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B. Wolf
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MINI 03 - PD1 Axis Inhibition and EGFR (ID 101)
- Event: WCLC 2015
- Type: Mini Oral
- Track: Treatment of Advanced Diseases - NSCLC
- Presentations: 1
- Moderators:L. Gandhi, Y. Ohe
- Coordinates: 9/07/2015, 16:45 - 18:15, Four Seasons Ballroom F1+F2
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MINI03.01 - Prior TKI Therapy in NSCLC EGFR Mutant Patients Associates with Lack of Response to Anti-PD-1 Treatment (ID 2172)
16:45 - 16:50 | Author(s): B. Wolf
- Abstract
- Presentation
Background:
Programmed cell death-1 (PD-1) inhibitors have shown significant potential to induce durable responses in non-small cell lung cancer (NSCLC). Although responses have been seen in patients (pts) whose tumors harbor epidermal growth factor receptor (EGFR) mutations (EGFRm), data to date with inhibitors of PD-1, or its ligand PD-L1, suggest that responses are less frequent in EGFRm NSCLC. Studies in which EGFRm pts receive EGFR tyrosine kinase inhibitors (TKIs) and PD-1 inhibitors in sequence or concurrently are being conducted. However, based on the high response rate with EGFR TKIs in EGFRm pts, PD-1 inhibition does not precede the EGFR TKIs in these study designs.
Methods:
We evaluated data from our experience at UCLA as part of the KEYNOTE-001 clinical trial, in which pts received pembrolizumab 2 mg/kg every 3 weeks or 10 mg/kg every 2 or 3 weeks. Early in the trial, an amendment excluded EGFRm, EGFR TKI naïve pts, however a subsequent amendment allowed such pts if their mutation was non-sensitizing to approved EGFR TKIs. Although the trial employed central radiographic assessment by RECIST v1.1 (available to the sponsor but not the sites), clinical decisions and the assessment we describe were based on investigator-assessed immune-related response criteria. Groups were compared using Fisher’s exact test. Western blot was performed using standard techniques, exposing human non-small cell lung cancer cell lines HCC-827, H1975, Calu3 and H460 to erlotinib or afatinib at 1µM or control using the antibody PD-L1 mAb #1368 (Cell Signaling) and α-tubulin antibody #2144 (Cell Signaling).
Results:
We enrolled 29 EGFRm pts. 2 of 3 EGFR TKI naïve pts experienced a partial response (PR) compared to 1 of 26 enrolled after a prior EGFR TKI (p<0.001). 18 of these 29 pts had a 9 week scan. Of these, PR was seen in both EGFR TKI naïve pts (one L858R mutation and one exon 20 insertion) compared to 1 of 16 enrolled after a prior EGFR TKI (p<0.001). Of note, a similar trend of increased responses in EGFR TKI naïve pts was not seen in EGFR wild type pts. In vitro experiments using erlotinib and afatinib showed unchanged PD-L1 levels in cell lines not inhibited by the EGFR TKI used, but reduced PD-L1 in EGFRm cell lines inhibited by the TKI. Of note, the only responder among the EGFR TKI-treated EGFRm pts was one of only 4 of the 16 scanned post-TKI pts who had a non-sensitizing mutation. So, 0 of 22 EGFRm pts with a sensitizing mutation responded after an EGFR TKI.
Conclusion:
A retrospective analysis in EGFRm NSCLC showed a strong correlation between response and lack of prior EGFR TKI treatment. PD-L1 levels decrease in response to an EGFR TKI in cell lines sensitive to the TKI. Immunohistochemistry evaluating the presence and location of relevant proteins and immune effector cells are ongoing as is whole exome sequencing. These results have implications for the design of clinical trials of PD-1 inhibitors in EGFRm pts. Supported by: 1K23CA149079, One Ball Matt Memorial Golf Tournament, Kasdan Family
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ORAL 13 - Immunotherapy Biomarkers (ID 104)
- Event: WCLC 2015
- Type: Oral Session
- Track: Biology, Pathology, and Molecular Testing
- Presentations: 1
- Moderators:D. Kim, D. Grunenwald
- Coordinates: 9/07/2015, 16:45 - 18:15, Four Seasons Ballroom F3+F4
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ORAL13.02 - Characterization of PD-L1 Expression Related to Unique Genes in NSCLC Tissue Samples (ID 2173)
16:56 - 17:07 | Author(s): B. Wolf
- Abstract
- Presentation
Background:
Programmed cell death protein 1 (PD-1) receptors are members of the B7:CD28 family that interact with PD-1 ligands PD-L1 and PD-L2 to regulate cytotoxic T cell (CTL) tolerance (Freeman, J Exp Med. 2000; Latchman, Nat Immunol. 2001). Successful evasion of transformed cells from host defense is a feature of cancer (Hanahan, Cell 2011). Immune evasion can occur via the engagement of PD-1 with PD-L1 or PD-L2 (Dong, Nature Med 2002). In metastatic non-small cell lung cancer (NSCLC), PD-L1 expression has been associated with increased response to inhibitors of PD-1 (Garon, NEJM 2015). Current adjuvant cytotoxic approaches are associated with a real but small survival increases and significant toxicity. Characterization of PD-L1 expression in resected tumors could guide development of immune checkpoint based adjuvant trials.
