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Vera Hirsh



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    MS 20 - Value-based Management for Special Populations (ID 542)

    • Event: WCLC 2017
    • Type: Mini Symposium
    • Track: Nursing/Palliative Care/Ethics
    • Presentations: 1
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      MS 20.01 - When is a Treatment Considered Futile? (ID 7737)

      11:00 - 12:30  |  Presenting Author(s): Vera Hirsh

      • Abstract
      • Presentation
      • Slides

      Abstract:
      Introduction: Futile care is defined as care that fails to provide a clinical benefit. This term can be controversial, especially when it’s value of the caregivers, patient or his family are different. Discussion: Poor communication between physicians, patients and their family members can lead to the misalignment of perceptions, ie. about life expectancy with or without treatments, about toxicities to be expected from a specific treatment, what quality of life (QOL) can be expected on certain treatments and what it means to receive as an alternative treatment a palliative care only.[1] [2] [3] [4] Sometimes the patient might refuse to know his prognosis and palliative care discussion.[5] [6]Doctor’s perception is frequently influenced by patient’s poor performance status (PS) of 3 or 4, very short estimated survival (sometimes in weeks only), difficulties with the management of the treatment toxicities which can cause a decline of QOL, different interventions and hospitalizations. The perceived patient’s compliance with the treatments is an important factor, too. The interventions, ie. management of toxicities of the therapies, more frequent patients’ visits, hospitalizations and the treatments without benefit further stress the futility with an increased cost for the society and institutions providing the health care. [7] The goals of patient care have to be discussed between oncologist, patient and his family. [8] [9]The final decision has to be shared and agreed on. The decisions have to include non-curative interventions, ie. other drugs, transfusions or even participation in Phase I trials,[10] which are conducted for safety of the drugs without an evidence of efficacy, but they are still not futile. It is very important to review if all the reasonable options of the interventions and the treatments were attempted, regardless of the timing of the situation at the time of the diagnosis or at the time of disease progression. The emotional needs of patients’ caregivers, ie. family members, have to be considered and addressed, too. Conclusion: The discussion of disagreements with the patient, his family and health care providers regarding the treatment goals and interventions when considering the disease prognosis will lead to reasonable conclusions and avoid the futilities. As it was quoted, “In Oncology: clear and unequivocal situations of right and wrong are rare.” The concerns and wishes of the patients, patients’ families and oncologists have to be well balanced to avoid a futile treatment. [1] Jecker NS, Pearlman RA (1992) Medical futility. Who decides? Arch Intern Med 152: 1140-1144. [2] Jecker NS, Schneiderman LJ (1993) Medical futility: the duty not to treat. Camb Q Healthc Ethics 2: 151-159 [3] Schneiderman LJ, Jecker NS, Jonsen AR (1990) Medical futility: its meaning and ethical implications. Ann Intern Med 112: 949-954. [4] Veatch RM (2013) So-called futile care: The experience of the United States. Medical Futility. A Cross-National Study. Imperial College Press. London. [5] Jox RJ, Schaider A, Marckmann G, Borasio GD (2012) Medical futility at the end of life: the perspectives of intensive care and palliative care clinicians. J Med Ethics 38: 540-545. [6] Lantos JD, Singer PA Walker RM, Gramelspacher GP, Shapiro GR, et al. (1989) The illusion of futility in clnical practice. AM J Med 87: 81-84 [7] LO B (1995) Futile interventions. Resolving ethical dilemmas: A guide for clinicians. Baltimore: Williams & Wilkins, 73-81. [8] Youngner SJ (1990) Who defines futility? JAMA 260: 2094-2095. [9] Youngner SJ (1990) Futility in context. JAMA 264: 1295-1296. [10] Chen EX, Tannock IF (2004) Risks and benefits of phase 1 clinical trials evaluating new anticancer agents: a case for more innovation.

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    P2.07 - Immunology and Immunotherapy (ID 708)

    • Event: WCLC 2017
    • Type: Poster Session with Presenters Present
    • Track: Immunology and Immunotherapy
    • Presentations: 1
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      P2.07-029 - CheckMate 169: Safety/Efficacy of Nivolumab in Canadian Pretreated Advanced NSCLC (including Elderly and PS 2) Patients (ID 9042)

      09:30 - 16:00  |  Author(s): Vera Hirsh

      • Abstract
      • Slides

      Background:
      Nivolumab demonstrated efficacy and safety in patients with previously treated advanced/metastatic NSCLC in the two phase 3 trials CheckMate 017 and 057 (median OS, 9.2–12.2 months; 1-year OS rate, 42–51%; 2-year OS rate, 23–29%; any-grade treatment-related AEs [TRAEs], 68%; grade 3–4 TRAEs, 10%). As patients with ECOG PS 2 were excluded from these phase 3 trials, there is limited evidence for nivolumab efficacy in this patient subgroup. CheckMate 169 (NCT02475382) is an expanded access program (EAP) of nivolumab in patients with advanced NSCLC and disease progression after ≥1 prior systemic therapy; efficacy/safety results from the Canadian cohort are presented here.

