Medical Abstracts

Keyword: lung cancer

1. N Engl J Med. 2018 Dec 6;379(23):2220-2229. doi: 10.1056/NEJMoa1809064. Epub 2018

Sep 25.

First-Line Atezolizumab plus Chemotherapy in Extensive-Stage Small-Cell Lung

Cancer.

Horn L, Mansfield AS, Szcz?sna A, Havel L, Krzakowski M, Hochmair MJ, Huemer F,

Losonczy G, Johnson ML, Nishio M, Reck M, Mok T, Lam S, Shames DS, Liu J, Ding B,

Lopez-Chavez A, Kabbinavar F, Lin W, Sandler A, Liu SV; IMpower133 Study Group.

BACKGROUND: Enhancing tumor-specific T-cell immunity by inhibiting programmed

death ligand 1 (PD-L1)-programmed death 1 (PD-1) signaling has shown promise in

the treatment of extensive-stage small-cell lung cancer. Combining checkpoint

inhibition with cytotoxic chemotherapy may have a synergistic effect and improve

efficacy.

METHODS: We conducted this double-blind, placebo-controlled, phase 3 trial to

evaluate atezolizumab plus carboplatin and etoposide in patients with

extensive-stage small-cell lung cancer who had not previously received treatment.

Patients were randomly assigned in a 1:1 ratio to receive carboplatin and

etoposide with either atezolizumab or placebo for four 21-day cycles (induction

phase), followed by a maintenance phase during which they received either

atezolizumab or placebo (according to the previous random assignment) until they

had unacceptable toxic effects, disease progression according to Response

Evaluation Criteria in Solid Tumors, version 1.1, or no additional clinical

benefit. The two primary end points were investigator-assessed progression-free

survival and overall survival in the intention-to-treat population.

RESULTS: A total of 201 patients were randomly assigned to the atezolizumab

group, and 202 patients to the placebo group. At a median follow-up of 13.9

months, the median overall survival was 12.3 months in the atezolizumab group and

10.3 months in the placebo group (hazard ratio for death, 0.70; 95% confidence

interval [CI], 0.54 to 0.91; P=0.007). The median progression-free survival was

5.2 months and 4.3 months, respectively (hazard ratio for disease progression or

death, 0.77; 95% CI, 0.62 to 0.96; P=0.02). The safety profile of atezolizumab

plus carboplatin and etoposide was consistent with the previously reported safety

profile of the individual agents, with no new findings observed.

CONCLUSIONS: The addition of atezolizumab to chemotherapy in the first-line

treatment of extensive-stage small-cell lung cancer resulted in significantly

longer overall survival and progression-free survival than chemotherapy alone.

(Funded by F. Hoffmann-La Roche/Genentech; IMpower133 ClinicalTrials.gov number,

NCT02763579 .).

DOI: 10.1056/NEJMoa1809064

PMID: 30280641 [Indexed for MEDLINE]

2. Cancer Cell. 2018 Dec 10;34(6):954-969.e4. doi: 10.1016/j.ccell.2018.11.007.

Targeting PKCδ as a Therapeutic Strategy against Heterogeneous Mechanisms of EGFR

Inhibitor Resistance in EGFR-Mutant Lung Cancer.

Lee PC(1), Fang YF(2), Yamaguchi H(1), Wang WJ(1), Chen TC(3), Hong X(4), Ke

B(1), Xia W(1), Wei Y(1), Zha Z(1), Wang Y(1), Kuo HP(5), Wang CW(3), Tu CY(6),

Chen CH(7), Huang WC(8), Chiang SF(9), Nie L(1), Hou J(1), Chen CT(1), Huo L(1),

Yang WH(1), Deng R(10), Nakai K(1), Hsu YH(1), Chang SS(1), Chiu TJ(11), Tang

J(10), Zhang R(12), Wang L(12), Fang B(12), Chen T(13), Wong KK(14), Hsu JL(15),

Hung MC(16).

Author information:

(1)Department of Molecular and Cellular Oncology, The University of Texas MD

Anderson Cancer Center, Houston, TX 77030, USA.