Methods:
Microarray analyses were performed to assess gene expression for 320 NSCLC and 15 normal lung resection specimens profiled on the Agilent Whole Human Genome 4x44K 2-color platform. The reference sample used in the experiments was an equal mixture of 258 of the 320 NSCLC samples included in the study. Microarray data was imported into Rosetta Resolver for analysis. The Rosetta Similarity Tool (ROAST) was utilized to find genes correlated to PD-L1 expression. Both PD-L1 and the target gene had to be differentially expressed for sample to be included in computation of correlation. Cosine correlation was used as the similarity metric. Functional genomic analysis on the list of PD-L1 correlated genes was performed using tools available with the DAVID Bioinformatics resources (david.abcc.ncifcrf.gov) Survival analyses based on PD-L1 expression were performed using the Kaplan-Meier method and compared using the log-rank test. Samples with PD-L1 log(ratio) > 0 and p-value < 0.01 were classified as upregulated, samples with p-value>0.01 were classified as unchanged, and sample with log(ratio) < 0 and p-value <0.01 were classified as downregulated.
Results:
The reference level of PD-L1 expression among the subset of normal lung and NSCLC tissue samples was higher compared to levels seen in 503 breast cancer and 149 endometrial cancer tissue samples. Within the 320 NSCLC tissue samples, 174 unique genes are highly correlated with PD-L1 expression (r range= 0.692-0.904). 80 tissue samples (25%) had a PD-L1 log ratio > 0, and 63 tissue samples had large sets of highly correlated genes, a similar prevalence to membranous staining in half the cells in metastatic NSCLC (Garon, NEJM 2015). Functional analyses revealed that the genes significantly correlated with PD-L1 expression were involved in immune and inflammatory response. No significant difference in overall survival was noted (p=.661), but increased PD-L1 expression was clearly not associated with better outcomes.
Conclusion:
Within the NSCLC cohort, there is a group of patients with high expression for PD-L1 and related genes. This group does not have a better prognosis in comparison to those with typical or decreased PD-L1 expression. Due to the relationship between PD-L1 expression and response to anti-PD-1 therapy in metastatic NSCLC, this data and its correlation with other clinical characteristics of the patients can guide the design of adjuvant approaches based on immune checkpoint inhibitors.
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ORAL 31 - PD1 Axis Inhibition (ID 143)
- Event: WCLC 2015
- Type: Oral Session
- Track: Treatment of Advanced Diseases - NSCLC
- Presentations: 1
- Moderators:J. Weiss, B. Luey
- Coordinates: 9/09/2015, 16:45 - 18:15, Four Seasons Ballroom F1+F2
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ORAL31.05 - High Intratumoral T Cell Infiltration Correlated with Mutational Load and Response to Pembrolizumab in Non-Small Cell Lung Cancer (ID 2728)
17:28 - 17:39 | Author(s): B. Wolf
- Abstract
- Presentation
Background:
Responses to PD-1 blockade have been induced in approximately 20% of advanced non-small cell lung cancer (NSCLC) patients with progressive disease after standard therapy [Garon, NEJM 2015]. One challenge is to understand how the immune response was initiated in responding patients. Tumor mutational burden has been associated with response to PD-1 checkpoint inhibitors in NSCLC [Rizvi, Science, 2015]. In addition, studies in melanoma patient-derived tumor specimens revealed that responses to PD-1/L1 blockade rely on pre-therapy tumor infiltration of activated T effector cells [Tumeh, Nature, 2014]. We hypothesize that clonal T cell infiltration is correlated with tumor mutational load and clinical response with PD-1 blockade.
Methods:
We studied tumor specimens in NSCLC patients treated with pembrolizumab at UCLA on the KEYNOTE -001 clinical trial. All patients signed informed consent for the trial as well as separate specimen acquisition protocols. Responses were classified by the investigators according to irRC. DNA was extracted and whole exome sequencing was performed at the UCLA Immunogenetics Core. DNA from the same patient’s PBMC or other non-cancerous tissue was sequenced for baseline comparison. Immunohistochemistry (IHC) was done for CD8 (Clone C8/144B, Dako), CD4 (Clone SP35, Cell Marque) and PD-L1 (Clone SP142, Spring Bioscience).
Results:
We report results from 27 patients (14 responders, and 13 nonresponders). Significantly higher density of pre-dosing CD8+ cells (percentage of CD8+ nucleated cells) in the tumors of the responding patients was observed (mean of 17.7% in responders vs 5.6% in non-responders, p=0.02 by unpaired t test) suggestive of a pre-existing immune response. Mutational load in 5 patients (3 responders and 2 nonresponders) showed a trend towards correlation with response (mean of 19 nonsynonymous somatic mutations per MB in responders vs 6 in nonresponders, p=0.33). Interestingly, a strikingly significant correlation between mutational load and CD8 expression was observed (R[2]=0.96, p=0.003). In addition, pre-dosing tumor PD-L1 expression demonstrated a trend towards correlation with response (mean of 72.1% in responders vs 51.5% in nonresponders, p=0.07) but not with CD8 tumor infiltration (R[2]=0.05, p=0.28). No significant association of CD4+ T cell tumor infiltration with response (mean of 37.4% CD4 + cells in responders vs 27.0% in nonresponders, p=0.32) was observed.