      Method:
      Eligible patients were aged ≥18 years with relapsed stage IIIb/IV NSCLC and an ECOG PS of 0–2 who had received ≥1 prior platinum-containing therapy. Patients with carcinomatous meningitis or untreated brain metastases were excluded. Nivolumab (3 mg/kg IV Q2W) was administered until disease progression or unacceptable toxicity for a maximum of 2 years. In addition to providing nivolumab to patients, the primary objective was to assess safety and OS. Outcomes in specific patient subgroups, including elderly patients (aged ≥70 years) and those with poor performance status (PS 2), were assessed in post hoc analyses.

      Result:
      Of 161 patients treated in Canada, 53% were male, 94% were current/former smokers, 32% had squamous NSCLC, and 43% had received ≥2 prior therapies. 30% were aged ≥70 years and 19% had an ECOG PS of 2. At the time of analysis, 76% of patients had discontinued treatment. Nivolumab was well tolerated. In the overall population, TRAEs of any grade were reported in 69% of patients, with grade 3 or 4 events in 14%; no TR deaths occurred. 9% of patients discontinued due to TRAEs. The safety profile of nivolumab in patient subgroups (age ≥70 years and PS 2) was similar to the overall population. The median OS (95% CI) in the overall population was 9.1 months (7.5, 14.4), with a 1-year OS rate of 44%. The median OS was 8.0 months (5.3, 12.9) for elderly patients and 5.9 months (3.6, 7.9) for those with PS 2. The presentation will include patient case studies from the subgroups.

      Conclusion:
      In this EAP of nivolumab in Canadian patients with previously treated NSCLC, safety and OS were consistent with observations from prior controlled trials. Safety in elderly patients and those with PS 2 was consistent with the overall population.

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    P3.01 - Advanced NSCLC (ID 621)

    • Event: WCLC 2017
    • Type: Poster Session with Presenters Present
    • Track: Advanced NSCLC
    • Presentations: 2
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      P3.01-026 - Analysis of Long-Term Response to First-Line Afatinib in the LUX-Lung 3, 6 and 7 Trials in Advanced EGFRm+ NSCLC (ID 9051)

      09:30 - 16:00  |  Author(s): Vera Hirsh

      • Abstract
      • Slides

      Background:
      In patients with advanced EGFR mutation-positive (EGFRm+) NSCLC, first-line afatinib significantly improved PFS and objective response rate (ORR) versus platinum-doublet chemotherapy in the phase III LUX-Lung (LL) 3 and LL6 studies, and PFS, time-to-treatment failure (TTF) and ORR versus gefitinib in the phase IIb LL7 study. Here, we present post-hoc analyses of efficacy, safety and patient-reported outcomes (PROs) in afatinib long-term responders (LTRs) in LL3/6/7.

      Method:
      Treatment-naïve patients with stage IIIb/IV EGFRm+ NSCLC who were randomized to 40mg/day afatinib in LL3/6/7 and remained on treatment for ≥3 years were defined as LTRs. In these patients, we assessed efficacy and safety outcomes, as well as PROs measured using the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life (QoL) Questionnaire and the EQ-5D™ health status self-assessment questionnaire; these included scores on the EORTC Global Health [GH]/QoL scale (0–100), EORTC Performance Functioning scale (PF; 0–100), EQ Visual Analogue Scale (VAS; 0–100) and EQ-5D UK utility scale (EQ UK utility; 0–1).