(2)Department of Molecular and Cellular Oncology, The University of Texas MD

Anderson Cancer Center, Houston, TX 77030, USA; Department of Thoracic Medicine,

Chang Gung Foundation, Chang Gung Memorial Hospital, Taoyuan 333, Taiwan;

Department of Pulmonary and Critical Care Medicine Saint Paul's Hospital, Taoyuan

City 33069, Taiwan; College of Medicine, Chang Gung University, Taoyuan 333,

Taiwan.

(3)College of Medicine, Chang Gung University, Taoyuan 333, Taiwan; Department of

Pathology, Chang Gung Foundation, Chang Gung Memorial Hospital, Taoyuan 333,

Taiwan.

Multiple mechanisms of resistance to epidermal growth factor receptor (EGFR)

tyrosine kinase inhibitors (TKIs) have been identified in EGFR-mutant non-small

cell lung cancer (NSCLC); however, recurrent resistance to EGFR TKIs due to the

heterogeneous mechanisms underlying resistance within a single patient remains a

major challenge in the clinic. Here, we report a role of nuclear protein kinase

Cδ (PKCδ) as a common axis across multiple known TKI-resistance mechanisms.

Specifically, we demonstrate that TKI-inactivated EGFR dimerizes with other

membrane receptors implicated in TKI resistance to promote PKCδ nuclear

translocation. Moreover, the level of nuclear PKCδ is associated with TKI

response in patients. The combined inhibition of PKCδ and EGFR induces marked

regression of resistant NSCLC tumors with EGFR mutations.

Copyright © 2018 Elsevier Inc. All rights reserved.

DOI: 10.1016/j.ccell.2018.11.007

PMID: 30537515

3. Lancet Oncol. 2018 Dec;19(12):1654-1667. doi: 10.1016/S1470-2045(18)30649-1. Epub 2018 Nov 6.

Lorlatinib in patients with ALK-positive non-small-cell lung cancer: results from

a global phase 2 study.

Solomon BJ(1), Besse B(2), Bauer TM(3), Felip E(4), Soo RA(5), Camidge DR(6),

Chiari R(7), Bearz A(8), Lin CC(9), Gadgeel SM(10), Riely GJ(11), Tan EH(12),

Seto T(13), James LP(14), Clancy JS(15), Abbattista A(16), Martini JF(17), Chen

J(14), Peltz G(18), Thurm H(17), Ou SI(19), Shaw AT(20).

Author information:

(1)Peter MacCallum Cancer Centre, Melbourne, VIC, Australia. Electronic address:

ben.solomon@petermac.org.

(2)Gustave Roussy Cancer Campus, Villejuif, France; Department of Cancer

Medicine, Paris-Sud University, Orsay, France.

(3)Sarah Cannon Cancer Research Institute/Tennessee Oncology, PLLC, Nashville,

TN, USA.

(4)Vall d'Hebron Institute of Oncology, Barcelona, Spain.

…

Erratum in

Lancet Oncol. 2019 Jan;20(1):e10.

BACKGROUND: Lorlatinib is a potent, brain-penetrant, third-generation inhibitor

of ALK and ROS1 tyrosine kinases with broad coverage of ALK mutations. In a phase

1 study, activity was seen in patients with ALK-positive non-small-cell lung

cancer, most of whom had CNS metastases and progression after ALK-directed

therapy. We aimed to analyse the overall and intracranial antitumour activity of

lorlatinib in patients with ALK-positive, advanced non-small-cell lung cancer.

METHODS: In this phase 2 study, patients with histologically or cytologically

ALK-positive or ROS1-positive, advanced, non-small-cell lung cancer, with or

without CNS metastases, with an Eastern Cooperative Oncology Group performance

status of 0, 1, or 2, and adequate end-organ function were eligible. Patients

were enrolled into six different expansion cohorts (EXP1-6) on the basis of ALK

and ROS1 status and previous therapy, and were given lorlatinib 100 mg orally

once daily continuously in 21-day cycles. The primary endpoint was overall and

intracranial tumour response by independent central review, assessed in pooled

subgroups of ALK-positive patients. Analyses of activity and safety were based on

the safety analysis set (ie, all patients who received at least one dose of

lorlatinib) as assessed by independent central review. Patients with measurable

CNS metastases at baseline by independent central review were included in the

intracranial activity analyses. In this report, we present lorlatinib activity

data for the ALK-positive patients (EXP1-5 only), and safety data for all treated

patients (EXP1-6). This study is ongoing and is registered with

ClinicalTrials.gov, number NCT01970865.

