusion of investigators in paper: “QOL was maintained …” Publication reports only data from end-of-treatment. The % of patients who completed the survey was 64% vs 61% for both Global QOL (EORTC QLQ-C30, range 0 to 100) and Health Questionnaire (EQ-5D, range to 1). Abstract from ASCO 2014 did not report which differences were statistically significant Wilke et al, 2014, Lancet Oncology

24 COUGAR: Chemo alone improves symptoms
Docetaxel vs BSC alone Docetaxel better BSC better Docetaxel Better (P <.05) General Pain (P <.001) Constipation (P =.02) Abdominal Pain (P =.01) Nausea or Vomiting (P =.02) Dysphagia (P =.02) Survey was collected at weeks 3, 6, 9, 12, 18, 24. As an example, Survey response at 6 weeks: 68% v 57% Ford et al, 2014, Lancet Oncology

25 My Position: RAM is not appropriate as 2nd-line Rx in gastric cancer, because it lacks value.
Chemo alone RAM + chemo adds minimal efficacy to chemo alone RAM monoRx has similar efficacy as chemo RAM has not been proven to improve QOL Value = Health outcomes Dollar spent Cost of RAM is high

26 My Position: RAM is not appropriate as 2nd-line Rx in gastric cancer, because it lacks value.
Chemo alone RAM + chemo adds minimal efficacy to chemo alone RAM monoRx has similar efficacy as chemo RAM has not been proven to improve QOL Value = Health outcomes Dollar spent Cost of RAM is high

27 Drug Price Estimates in US, effective Oct 2014
Monthly US dollars a Paclitaxel $55 Irinotecan $116 Ramucirumab $12,000 Does not include … Doctor’s fees Supportive meds Diagnostic tests a Estimated for 70 kg man (170 cm height). Price data obtained from Drug Reimbursement Code Pricing reflecting U.S. Medicare reimbursements, effective 10/1/2014 (cms.gov, medlearndrugs.com, and adapted from mskcc.org/research/health-policy-outcomes/cost-drugs). For ramucirumab (code 9025), prices were updated as of 01/01/2015.

28 Sponsor offers Co-Pay program for RAM …
Monthly US dollars a Paclitaxel $55 Irinotecan $116 Ramucirumab $12,000 Patient pays no more than $50 per infusion

29 … but program excludes Medicare and Medicaid.
Lilly offers Co-Pay program for RAM … Monthly US dollars a Paclitaxel $55 Irinotecan $116 Ramucirumab $12,000 Patient pays no more than $50 per infusion Cancer Patients … but program excludes Medicare and Medicaid. ~60% Medicaid 2012 2013 2014 Medicare American Society of Clinical Oncology JOP 2015;11:79-113

30 Out-of-pocket costs for RAM
Most patients have 20% Co-Pay (private insurance or Medicare-only) Monthly US dollars a Paclitaxel $55 Irinotecan $116 Ramucirumab $12,000 RAM monoRx = $4,800 (2 months) RAM + paclitaxel = $10,800 (4.5 months)

31 … but also cancer patients in general.
This issue affects not only society … … but also cancer patients in general. 25% used up most or all savings paying for care a 2.7 times higher risk of bankruptcy than people without cancer b 10% spend >$18,000 out of pocket on care c. Monthly US dollars a Paclitaxel $55 Irinotecan $116 Ramucirumab $12,000 a Telephone survey 2006 (National survey of households affected by cancer; USA Today/Kaiser Family Foundation/Harvard School of Public Health Survey); N = 930 adults who say they or another family member in their household were diagnosed or treated for cancer in last 5 y (excluding non-melanoma skin). b 2.65 refers to multivariate hazard rates (Cox); 2.4% of 197,480 people filed for bankruptcy after cancer diagnosis, vs 1.1% of 197,840 controls who were not diagnosed with cancer ( ). Controls were matched by year of birth, ZIP, and sex. Adjustment included marital status. Incidence of bankruptcy in Western District of Washington State in US Bankruptcy Court cross-referenced with SEER data; Ramsey et al 2013; Health Affairs 32; 6; 1143 c N = 42,997 cancer patients ( ). Goldman DP et al 2006; Health Affairs 25; 5; 1319

32 Costs may decrease in the future …
Biosimilars may be developed Patent will end someday (filed ~2004) Recent FDA approval of RAM in NSCLC and CRC may press drug price downward RAM price is lower in Europe. … but in the US, for now, RAM remains expensive.

33 RAM benefit is not clinically meaningful according to published criteria
Sobrero et al 2014

34 RAM benefit is not clinically meaningful according to published criteria
Sobrero et al 2014 Value = Health outcomes Dollar spent Outcome Threshold $ and toxic $ and non-toxic Less $ and toxic Less $ and non-toxic High Medium Low

35 RAM benefit is not clinically meaningful according to published criteria
Sobrero et al 2014 Value = Health outcomes Dollar spent RAM Outcome Threshold $ and toxic $ and non-toxic Less $ and toxic Less $ and non-toxic High Medium Low

36 HR Median % pts alive at 2 y
2014 Study HR Median months % pts alive at 2 y Absolute Relative RAINBOW Medium threshold; Prognosis <9 m OS 0.65 2.5 10% 50% .

