Patient-reported tolerability of veliparib combined with cisplatin and etoposide for treatment of extensive stage small cell lung cancer: Neurotoxicity and adherence data from the ECOG ACRIN cancer research group E2511 phase II randomized trial

Abstract

Objectives: The ECOG-ACRIN Cancer Research Group trial E2511 recently demonstrated a potential benefit for the addition of veliparib to cisplatin-etoposide (CE) in patients with extensive stage small cell lung cancer (ES-SCLC) in a phase II randomized controlled trial. Secondary trial endpoints included comparison of the incidence and severity of neurotoxicity, hypothesized to be lower in the veliparib arm, and tolerability of the addition of veliparib to CE. Physician-rated and patient-reported neurotoxicity was also compared.

Materials and methods: Patients randomized to veliparib plus CE (n = 64) or placebo plus CE (n = 64) completed the 11-item Functional Assessment of Cancer Therapy Gynecologic Oncology Group Neurotoxicity (questionnaire pre-treatment, end of cycle 4 [ie 3 months after randomization] and 3 months post-treatment [ie 6-months]). Adherence analysis was based on treatment forms.

Results and conclusion: No significant differences in mean or magnitude of change in neurotoxicity scores were observed between treatment arms at any time point. However, patients in the placebo arm reported worsening neurotoxicity from baseline to 3-months (M difference = -1.5, P = .045), compared to stable neurotoxicity in the veliparib arm (M difference = -0.2, P = .778). Weakness was the most common treatment-emergent (>50%) and moderate to severe (>16%) symptom reported, but did not differ between treatment arms. The proportion of adherence to oral therapy in the overall sample was 75%. Three percent of patients reported clinically significant neurotoxicity that was not captured by physician assessment. Neurotoxicity scores were not different between treatment arms. The addition of veliparib to CE appeared tolerable, though weakness should be monitored. CLINICALTRIALS.

Gov identifier: NCT01642251.

Keywords: chemotherapy-induced peripheral neuropathy; patient-reported outcomes; small cell; tolerability; veliparib.

Conflict of interest statement

Drs. McLouth and Zhao have no conflicts of interest to disclose. Dr Owonikoko discloses a consulting or advisory role with: Novartis, Celgene, Eli Lilly, Sandoz, Abbvie, Eisai, G1 Therapeutics, Takeda, Seattle Genetics, Bristol‐Myers Squibb, MedImmune. Institutional research funding with: Novartis, Astellas Pharma, Celegene, Bayer Stem CentRx, Regeneron, AstraZeneca/MedImmune, Abbvie, G1 Therapeutics, and Bristol‐Myers Squibb. Patients, Royalties, and Other Intellectual Property with: Overcoming Acquired Resistance to Chemotherapy Treatments Through Suppression of STAT3 (Institutional), Selective Chemotherapy Treatments and Diagnostics Methods Related Thereto (Institutional). Dr Feliciano discloses a consulting or advisory role with: Genentech, AstraZeneca, Merck, Takeda, and Pfizer. Dr Mohindra discloses a consulting or advisory role with: Genentech, Abbvie, and AstraZeneca. Dr Dahlberg discloses a grant from the EA statistical center grant that supported this work, consulting or advisory role to AstraZeneca, and a patent pending for a statistical model assessing tumor growth (Institutional). Dr Wade discloses immediate family member employment with Johnson & Johnson, and stock or other ownership interests with: Celgene, Abbott (immediate family member), GlaxoSmithKline (immediate family member), Johnson & Johnson (immediate family member), and Novartis (immediate family member). Dr Srkalovic discloses speakers’ bureau with Takeda and Janssen. Dr Leach discloses a consulting or advisory role with PRA International. Dr Leal discloses a consulting or advisory role with: Takeda, AstraZeneca, Novartis, Abbvie, Bristol‐Meyers Squibb, Bayer and Genentech and travel, accommodations, or expenses supported by Xcovery and Mirati Therapeutics. Dr Aggarwal discloses a consulting or advisory role with Genentech, Bristol‐Myers Squibb, Celgene, MedImmune, and institutional research funding supported by Incyte, Macrogenics, Merck Sharp & Dohme, and AstraZeneca/MedImmune. Dr Cella is President of FACIT.org and discloses research grants to his institution from Abbvie, Bristol‐Myers Squibb, PledPharma and Pfizer, as well as a consulting or advisory role with Abbvie, Pfizer, Novartis, PledPharma, and Asahi‐Kaseo. Dr Ramalingam discloses a consulting or advisory role with Amgen, Abbvie, Bristol‐Myers Squibb, Eli Lilly/ImClone, Genentech, Takeda, and Luxo, and research grants from AstraZeneca, Merck, and Tesaro. Dr Wagner discloses a consulting or advisory role with EveryFit, Janssen, and Celgene.