FINDINGS: Between Sept 15, 2015, and Oct 3, 2016, 276 patients were enrolled: 30

who were ALK positive and treatment naive (EXP1); 59 who were ALK positive and

received previous crizotinib without (n=27; EXP2) or with (n=32; EXP3A) previous

chemotherapy; 28 who were ALK positive and received one previous non-crizotinib

ALK tyrosine kinase inhibitor, with or without chemotherapy (EXP3B); 112 who were

ALK positive with two (n=66; EXP4) or three (n=46; EXP5) previous ALK tyrosine

kinase inhibitors with or without chemotherapy; and 47 who were ROS1 positive

with any previous treatment (EXP6). One patient in EXP4 died before receiving

lorlatinib and was excluded from the safety analysis set. In treatment-naive

patients (EXP1), an objective response was achieved in 27 (90·0%; 95% CI

73·5-97·9) of 30 patients. Three patients in EXP1 had measurable baseline CNS

lesions per independent central review, and objective intracranial responses were

observed in two (66·7%; 95% CI 9·4-99·2). In ALK-positive patients with at least

one previous ALK tyrosine kinase inhibitor (EXP2-5), objective responses were

achieved in 93 (47·0%; 39·9-54·2) of 198 patients and objective intracranial

response in those with measurable baseline CNS lesions in 51 (63·0%; 51·5-73·4)

of 81 patients. Objective response was achieved in 41 (69·5%; 95% CI 56·1-80·8)

of 59 patients who had only received previous crizotinib (EXP2-3A), nine (32·1%;

15·9-52·4) of 28 patients with one previous non-crizotinib ALK tyrosine kinase

inhibitor (EXP3B), and 43 (38·7%; 29·6-48·5) of 111 patients with two or more

previous ALK tyrosine kinase inhibitors (EXP4-5). Objective intracranial response

was achieved in 20 (87·0%; 95% CI 66·4-97·2) of 23 patients with measurable

baseline CNS lesions in EXP2-3A, five (55·6%; 21·2-86·3) of nine patients in

EXP3B, and 26 (53·1%; 38·3-67·5) of 49 patients in EXP4-5. The most common

treatment-related adverse events across all patients were hypercholesterolaemia

(224 [81%] of 275 patients overall and 43 [16%] grade 3-4) and

hypertriglyceridaemia (166 [60%] overall and 43 [16%] grade 3-4). Serious

treatment-related adverse events occurred in 19 (7%) of 275 patients and seven

patients (3%) permanently discontinued treatment because of treatment-related

adverse events. No treatment-related deaths were reported.

INTERPRETATION: Consistent with its broad ALK mutational coverage and CNS

penetration, lorlatinib showed substantial overall and intracranial activity both

in treatment-naive patients with ALK-positive non-small-cell lung cancer, and in

those who had progressed on crizotinib, second-generation ALK tyrosine kinase

inhibitors, or after up to three previous ALK tyrosine kinase inhibitors. Thus,

lorlatinib could represent an effective treatment option for patients with

ALK-positive non-small-cell lung cancer in first-line or subsequent therapy.

FUNDING: Pfizer.

Copyright © 2018 Elsevier Ltd. All rights reserved.

DOI: 10.1016/S1470-2045(18)30649-1

PMID: 30413378

4. Nat Med. 2018 Dec;24(12):1845-1851. doi: 10.1038/s41591-018-0232-2. Epub 2018 Nov 5.

Radiotherapy induces responses of lung cancer to CTLA-4 blockade.

Formenti SC(1), Rudqvist NP(2), Golden E(2)(3), Cooper B(4), Wennerberg E(2),

Lhuillier C(2), Vanpouille-Box C(2), Friedman K(5), Ferrari de Andrade L(6)(7),

Wucherpfennig KW(6)(7), Heguy A(8)(9), Imai N(10), Gnjatic S(10), Emerson RO(11),

Zhou XK(12), Zhang T(13), Chachoua A(14), Demaria S(15)(16).

Author information:

(1)Department of Radiation Oncology, Weill Cornell Medicine, New York, NY, USA.

formenti@med.cornell.edu.