37 0.81 2.2 2014 Study HR Median % pts alive at 2 y RAINBOW 0.65 2.5 10%
months % pts alive at 2 y Absolute Relative RAINBOW Medium threshold; Prognosis <9 m OS 0.65 0.81 2.5 2.2 10% 50% . Each cell shows the threshold value over the observed value. All values refer to overall survival.

38 0.81 2.2 2014 Study HR Median % pts alive at 2 y RAINBOW 0.65 2.5 10%
months % pts alive at 2 y Absolute Relative RAINBOW Medium threshold; Prognosis <9 m OS 0.65 0.81 2.5 2.2 10% 50% ToGA Low threshold; Prognosis 9-12 m OS 0.75 5% 25% Each cell shows the threshold value over the observed value. All values refer to overall survival. Trastuzumab = $5,000 per month and Non-Toxic

39 0.81 2.2 0.74 2.7 6% 38% 2014 Study HR Median % pts alive at 2 y
months % pts alive at 2 y Absolute Relative RAINBOW Medium threshold; Prognosis <9 m OS 0.65 0.81 2.5 2.2 10% 50% ToGA Low threshold; Prognosis 9-12 m OS 0.75 0.74 2.7 5% 6% 25% 38% Each cell shows the threshold value over the observed value. All values refer to overall survival. Trastuzumab = $5,000 per month and Non-Toxic

40 0.78 1.4 0.66 1.5 0.67 1.6 2014 Study HR Median % pts alive at 2 y
months % pts alive at 2 y Absolute Relative REGARD RAM vs BSC Medium threshold 0.65 0.78 2.5 1.4 10% 50% Korean irinotecan or docetaxel vs BSC Low threshold 0.70 0.66 2.0 1.5 5% 25% COUGAR docetaxel vs BSC 0.67 1.6 Each cell shows the threshold value over the observed value. All values refer to overall survival.

41 ASCO incorporated opinions of patients and other stakeholders.
2014 ASCO incorporated opinions of patients and other stakeholders. Thresholds of meaningful benefit were similar to Sobrero et al. If applied to gastric cancer: RAM + paclitaxel, or RAM monoRx, do NOT provide clinically meaningful benefit for any parameter a. Whereas chemo alone meets one parameter (HR). a Extrapolation from pancreatic cancer (8-9 m OS)

42 Caveat: These thresholds have limitations
Limitations of thresholds include: It’s not clear how low vs high threshold is defined It’s not clear how to evaluate endpoints other than OS. If we followed the rules strictly, we may have ignored small gains of other drugs (eg, oxaliplatin in mCRC). Etc … However, development of thresholds reflect a growing perspective that small, expensive gains (e.g., RAM in 2nd-line) are not clinically meaningful.

43 Summary RAM is not appropriate as 2nd-line Rx in gastric cancer, because it lacks value Chemo alone improves OS RAM adds 2.2 m OS to chemo RAM monoRx has similar efficacy as chemo (∆1.4 m OS) RAM has not been proven to improve QOL Value = Health outcomes Dollar spent Cost of RAM is high $12,000 per month

44 Conclusion We often celebrate small incremental gains, which over many years have translated into big improvements.* But the time has come to accept that drug cost matters. Failure to acknowledge this is hurting our patients. Ramucirumab (RAINBOW) $12,000 per month Trastuzumab (ToGA EMA) $5,000 per month ∆OS 2.2m ∆OS 4.2m * Schilsky 2015, cancertherapyadvisor.com

45 Thank you

Download ppt "Harry H. Yoon, MD MHS Mayo Clinic Rochester, MN, USA"

Similar presentations

First Efficacy Results of a Randomized, Open- Label, Phase III Study of Adjuvant Doxorubicin Plus Cyclophosphamide, Followed by Docetaxel with or without.

First Efficacy Results of a Randomized, Open- Label, Phase III Study of Adjuvant Doxorubicin Plus Cyclophosphamide, Followed by Docetaxel with or without.
Paz-Ares LG et al. Proc ASCO 2011;Abstract CRA7510.

Paz-Ares LG et al. Proc ASCO 2011;Abstract CRA7510.
Facon T et al. Proc ASH 2013;Abstract 2.

Facon T et al. Proc ASH 2013;Abstract 2.
Www.OncologyEducation.com ECCO ESMO 2011 GI Cancer Updates “ VELOUR” Study Author: J Tabernero et al Reviewed by: Dr. Scott Berry Date posted: October.

ECCO ESMO 2011 GI Cancer Updates “ VELOUR” Study Author: J Tabernero et al Reviewed by: Dr. Scott Berry Date posted: October.
Clinical Relevance of HER2 Overexpression/Amplification in Patients with Small Tumor Size and Node-Negative Breast Cancer Curigliano G et al. J Clin Oncol.

