Transformation Into Small Cell Lung Cancer : a Mode of Resistance to Treatment

Small Cell Lung Cancer Clinical Trial

— TransCPC  

Official title:

Retrospective Study of Cases of Small Cell Lung Cancer (SCLC) That Appeared During Treatment of Another Lung Carcinoma With or Without Oncogenic Activation (TransCPC)

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03419286
• Other study ID #: 38RC16.053
• Status: Completed
• Phase: N/A
• First received: January 18, 2018
• Last updated: January 25, 2018
• Start date: February 2016
• Est. completion date: November 2017

Study information

• Verified date: January 2018
• Source: University Hospital, Grenoble
• Contact: n/a
• Is FDA regulated: No
• Study type: Observational

Clinical Trial Summary

The discovery of oncogenic mutations and the use of targeted therapies have transformed the management of certain tumors. Thus 12 to 15% of bronchial adenocarcinomas (AD) carry mutations of EGFR and receive from the first line inhibitors of this kinase (ITK). Despite spectacular results, relapse and resistance are quasi-general phenomena. In most known cases, EGFR-TKI resistance mechanisms involve secondary mutations of EGFR or the activation of alternative oncogenic pathways. However, in 5 to 15% of patients, resistance is manifested by the emergence of a small cell carcinoma (CPC), a cancer of neuroendocrine origin very different from AD by its cellular, molecular and epidemiological characteristics. This phenotypic transformation is an almost unique phenomenon in oncology and its molecular bases are not understood. To study this phenomenon, a Franco-Italian network was established that documented and collected cases of this rare tumor. This series is the subject of detailed anatomopathological, clinical and therapeutic documentation. This project aims to investigate the exome of one or more matched lesion regions to evaluate the evolutionary processes leading from the initial AD to the relapsing CPC. These results will guide future research on predictive markers of relapse and their targeted treatment.

Description:

An international multicentric retrospective collection of cases was performed between 2005 and 2017. A global e-mailing to a network of thoracic oncology centers in France and Italy called for the selection of retrospective cases. Consecutive non small cell lung cancer (NSCLC) patients with stage III or IV EGFR NSCLC with or without initial EGFR mutation with a secondary transformation to small cell lung cancer (SCLC) in participating centers in France and Italy were included. Patients with a previous history of SCLC or neuroendocrine tumor of the lung were excluded as well as patients with combined Small cell/ Non-small cell lung cancer on the initial pathology sample.

Study ethics approval was obtained on December 8th of 2015 (CECIC Rhône-Alpes-Auvergne, Clermont-Ferrand, IRB 5891). Anonymized data were collected at each center then centrally analyzed at the Albert Bonniot Institute, Inserm U 823, Grenoble Alpes University, in Grenoble, France.

The primary objective of this study was to analyze survival data after transformation to SCLC. The secondary objectives were to define: the epidemiological characteristics at the time of diagnosis of NSCLC, the histomolecular characteristics at the time of diagnosis of NSCLC and at the time of diagnosis of SCLC; the clinical characteristics at the time of diagnosis of NSCLC and SCLC and the treatment characteristics before and after transformation from NSCLC to SCLC.

All identified cases will be analyzed. This concerns about sixty two patients because the transformation into small cell lung cancer is a rare mechanism of resistance, it is for this reason that all the cases will be included in order to obtain the most exhaustive data possible.

Continuous variables were described as median (25%-75% interquartile range [IQR]) and categorical variables as number (%). Associations between categorical variables were compared using the chi-2 test or Fisher's exact test and those between continuous variables using the Wilcoxon test. Patients were followed until November of 2017. Overall survival (OS) is the time from the initial diagnosis of lung cancer to death and survival after SCLC transformation is from the rebiopsy to death. Kaplan-Meier plots of survival curves were compared between groups using the log-rank test. All tests were two-sided, and P values <0.05 were considered statistically significant. All statistical analyses were performed using SAS 9.3 (SAS Institute, Cary, NC, USA).