(2)Department of Radiation Oncology, Weill Cornell Medicine, New York, NY, USA.

(3)Department of Radiation Oncology, University of California, San Francisco, CA,

USA.

(4)Department of Radiation Oncology, New York University School of Medicine, New

York, NY, USA.

…

Focal radiation therapy enhances systemic responses to anti-CTLA-4 antibodies in

preclinical studies and in some patients with melanoma1-3, but its efficacy in

inducing systemic responses (abscopal responses) against tumors unresponsive to

CTLA-4 blockade remained uncertain. Radiation therapy promotes the activation of

anti-tumor T cells, an effect dependent on type I interferon induction in the

irradiated tumor4-6. The latter is essential for achieving abscopal responses in

murine cancers6. The mechanisms underlying abscopal responses in patients treated

with radiation therapy and CTLA-4 blockade remain unclear. Here we report that

radiation therapy and CTLA-4 blockade induced systemic anti-tumor T cells in

chemo-refractory metastatic non-small-cell lung cancer (NSCLC), where anti-CTLA-4

antibodies had failed to demonstrate significant efficacy alone or in combination

with chemotherapy7,8. Objective responses were observed in 18% of enrolled

patients, and 31% had disease control. Increased serum interferon-β after

radiation and early dynamic changes of blood T cell clones were the strongest

response predictors, confirming preclinical mechanistic data. Functional analysis

in one responding patient showed the rapid in vivo expansion of CD8 T cells

recognizing a neoantigen encoded in a gene upregulated by radiation, supporting

the hypothesis that one explanation for the abscopal response is

radiation-induced exposure of immunogenic mutations to the immune system.

DOI: 10.1038/s41591-018-0232-2

PMCID: PMC6286242 [Available on 2019-05-05]

PMID: 30397353

5. Cell Metab. 2018 Dec 21. pii: S1550-4131(18)30748-4. doi:

10.1016/j.cmet.2018.12.011. [Epub ahead of print]

AMPK-Mediated Lysosome Biogenesis in Lung Cancer Growth.

Patra KC(1), Weerasekara VK(1), Bardeesy N(2).

Author information:

(1)Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston,

MA 02114, USA; Center for Regenerative Medicine, Massachusetts General Hospital,

Harvard Medical School, Boston, MA 02114, USA; Broad Institute of Harvard and

Massachusetts Institute of Technology, Boston, MA 02113, USA.

(2)Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston,

MA 02114, USA; Center for Regenerative Medicine, Massachusetts General Hospital,

Harvard Medical School, Boston, MA 02114, USA; Broad Institute of Harvard and

Massachusetts Institute of Technology, Boston, MA 02113, USA. Electronic address:

bardeesy.nabeel@mgh.harvard.edu.

Cancer cells must adapt to metabolic stress during tumor progression. In this

issue of Cell Metabolism, Eichner et al. (2019) report that lung cancer

development in genetically engineered mice requires the energy sensor

AMP-activated protein kinase (AMPK). Their findings suggest that AMPK-mediated

induction of lysosomal function supports cancer cell fitness, particularly during

the early stages of tumorigenesis.

Copyright © 2018. Published by Elsevier Inc.

DOI: 10.1016/j.cmet.2018.12.011

PMID: 30612899

6. J Clin Invest. 2018 Dec 27. pii: 123319. doi: 10.1172/JCI123319. [Epub ahead of

print]

PARP inhibition enhances tumor cell-intrinsic immunity in ERCC1-deficient

non-small cell lung cancer.

Chabanon RM, Muirhead G, Krastev DB, Adam J, Morel D, Garrido M, Lamb A, Hénon C,

Dorvault N, Rouanne M, Marlow R, Bajrami I, Cardeñosa ML, Konde A, Besse B,

Ashworth A, Pettitt SJ, Haider S, Marabelle A, Tutt AN, Soria JC, Lord CJ,

Postel-Vinay S.

The cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS/STING) pathway

detects cytosolic DNA to activate innate immune responses. Poly(ADP-ribose)

polymerase inhibitors (PARPi) selectively target cancer cells with DNA repair

deficiencies such as those caused by BRCA1 mutations or ERCC1 defects. Using

isogenic cell lines and patient-derived samples, we showed that ERCC1-defective

non-small cell lung cancer (NSCLC) cells exhibit an enhanced type I interferon

transcriptomic signature, and that low ERCC1 expression correlates with increased

lymphocytic infiltration. We demonstrated that clinical PARPi, including olaparib

and rucaparib, have cell-autonomous immunomodulatory properties in

ERCC1-defective NSCLC and BRCA1-defective triple-negative breast cancer (TNBC)

cells. Mechanistically, PARPi generated cytoplasmic chromatin fragments with

micronuclei characteristics; these were found to activate cGAS/STING, downstream

type I interferon signaling and CCL5 secretion. Importantly, these effects were

suppressed in PARP1-null TNBC cells, suggesting that this phenotype resulted from

an on-target effect of PARPi on PARP1. PARPi also potentiated

interferon-γ-induced PD-L1 expression in NSCLC cell lines and in fresh patient

tumor cells; this effect was enhanced in ERCC1-deficient contexts. Our data

provide the preclinical rationale for using PARPi as immunomodulatory agents in

appropriately molecularly-selected populations.

DOI: 10.1172/JCI123319

PMID: 30589644

7. Nat Commun. 2018 Dec 18;9(1):5361. doi: 10.1038/s41467-018-07767-w.

Local mutational diversity drives intratumoral immune heterogeneity in non-small

cell lung cancer.

Jia Q(1)(2), Wu W(3), Wang Y(4), Alexander PB(5), Sun C(1)(2), Gong Z(1)(2),

Cheng JN(1)(2)(6), Sun H(4), Guan Y(4), Xia X(4)(7), Yang L(4), Yi X(4), Wan

YY(8), Wang H(3), He J(9), Futreal PA(10), Li QJ(11)(12), Zhu B(13)(14).

Author information:

(1)Institute of Cancer, Xinqiao Hospital, Third Military Medical University,

Chongqing, 400037, China.

(2)Chongqing Key Laboratory of Tumor Immunotherapy, Chongqing, 400037, China.

(3)Department of Cardiothorathic Surgery, Southwest Hospital, Third Military

Medical University, Chongqing, 400038, China.

…

Combining whole exome sequencing, transcriptome profiling, and T cell repertoire

analysis, we investigate the spatial features of surgically-removed biopsies from

multiple loci in tumor masses of 15 patients with non-small cell lung cancer

(NSCLC). This revealed that the immune microenvironment has high spatial

heterogeneity such that intratumoral regional variation is as large as

inter-personal variation. While the local total mutational burden (TMB) is

associated with local T-cell clonal expansion, local anti-tumor cytotoxicity does

not directly correlate with neoantigen abundance. Together, these findings

caution against that immunological signatures can be predicted solely from TMB or

microenvironmental analysis from a single locus biopsy.

DOI: 10.1038/s41467-018-07767-w

PMCID: PMC6299138

PMID: 30560866 [Indexed for MEDLINE]

8. J Clin Oncol. 2018 Dec 14:JCO1801585. doi: 10.1200/JCO.18.01585. [Epub ahead of

print]

EGFR-Mutant Adenocarcinomas That Transform to Small-Cell Lung Cancer and Other

Neuroendocrine Carcinomas: Clinical Outcomes.

Marcoux N(1)(2), Gettinger SN(3), O'Kane G(4), Arbour KC(5), Neal JW(6), Husain

H(7), Evans TL(8)(2), Brahmer JR(9), Muzikansky A(1), Bonomi PD(10), Del Prete

S(11), Wurtz A(3), Farago AF(1), Dias-Santagata D(1), Mino-Kenudson M(1), Reckamp

KL(2), Yu HA(5), Wakelee HA(6), Shepherd FA(4), Piotrowska Z(1), Sequist LV(1).

Author information:

(1)1 Massachusetts General Hospital, Boston, MA.

(2)11 City of Hope National Medical Center, Duarte, CA.

(3)2 Yale Cancer Center, New Haven, CT.

(4)3 Princess Margaret Cancer Centre, Toronto, Ontario, Canada.

…

PURPOSE: Approximately 3% to 10% of EGFR (epidermal growth factor receptor)

-mutant non-small cell lung cancers (NSCLCs) undergo transformation to small-cell

lung cancer (SCLC), but their clinical course is poorly characterized.