      Result:
      In LL3/6/7, there were 24/229 (10%)/ 23/239 (10%)/ 19/160 (12%) afatinib-treated LTRs; 6/9/14 remained on treatment at time of analysis. Baseline characteristics were similar to the overall study populations, except for the proportion of women (LL3/6 only [LTRs versus overall]: 92/78% vs 64/64%) and Del19+ patients (LL3/6/7: 63–79% vs 49–58%). In LL3/6/7, 4–11% of LTRs had brain metastases at enrolment. Median (range) duration of treatment in LL3/6/7 LTRs was 50 (41–73)/56 (37–68)/42 (37–50) months. Due to few deaths, median OS could not be estimated. Median follow-up for OS in LL3/6/7 was 64.6/57.0/42.1 months. ORR among LTRs in LL3/6/7 was 70.8% (complete response: 4.2%; n=1)/78.3% (13.0%; n=3)/89.5% (5.3%; n=1). The frequency of afatinib dose reductions due to treatment-related AEs, and the frequency/duration of subsequent treatments were similar to the overall LL3/6/7 populations. In afatinib-treated LTRs in LL3/6/7, PROs appeared stable between ~Week 24 to ~Week 160, with slight improvements after ~3 years afatinib treatment versus scores at the start of treatment.

      Conclusion:
      In LL3/6/7, 10%–12% of afatinib-treated patients were LTRs. Afatinib was well tolerated among these patients. Long-term treatment was independent of tolerability-guided dose adjustment or presence of brain metastases at time of enrolment, and had no detrimental impact on subsequent treatment. In afatinib-treated LTRs, PROs were not negatively affected by long-term treatment, and were slightly improved after ~3 years of treatment versus scores at treatment initiation.

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      P3.01-075 - Afatinib Dose Adjustment: Effect on Safety, Efficacy and Patient-Reported Outcomes in the LUX-Lung 3/6 Trials in EGFRm+ NSCLC (ID 9365)

      09:30 - 16:00  |  Presenting Author(s): Vera Hirsh

      • Abstract
      • Slides

      Background:
      Afatinib 40mg/day is approved globally for first-line treatment of EGFR mutation-positive (EGFRm+) NSCLC. Afatinib is available in several tablet strengths (20/30/40/50mg), and tolerability-guided dose adjustment schemes are well established. Here, we evaluate the impact of afatinib dose reduction on safety (AEs), pharmacokinetics, PFS and patient-reported outcomes (PROs) in the Phase III LUX-Lung (LL) 3 and 6 trials.

      Method:
      Treatment-naïve patients with stage IIIB/IV EGFRm+ NSCLC in LL3/6 received either 40mg/day afatinib or chemotherapy. In case of any treatment-related grade ≥3 AEs or selected prolonged grade 2 AEs, afatinib dose was reduced by 10mg decrements (minimum dose 20mg/day). In this post-hoc analysis of all afatinib-treated patients in LL3/6 (n=229/n=239), we compared incidence and severity of common AEs before and after dose reduction, afatinib plasma concentrations in patients who reduced to 30mg versus those remaining on 40mg, and PFS in patients with/without dose reductions in the first 6 months of treatment. PROs were measured using the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire and the EQ-5D™ health status self-assessment questionnaire, and pooled data from both trials were assessed before/after dose reduction; these included scores on the EORTC Global Health/Quality of Life scale (GH/QoL; 0–100), EORTC Performance Functioning scale (PF; 0–100), EQ Visual Analogue Scale (VAS; 0–100) and EQ-5D UK utility scale (EQ UK utility; 0–1).

      Result:
      Dose reductions occurred in 122/229 (53.3%) patients in LL3 and 67/239 (28.0%) in LL6; >80% of dose reductions occurred in the first 6 months of treatment. Dose reductions decreased the incidence of treatment-related AEs (grade ≥3 AEs before/after dose reduction: LL3, 73%/20%; LL6, 81%/12%), and were more likely among patients who had higher afatinib plasma concentrations prior to subsequent dose reduction (Day 22). On Day 43, geometric mean afatinib plasma concentrations were comparable between patients who had dose reduced (n=59; 23.3ng/mL) and patients who remained on 40mg (n=284; 22.8ng/mL). Median PFS was comparable between patients with or without dose reductions in the first 6 months (LL3: 11.3 versus 11.0 months; HR [95% CI] 1.25 [0.91–1.72]; p=0.175; LL6: 12.3 versus 11.0 months; 1.00 [0.69–1.46]; p=0.982). There were no clinically meaningful changes in PROs following afatinib dose reduction: GH (40/30mg: 59.1/66.9; n=136); PF (79.4/83.0; n=136); EQ VAS (70.1/75.1; n=135); EQ UK utility (0.70/0.78; n=135).

      Conclusion:
      Tolerability-guided dose adjustments effectively reduced afatinib-related AEs without negatively affecting therapeutic efficacy and PROs.

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