Clinical Relevance of HER2 Overexpression/Amplification in Patients with Small Tumor Size and Node-Negative Breast Cancer Curigliano G et al. J Clin Oncol.
CR-1 Concluding Remarks and Risk/Benefit Summary Mace L. Rothenberg, MD Professor of Medicine Vanderbilt Ingram Cancer Center.

CR-1 Concluding Remarks and Risk/Benefit Summary Mace L. Rothenberg, MD Professor of Medicine Vanderbilt Ingram Cancer Center.
Efficacy results from the ToGA trial: a phase III study of trastuzumab added to standard chemotherapy in first-line human epidermal growth factor receptor.

Efficacy results from the ToGA trial: a phase III study of trastuzumab added to standard chemotherapy in first-line human epidermal growth factor receptor.
What would you recommend as first line therapy for a 68 y/o woman with advanced pancreatic cancer and limited metastatic disease with ECOG-1? Gemcitabine.

What would you recommend as first line therapy for a 68 y/o woman with advanced pancreatic cancer and limited metastatic disease with ECOG-1? Gemcitabine.
Pancreatic Cancer Ali Shamseddine MD Proessor of Medicine AUBMC

Pancreatic Cancer Ali Shamseddine MD Proessor of Medicine AUBMC
In 2003, Medicaid spent $33.7 billion on drugs (19% of national spending for drugs and more than 10% of the Medicaid budget) Medicaid expenditures ($ billions)

In 2003, Medicaid spent $33.7 billion on drugs (19% of national spending for drugs and more than 10% of the Medicaid budget) Medicaid expenditures ($ billions)
Targeting VEGF for the Treatment of Colorectal Cancer Herbert Hurwitz Duke University Medical Center Durham, North Carolina, USA.

Targeting VEGF for the Treatment of Colorectal Cancer Herbert Hurwitz Duke University Medical Center Durham, North Carolina, USA.
The Use of Trastuzumab in the Elderly in the Adjuvant Setting and After Disease Progression in Patients with HER2-Positive Advanced Breast Cancer Dall.

The Use of Trastuzumab in the Elderly in the Adjuvant Setting and After Disease Progression in Patients with HER2-Positive Advanced Breast Cancer Dall.
This house believes that FOLFIRINOX is the best treatment for patients with metastatic pancreatic adenocarcinoma Pro Marc YCHOU Montpellier.

This house believes that FOLFIRINOX is the best treatment for patients with metastatic pancreatic adenocarcinoma Pro Marc YCHOU Montpellier.
Axel Grothey, MD Professor of Oncology Mayo Clinic Rochester, Minnesota Strategies to Improve Patient Outcomes in Gastric and Gastroesophageal Junction.

Axel Grothey, MD Professor of Oncology Mayo Clinic Rochester, Minnesota Strategies to Improve Patient Outcomes in Gastric and Gastroesophageal Junction.
Treatment Regimens of HER2+ Adjuvant Patients (Actuals) Source: Genentech ASCO 2005 (data release) Nov 2006 (Approval)

Treatment Regimens of HER2+ Adjuvant Patients (Actuals) Source: Genentech ASCO 2005 (data release) Nov 2006 (Approval)
Response rate using conventional criteria is a poor surrogate for clinical benefit on progression-free (PFS) and overall survival (OS) in metastatic colorectal.

Response rate using conventional criteria is a poor surrogate for clinical benefit on progression-free (PFS) and overall survival (OS) in metastatic colorectal.
Randomized Phase III Trial Comparing FOLFIRINOX (F: 5FU/Leucovorin [LV], Irinotecan [I], and Oxaliplatin [O]) versus Gemcitabine (G) as First-Line Treatment.

Randomized Phase III Trial Comparing FOLFIRINOX (F: 5FU/Leucovorin [LV], Irinotecan [I], and Oxaliplatin [O]) versus Gemcitabine (G) as First-Line Treatment.
Quality of life results from a Phase III trial of trastuzumab plus chemotherapy in first-line HER2-positive advanced gastric and GE junction cancer Taroh.

Quality of life results from a Phase III trial of trastuzumab plus chemotherapy in first-line HER2-positive advanced gastric and GE junction cancer Taroh.
Final Efficacy Results from OAM4558g, a Randomized Phase II Study Evaluating MetMAb or Placebo in Combination with Erlotinib in Advanced NSCLC Spigel DR.

Final Efficacy Results from OAM4558g, a Randomized Phase II Study Evaluating MetMAb or Placebo in Combination with Erlotinib in Advanced NSCLC Spigel DR.
AVADO TRIAL David Miles Mount Vernon Cancer Centre, Middlesex, United Kingdom A randomized, double-blind study of bevacizumab in combination with docetaxel.

AVADO TRIAL David Miles Mount Vernon Cancer Centre, Middlesex, United Kingdom A randomized, double-blind study of bevacizumab in combination with docetaxel.

Similar presentations

Ads by Google