METHODS: We retrospectively identified patients with EGFR-mutant SCLC and other

high-grade neuroendocrine carcinomas seen at our eight institutions.

Demographics, disease features, and outcomes were analyzed.

RESULTS: We included 67 patients-38 women and 29 men; EGFR mutations included

exon 19 deletion (69%), L858R (25%), and other (6%). At the initial lung cancer

diagnosis, 58 patients had NSCLC and nine had de novo SCLC or mixed histology.

All but these nine patients received one or more EGFR tyrosine kinase inhibitor

before SCLC transformation. Median time to transformation was 17.8 months (95%

CI, 14.3 to 26.2 months). After transformation, both platinum-etoposide and

taxanes yielded high response rates, but none of 17 patients who received

immunotherapy experienced a response. Median overall survival since diagnosis was

31.5 months (95% CI, 24.8 to 41.3 months), whereas median survival since the time

of SCLC transformation was 10.9 months (95% CI, 8.0 to 13.7 months). Fifty-nine

patients had tissue genotyping at first evidence of SCLC. All maintained their

founder EGFR mutation, and 15 of 19 with prior EGFR T790M positivity were T790

wild-type at transformation. Other recurrent mutations included TP53, Rb1, and

PIK3CA. Re-emergence of NSCLC clones was identified in some cases. CNS metastases

were frequent after transformation.

CONCLUSION: There is a growing appreciation that EGFR-mutant NSCLCs can undergo

SCLC transformation. We demonstrate that this occurs at an average of 17.8 months

after diagnosis and cases are often characterized by Rb1, TP53, and PIK3CA

mutations. Responses to platinum-etoposide and taxanes are frequent, but

checkpoint inhibitors yielded no responses. Additional investigation is needed to

better elucidate optimal strategies for this group.

DOI: 10.1200/JCO.18.01585

PMID: 30550363

9. J Clin Oncol. 2019 Jan 20;37(3):222-229. doi: 10.1200/JCO.18.00264. Epub 2018 Dec 5.

Randomized Phase II Trial of Cisplatin and Etoposide in Combination With

Veliparib or Placebo for Extensive-Stage Small-Cell Lung Cancer: ECOG-ACRIN 2511

Study.

Owonikoko TK(1), Dahlberg SE(2), Sica GL(1), Wagner LI(3), Wade JL 3rd(4),

Srkalovic G(5), Lash BW(6), Leach JW(7), Leal TB(8), Aggarwal C(9), Ramalingam

SS(1).

Author information:

(1)1 Emory University, Atlanta, GA.

(2)2 Dana-Farber Cancer Institute, Boston, MA.

(3)3 Northwestern University, Chicago, IL.

(4)4 Decatur Memorial Hospital, Decatur, IL.

…

PURPOSE: Veliparib, a poly (ADP ribose) polymerase inhibitor, potentiated

standard chemotherapy against small-cell lung cancer (SCLC) in preclinical

studies. We evaluated the combination of veliparib with cisplatin and etoposide

(CE; CE+V) doublet in untreated, extensive-stage SCLC (ES-SCLC).

MATERIALS AND METHODS: Patients with ES-SCLC, stratified by sex and serum lactate

dehydrogenase levels, were randomly assigned to receive four 3-week cycles of CE

(75 mg/m2 intravenously on day 1 and 100 mg/m2 on days 1 through 3) along with

veliparib (100 mg orally twice per day on days 1 through 7) or placebo (CE+P).

The primary end point was progression-free survival (PFS). Using an overall

one-sided 0.10-level log-rank test, the study had 88% power to demonstrate a

37.5% reduction in the PFS hazard rate.