Recruitment information / eligibility

• Status: Completed
• Enrollment: 62
• Est. completion date: November 2017
• Est. primary completion date: November 2017
• Accepts healthy volunteers: No
• Gender: All
• Age group: N/A and older

Eligibility

Inclusion Criteria:

• Patient with no history of small cell cancer or Neuroendocrine cancer

• Patients with non-small cell lung cancer at baseline, stage IIIB or IV

• Transformation during treatment of non small cell lung cancer, in small cell cancer proven by biopsy

Exclusion Criteria:

• History of small cell cancer or Neuroendocrine cancer

• Absence of histological evidence of the transformation into small cell lung cancer after treatment of non small cell lung cancer

• Patients with non-small cell lung cancer at initial biopsy, stage I, II, IIIA

Related Conditions & MeSH terms

• Lung Neoplasms
• Small Cell Lung Cancer
• Small Cell Lung Carcinoma

Locations

Country	Name	City	State
n/a

Sponsors (1)

Lead Sponsor	Collaborator
University Hospital, Grenoble

References & Publications (10)

Crystal AS, Shaw AT, Sequist LV, Friboulet L, Niederst MJ, Lockerman EL, Frias RL, Gainor JF, Amzallag A, Greninger P, Lee D, Kalsy A, Gomez-Caraballo M, Elamine L, Howe E, Hur W, Lifshits E, Robinson HE, Katayama R, Faber AC, Awad MM, Ramaswamy S, Mino-Kenudson M, Iafrate AJ, Benes CH, Engelman JA. Patient-derived models of acquired resistance can identify effective drug combinations for cancer. Science. 2014 Dec 19;346(6216):1480-6. doi: 10.1126/science.1254721. Epub 2014 Nov 13. — View Citation

Du L, Schageman JJ, Irnov, Girard L, Hammond SM, Minna JD, Gazdar AF, Pertsemlidis A. MicroRNA expression distinguishes SCLC from NSCLC lung tumor cells and suggests a possible pathological relationship between SCLCs and NSCLCs. J Exp Clin Cancer Res. 2010 Jun 17;29:75. doi: 10.1186/1756-9966-29-75. — View Citation

Lee JK, Lee J, Kim S, Kim S, Youk J, Park S, An Y, Keam B, Kim DW, Heo DS, Kim YT, Kim JS, Kim SH, Lee JS, Lee SH, Park K, Ku JL, Jeon YK, Chung DH, Park PJ, Kim J, Kim TM, Ju YS. Clonal History and Genetic Predictors of Transformation Into Small-Cell Carcinomas From Lung Adenocarcinomas. J Clin Oncol. 2017 Sep 10;35(26):3065-3074. doi: 10.1200/JCO.2016.71.9096. Epub 2017 May 12. — View Citation

Niederst MJ, Sequist LV, Poirier JT, Mermel CH, Lockerman EL, Garcia AR, Katayama R, Costa C, Ross KN, Moran T, Howe E, Fulton LE, Mulvey HE, Bernardo LA, Mohamoud F, Miyoshi N, VanderLaan PA, Costa DB, Jänne PA, Borger DR, Ramaswamy S, Shioda T, Iafrate AJ, Getz G, Rudin CM, Mino-Kenudson M, Engelman JA. RB loss in resistant EGFR mutant lung adenocarcinomas that transform to small-cell lung cancer. Nat Commun. 2015 Mar 11;6:6377. doi: 10.1038/ncomms7377. — View Citation

Oser MG, Niederst MJ, Sequist LV, Engelman JA. Transformation from non-small-cell lung cancer to small-cell lung cancer: molecular drivers and cells of origin. Lancet Oncol. 2015 Apr;16(4):e165-72. doi: 10.1016/S1470-2045(14)71180-5. Review. — View Citation

Ross JS, Wang K, Elkadi OR, Tarasen A, Foulke L, Sheehan CE, Otto GA, Palmer G, Yelensky R, Lipson D, Chmielecki J, Ali SM, Elvin J, Morosini D, Miller VA, Stephens PJ. Next-generation sequencing reveals frequent consistent genomic alterations in small cell undifferentiated lung cancer. J Clin Pathol. 2014 Sep;67(9):772-6. — View Citation