© 2020 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.

Figures

FIGURE 1

Consolidated Standards of Reporting Trials (CONSORT) Flowchart. PRO = Patient‐reported outcome. CONSORT flow diagram depicting study recruitment and retention. See text for patient‐reported outcome completion rates calculated with a denominator of those alive at each time point

FIGURE 2

Mean and 95% CI of FACT/GOG‐Ntx neurotoxicity total score and total change score from baseline by treatment arm in eligible and treated patients. FACT/GOG‐Ntx = Functional Assessment of Cancer Therapy/Gynecologic Oncology Group Neurotoxicity (11‐items). PRO = Patient‐reported outcome. LB/UB = lower bound/upper bound of 95% confidence interval. Lower scores on the FACT/GOG‐Ntx indicate higher neurotoxicity. No statistically significant differences were observed between treatment arms in mean total neurotoxicity scores or in mean neurotoxicity change scores. The placebo arm experienced worsening neurotoxicity between baseline and 3‐month assessment

FIGURE 3

A Treatment‐emergent patient‐reported neurotoxicity symptom at 3 and 6 mo based on individual FACT‐GOG‐NTX items (% of patients rating as ≥“a little bit”) by treatment arm. FACT/GOG‐Ntx = Functional Assessment of Cancer Therapy/Gynecologic Oncology Group Neurotoxicity (11‐items). 3‐month assessment corresponds to end of cycle 4. 6‐mo assessment corresponds to 3‐mo post‐treatment. Items from the FACT/GOG‐NTX are as follows: difficulty walking = AN6; weakness = HI12; numbness/tingling, hands = NTX1; numbness/tingling, feet = NTX2; discomfort, hands = NTX3; discomfort, feet = NTX4; arthralgia/myalgia = NTX5; difficulty hearing = NTX6; tinnitus = NTX7; motor, hands = NTX8; sensory, hands = NTX9. Weakness was the most common treatment‐emergent symptom at 3 mo (50.0% in veliparib; 63.6% in placebo) and 6 mo (77.8% in veliparib; 58.8% in placebo). B, Most common moderate or severe patient‐reported neurotoxicity symptoms at 3 and 6 mo based on individual FACT‐GOG‐NTX items (% of patients rating as “quite a bit” or “very much”) by treatment arm. FACT/GOG‐Ntx = Functional Assessment of Cancer Therapy/Gynecologic Oncology Group Neurotoxicity (11‐items). 3‐month assessment corresponds to end of cycle 4. 6‐month assessment corresponds to 3‐months post‐treatment. Items from the FACT/GOG‐NTX are as follows: difficulty walking = AN6; weakness = HI12; numbness/tingling, hands = NTX1; numbness/tingling, feet = NTX2; discomfort, hands = NTX3; discomfort, feet = NTX4; arthralgia/myalgia = NTX5; difficulty hearing = NTX6; tinnitus = NTX7; motor, hands = NTX8; sensory, hands = NTX9. The proportion of patients endorsing moderate or severe symptoms (ie item response = 3 [quite a bit] or 4 [very much] did not differ significantly between treatment arms at any time point. Weakness was most common moderate or severe symptom reported at 3‐months (15.5% in veliparib; 26.5% in placebo) and 6‐month (32.5% in veliparib; 22.6% in placebo)