RESULTS: A total of 128 eligible patients received treatment on protocol. The

median age was 66 years, 52% of patients were men, and Eastern Cooperative

Oncology Group performance status was 0 for 29% of patients and 1 for 71%. The

respective median PFS for the CE+V arm versus the CE+P arm was 6.1 versus 5.5

months (unstratified hazard ratio [HR], 0.75 [one-sided P = .06]; stratified HR,

0.63 [one-sided P = .01]), favoring CE+V. The median overall survival was 10.3

versus 8.9 months (stratified HR, 0.83; 80% CI, 0.64 to 1.07; one-sided P = .17)

for the CE+V and CE+P arms, respectively. The overall response rate was 71.9%

versus 65.6% (two-sided P = .57) for CE+V and CE+P, respectively. There was a

significant treatment-by-strata interaction in PFS: Male patients with high

lactate dehydrogenase levels derived significant benefit (PFS HR, 0.34; 80% CI,

0.22 to 0.51) but there was no evidence of benefit among patients in other strata

(PFS HR, 0.81; 80% CI, 0.60 to 1.09). The following grade ≥ 3 hematology

toxicities were more frequent in the CE+V arm than the CE+P arm: CD4 lymphopenia

(8% v 0%; P = .06) and neutropenia (49% v 32%; P = .08), but treatment delivery

was comparable.

CONCLUSION: The addition of veliparib to frontline chemotherapy showed signal of

efficacy in patients with ES-SCLC and the study met its prespecified end point.

DOI: 10.1200/JCO.18.00264

PMID: 30523756

10. J Exp Med. 2018 Dec 3;215(12):3115-3135. doi: 10.1084/jem.20180801. Epub 2018 Nov 28.

Ezh2 inhibition in Kras-driven lung cancer amplifies inflammation and associated

vulnerabilities.

Serresi M(1), Siteur B(2), Hulsman D(3)(4), Company C(1), Schmitt MJ(1), Lieftink

C(5), Morris B(5), Cesaroni M(6), Proost N(2), Beijersbergen RL(5), van Lohuizen

M(7)(4), Gargiulo G(8).

Author information:

(1)Molecular Oncology, Max Delbrück Center for Molecular Medicine in the

Helmholtz Association, Berlin, Germany.

(2)Mouse Cancer Clinic, Netherlands Cancer Institute, Amsterdam, Netherlands.

(3)Division of Molecular Genetics and Cancer Genomics Centre, Netherlands Cancer

Institute, Amsterdam, Netherlands.

…

Kras-driven non-small-cell lung cancers (NSCLCs) are a leading cause of death

with limited therapeutic options. Many NSCLCs exhibit high levels of Ezh2, the

enzymatic subunit of polycomb repressive complex 2 (PRC2). We tested Ezh2

inhibitors as single agents or before chemotherapy in mice with orthotopic

Kras-driven NSCLC grafts, which homogeneously express Ezh2. These tumors display

sensitivity to EZH2 inhibition by GSK126 but also amplify an inflammatory program

involving signaling through NF-κB and genes residing in PRC2-regulated chromatin.

During this process, tumor cells overcome GSK126 antiproliferative effects. We

identified oncogenes that may mediate progression through an in vivo RNAi screen

aimed at targets of PRC2/NF-κB. An in vitro compound screening linked

GSK126-driven inflammation and therapeutic vulnerability in human cells to

regulation of RNA synthesis and proteostasis. Interestingly, GSK126-treated

NSCLCs in vivo also showed an enhanced response to a combination of nimesulide

and bortezomib. Thus, Ezh2 inhibition may restrict cell proliferation and promote

defined adaptive responses. Targeting these responses potentially improves

outcomes in Kras-driven NSCLCs.

© 2018 Serresi et al.

DOI: 10.1084/jem.20180801

PMCID: PMC6279402

PMID: 30487290

11. Adv Mater. 2018 Dec;30(51):e1805437. doi: 10.1002/adma.201805437. Epub 2018 Oct

21.

Construction of a Novel Bispecific Antibody to Enhance Antitumor Activity against

Lung Cancer.

Yin W(1), Zhu J(2), Gonzalez-Rivas D(2)(3), Okumura M(4), Rocco G(5), Pass H(6),

Jiang G(2), Yang Y(2)(7).

Author information:

(1)Key laboratory of Oral Biomedical engineering of Ministry of education,

Hospital of Stomatology, School of Stomatology, Wuhan University, Wuhan, 430079,

China.

(2)Department of Thoracic Surgery, Shanghai Pulmonary Hospital, 507 Zhengmin

Road, Shanghai, 200433, China.

(3)Department of thoracic surgery and Minimally Invasive Thoracic Surgery Unit

(UCTMI). Coruña University Hospital, Coruña, 15706, Spain.