Sequist LV, Waltman BA, Dias-Santagata D, Digumarthy S, Turke AB, Fidias P, Bergethon K, Shaw AT, Gettinger S, Cosper AK, Akhavanfard S, Heist RS, Temel J, Christensen JG, Wain JC, Lynch TJ, Vernovsky K, Mark EJ, Lanuti M, Iafrate AJ, Mino-Kenudson M, Engelman JA. Genotypic and histological evolution of lung cancers acquiring resistance to EGFR inhibitors. Sci Transl Med. 2011 Mar 23;3(75):75ra26. doi: 10.1126/scitranslmed.3002003. — View Citation

Shoemaker AR, Mitten MJ, Adickes J, Ackler S, Refici M, Ferguson D, Oleksijew A, O'Connor JM, Wang B, Frost DJ, Bauch J, Marsh K, Tahir SK, Yang X, Tse C, Fesik SW, Rosenberg SH, Elmore SW. Activity of the Bcl-2 family inhibitor ABT-263 in a panel of small cell lung cancer xenograft models. Clin Cancer Res. 2008 Jun 1;14(11):3268-77. doi: 10.1158/1078-0432.CCR-07-4622. — View Citation

Suda K, Murakami I, Sakai K, Mizuuchi H, Shimizu S, Sato K, Tomizawa K, Tomida S, Yatabe Y, Nishio K, Mitsudomi T. Small cell lung cancer transformation and T790M mutation: complimentary roles in acquired resistance to kinase inhibitors in lung cancer. Sci Rep. 2015 Sep 24;5:14447. doi: 10.1038/srep14447. — View Citation

Yu HA, Arcila ME, Rekhtman N, Sima CS, Zakowski MF, Pao W, Kris MG, Miller VA, Ladanyi M, Riely GJ. Analysis of tumor specimens at the time of acquired resistance to EGFR-TKI therapy in 155 patients with EGFR-mutant lung cancers. Clin Cancer Res. 2013 Apr 15;19(8):2240-7. doi: 10.1158/1078-0432.CCR-12-2246. Epub 2013 Mar 7. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	survival time after transformation to small cell lung cancer (SCLC)	months of survival after transformation into small cell lung cancer	2005 to 2017
Secondary	time from initial diagnosis of non small cell lung cancer (NSCLC) to small cell lung cancer transformation	median of months between initial diagnosis of non small cell lung cancer and small cell lung cancer transformation	2005 to 2017
Secondary	histology type at the time of diagnosis of NSCLC and at the time of diagnosis of small cell lung cancer (SCLC)	histology on biopsy at the initial diagnosis and at transformation according with OMS classification	2005 to 2017
Secondary	type of specific treatments administered before and after transformation from non small cell lung cancer into small cell lung cancer	The type of treatment administered before and after SCLC transformation. percentage of patients in each type of specific treatment used	2005 to 2017
Secondary	sexe of patients	sexe female or male in percentage of patients	2005 to 2017
Secondary	stage of NSCLC at initial diagnosis	percentage of patients with stage III and with IV of NSCLC	2005 to 2017
Secondary	smocking status at diagnosis initial of non small cell lung cancer	percentage of patients in never, former or active smokers	2005 to 2017
Secondary	type of mutations at the diagnostic initial NSCLC and at transformation	the mutation on initial biopsy and on biopsy at transformation in SCLC in percentage of patients	2005 to 2017
Secondary	treatment lines before transformation into small cell lung cancer (SCLC)	Median number of lines of treatment for the NSCLC before transformation into SCLC	2005 to 2017
Secondary	response rates to first line treatment after transformation into small cell lung cancer	response rate in percentage of patients after transformation into SCLC according with the RECIST criteria	2005 to 2017
Secondary	lines of treatment after transformation into SCLC	median number of lines of treatment after transformation into SCLC	2005 to 2017
Secondary	age of patients	the median in years at the he diagnosis initial of non small cell lung cancer	2005 to 2017