Partial Response in an RRx-001-Primed Patient with Refractory Small-Cell Lung Cancer after a Third Introduction of Platinum Doublets

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Abstract

Small-cell lung cancer (SCLC), initially exquisitely sensitive to first-line cisplatin/etoposide, invariably relapses and acquires a multidrug chemoresistant phenotype that generally renders retreatment with first-line therapy both futile and counterproductive. This report presents the case of a 77-year-old Caucasian male with extensive-stage refractory SCLC who was restarted on platinum doublets as part of a clinical trial called TRIPLE THREAT (NCT02489903) involving pretreatment with the epi-immunotherapeutic agent RRx-001, and who achieved a partial response after only 4 cycles. The patient had received a platinum drug twice before, in 2009 for a diagnosis of non-small-cell lung cancer (squamous cell carcinoma) and in 2015 for SCLC, suggesting that RRx-001 pretreatment may sensitize or resensitize refractory SCLC patients to first-line chemotherapy.

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A small cell lung cancer genome reports complex tobacco exposure signatures

Erin Pleasance, Philip J. Stephens, Sarah O’Meara … (2009)

SUMMARY Cancer is driven by mutation. Worldwide, tobacco smoking is the major lifestyle exposure that causes cancer, exerting carcinogenicity through >60 chemicals that bind and mutate DNA. Using massively parallel sequencing technology, we sequenced a small cell lung cancer cell line, NCI-H209, to explore the mutational burden associated with tobacco smoking. 22,910 somatic substitutions were identified, including 132 in coding exons. Multiple mutation signatures testify to the cocktail of carcinogens in tobacco smoke and their proclivities for particular bases and surrounding sequence context. Effects of transcription-coupled repair and a second, more general expression-linked repair pathway were evident. We identified a tandem duplication that duplicates exons 3-8 of CHD7 in-frame, and another two lines carrying PVT1-CHD7 fusion genes, suggesting that CHD7 may be recurrently rearranged in this disease. These findings illustrate the potential for next-generation sequencing to provide unprecedented insights into mutational processes, cellular repair pathways and gene networks associated with cancer.

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Topotecan versus cyclophosphamide, doxorubicin, and vincristine for the treatment of recurrent small-cell lung cancer.

P. Clark, R Gralla, A Depierre … (1999)

Topotecan and cyclophosphamide, doxorubicin, and vincristine (CAV) were evaluated in a randomized, multicenter study of patients with small-cell lung cancer (SCLC) who had relapsed at least 60 days after completion of first-line therapy. Patients received either topotecan (1.5 mg/m2) as a 30-minute infusion daily for 5 days every 21 days (n = 107) or CAV (cyclophosphamide 1,000 mg/m2, doxorubicin 45 mg/m2, and vincristine 2 mg) infused on day 1 every 21 days (n = 104). Eligibility included the following: bidimensionally measurable disease, Eastern Cooperative Oncology Group performance status of less than or equal to 2, and adequate marrow, liver, and renal function. Response was confirmed by blinded independent radiologic review. Response rate was 26 of 107 patients (24.3%) treated with topotecan and 19 of 104 patients (18.3%) treated with CAV (P = .285). Median times to progression were 13.3 weeks (topotecan) and 12.3 weeks (CAV) (P = .552). Median survival was 25.0 weeks for topotecan and 24.7 weeks for CAV (P = .795). The proportion of patients who experienced symptom improvement was greater in the topotecan group than in the CAV group for four of eight symptoms evaluated, including dyspnea, anorexia, hoarseness, and fatigue, as well as interference with daily activity (P< or =.043). Grade 4 neutropenia occurred in 37.8% of topotecan courses versus 51.4% of CAV courses (P<.001). Grade 4 thrombocytopenia and grade 3/4 anemia occurred more frequently with topotecan, occurring in 9.8% and 17.7% of topotecan courses versus 1.4% and 7.2% of CAV courses, respectively (P<.001 for both). Nonhematologic toxicities were generally grade 1 to 2 for both regimens. Topotecan was at least as effective as CAV in the treatment of patients with recurrent SCLC and resulted in improved control of several symptoms.

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Randomized phase III trial of amrubicin versus topotecan as second-line treatment for patients with small-cell lung cancer.

Joachim von Pawel, Robert Jotte, David Spigel … (2014)

Amrubicin, a third-generation anthracycline and potent topoisomerase II inhibitor, showed promising activity in small-cell lung cancer (SCLC) in phase II trials. This phase III trial compared the safety and efficacy of amrubicin versus topotecan as second-line treatment for SCLC.

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Journal

Journal ID (publisher-id): CRO

Journal ID (pmc): CRO

Journal ID (doi): 10.1159/issn.1662-6575

Title: Case Reports in Oncology

Publisher: S. Karger AG

ISSN (Electronic): 1662-6575

Publication date Subscription-year: 2016

Publication date Collection: May – August 2016

Publication date (Electronic): 24 May 2016

Volume: 9

Issue: 2

Pages: 285-289

Affiliations

^aWalter Reed Medical Center, Bethesda, Md., ^bEpicentRx, Inc., Mountain View, Calif., ^cDepartment of Bioengineering, University of California, La Jolla, Calif., and ^dMoores Cancer Center, La Jolla, Calif., USA

Author notes

*Dr. Jan Scicinski, EpicentRx, Inc., 800 W El Camino Real, Suite 180, Mountain View, CA 94040 (USA), E-Mail jscicinski@epicentrx.com

Article

Publisher ID: 446209 Pmcid ID: PMC4924447 Other ID: Case Rep Oncol 2016;9:285-289

DOI: 10.1159/000446209

PMC ID: PMC4924447

PubMed ID: 27403127

SO-VID: 8d4a0d44-92bf-440d-acaa-906d05cc3b56

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This article is licensed under the Creative Commons Attribution-NonCommercial 4.0 International License (CC BY-NC). Usage and distribution for commercial purposes requires written permission. Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug. Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

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Partial Response in an RRx-001-Primed Patient with Refractory Small-Cell Lung Cancer after a Third Introduction of Platinum Doublets

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Abstract

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Karger: Oncology

Most cited references 21

A small cell lung cancer genome reports complex tobacco exposure signatures

Topotecan versus cyclophosphamide, doxorubicin, and vincristine for the treatment of recurrent small-cell lung cancer.

Randomized phase III trial of amrubicin versus topotecan as second-line treatment for patients with small-cell lung cancer.

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