…

HER2 and VEGF are closely related to the progression of several tumors. The

inhibitor simultaneously targeting these two proteins will effectively inhibit

the progression of tumors. Here, a bispecific antibody, termed as YY0411,

targeting both HER2 and VEGF as a potent anticancer therapeutic antibody is

reported. YY0411 is the first bispecific antibody constructed in IgG-Decoy

receptor format. It efficiently identifies and combines both HER2 and VEGF

protein. YY0411 is believed to be a candidate tumor suppressor as it

significantly inhibits the colony formation ability of human cancer cells

(Calu-3, MDA-MB-453, and NCI-N87 cells). The phosphorylation of HER2 and VEGF

downstream components are also decreased in these cells with the treatment of

YY0411. Similar to other antibodies, YY0411 has the ability to promote the

secretion of IFN-γ by T lymphocytes. In addition, YY0411 significantly inhibits

the growth of Calu-3 cells-induced xenograft in nude mice. This work demonstrates

that YY0411 may be a potential anti-lung cancer drug.

© 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

DOI: 10.1002/adma.201805437

PMID: 30345557

12. Cancer Discov. 2018 Dec;8(12):1598-1613. doi: 10.1158/2159-8290.CD-18-0277. Epub 2018 Sep 25.

Exploiting MCL1 Dependency with Combination MEK + MCL1 Inhibitors Leads to

Induction of Apoptosis and Tumor Regression in KRAS-Mutant Non-Small Cell Lung

Cancer.

Nangia V(#)(1), Siddiqui FM(#)(1), Caenepeel S(2), Timonina D(1), Bilton SJ(1),

Phan N(1), Gomez-Caraballo M(1), Archibald HL(1), Li C(1), Fraser C(3), Rigas

D(2), Vajda K(1), Ferris LA(1), Lanuti M(4), Wright CD(4), Raskin KA(5), Cahill

DP(6), Shin JH(6), Keyes C(7), Sequist LV(8)(9), Piotrowska Z(8)(9), Farago

AF(8)(9), Azzoli CG(8)(9), Gainor JF(8)(9), Sarosiek KA(3), Brown SP(10), Coxon

A(2), Benes CH(1)(9), Hughes PE(2), Hata AN(11)(8)(9).

Author information:

(1)Massachusetts General Hospital Cancer Center, Charlestown, Massachusetts.

(2)Department of Oncology Research, Amgen, Thousand Oaks, California.

(3)Department of Environmental Health, Harvard T. H. Chan School of Public

Health, Boston, Massachusetts.

(4)Department of Surgery, Massachusetts General Hospital, Boston, Massachusetts.

…

: BH3 mimetic drugs, which inhibit prosurvival BCL2 family proteins, have limited

single-agent activity in solid tumor models. The potential of BH3 mimetics for

these cancers may depend on their ability to potentiate the apoptotic response to

chemotherapy and targeted therapies. Using a novel class of potent and selective

MCL1 inhibitors, we demonstrate that concurrent MEK + MCL1 inhibition induces

apoptosis and tumor regression in KRAS-mutant non-small cell lung cancer (NSCLC)

models, which respond poorly to MEK inhibition alone. Susceptibility to BH3

mimetics that target either MCL1 or BCL-xL was determined by the differential

binding of proapoptotic BCL2 proteins to MCL1 or BCL-xL, respectively. The

efficacy of dual MEK + MCL1 blockade was augmented by prior transient exposure to

BCL-xL inhibitors, which promotes the binding of proapoptotic BCL2 proteins to

MCL1. This suggests a novel strategy for integrating BH3 mimetics that target

different BCL2 family proteins for KRAS-mutant NSCLC. SIGNIFICANCE: Defining the

molecular basis for MCL1 versus BCL-xL dependency will be essential for effective

prioritization of BH3 mimetic combination therapies in the clinic. We discover a

novel strategy for integrating BCL-xL and MCL1 inhibitors to drive and

subsequently exploit apoptotic dependencies of KRAS-mutant NSCLCs treated with

MEK inhibitors.See related commentary by Leber et al., p. 1511.This article is

highlighted in the In This Issue feature, p. 1494.

©2018 American Association for Cancer Research.

DOI: 10.1158/2159-8290.CD-18-0277

PMCID: PMC6279543 [Available on 2019-12-01]

PMID: 30254092