Conclusion:
We observed strong correlation of pre-dosing intratumoral T cell infiltration with response and mutational load in NSCLC patients treated with pembrolizumab. Our results have direct implications for the design and interpretation of ongoing and planned immunotherapy studies for NSCLC and evaluation of potential predictive biomarkers to select patients most likely to benefit.
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P2.01 - Poster Session/ Treatment of Advanced Diseases – NSCLC (ID 207)
- Event: WCLC 2015
- Type: Poster
- Track: Treatment of Advanced Diseases - NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 9/08/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P2.01-092 - A Phase IB Dose-Escalation Study of Pemetrexed and AUY922 in Previously Treated Metastatic Non-Squamous, Non-Small Cell Lung Cancer (ID 2164)
09:30 - 09:30 | Author(s): B. Wolf
- Abstract
Background:
Despite advances in targeted therapy, treatment options for metastatic NSCLC progressing after initial therapy remains limited. HSP90 is an ATP-dependent molecular chaperone that plays a vital role in protein stabilization. Some HSP90 client proteins are key regulators in cell proliferation and survival. Many mutant oncoproteins are more dependent on HSP90 for proper folding and stability compared to their wildtype counterparts. AUY922 potently inhibits HSP90, showing preclinical activity in a wide range of cancer cell lines, including NSCLC (1). Phase I clinical trials established 70 mg/m[2] as the dose for further development (2). A single agent phase II trial demonstrated clinical activity of AUY922 in NSCLC, particularly molecular subsets with driver mutations in the known HSP90 client proteins, epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) (3). Pemetrexed is a folate antimetabolite chemotherapeutic approved for use in advanced non-squamous, NSCLC. In pre-clinical models, mRNA for dihydrofolate reductase (DHFR), a target of pemetrexed, reliably decreased in response to AUY922 exposure (1). These findings suggest that the combination of AUY922 and premetrexed in NSCLC is worthy of investigation.
Methods:
Adult patients with previously treated stage IV non-squamous, NSCLC, measureable disease per RECIST 1.1, ECOG performance status < 2, and life expectancy > 3 months are eligible for this open label phase Ib clinical trial (NCT01784640). A standard 3 x 3 design will evaluate 3 cohorts, all with pemetrexed at the standard 500 mg/m[2] dose, plus: AUY922 40 mg/m[2], 55 mg/m[2], and 70 mg/m[2] qwk. Enrollment of the 70 mg/m[2] qwk cohort has been open since November 2014 and is currently ongoing. After the optimal dose for further evaluation is determined, an additional 20 patients will be enrolled at that dose. This expansion phase will focus on patients with EGFR mutations and ALK gene rearrangements. The primary endpoint is safety and tolerability of AUY922 combined with pemetrexed in patients with previously treated non-squamous NSCLC. [Funding by Novartis, K23CA149079, Wolfen Family, One Ball Matt Memorial Golf Tournament]. References 1) Garon EB et. al. Mol Cancer Ther. 2013 2) Sessa C et. al. Clin Cancer Res. 2013 3) Garon EB et. al. ASCO 2012
Results:
Not applicable
Conclusion:
Not applicable
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P3.01 - Poster Session/ Treatment of Advanced Diseases – NSCLC (ID 208)
- Event: WCLC 2015
- Type: Poster
- Track: Treatment of Advanced Diseases - NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 9/09/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P3.01-087 - A Phase I Study of Exemestane with Carboplatin and Pemetrexed in Postmenopausal Women with Metastatic, Non-Squamous Non-Small Cell Lung Cancer (ID 2171)
09:30 - 09:30 | Author(s): B. Wolf
- Abstract
Background:
Lung cancer is the most common cause of cancer-related deaths in the US, with adenocarcinoma being the most common histologic subtype. Aromatase, a critical rate-limiting enzyme in estrogen biosynthesis, is notably expressed in NSCLC cells. Retrospective studies show that high NSCLC aromatase levels are associated with worse clinical outcome, particularly in postmenopausal women (Weinberg et al., Cancer Res, 2005; Mah et al., Cancer Res, 2007; Garon et al., J Thoracic Oncol, 2013). Estrogens are known survival factors in lung and promote expression of nucleotide excision repair enzyme ERCC1 that is implicated in resistance to platinum-therapy. In NSCLC cells, ERCC1 transcript expression is blocked by exemestane, an aromatase inhibitor (AI), enhancing cisplatin-induced apoptosis. In preclinical NSCLC xenograft models, exemestane exerts synergistic antitumor activity combined with cisplatin and results in prolonged tumor suppression (Marquez-Garban et al., Ann NY Acad Sci, 2009). These data provide a rationale to assess an AI in the clinic.
Methods:
Based on our preclinical studies, we are conducting a phase IB, open-label, single-center study in postmenopausal, treatment-naïve (except prior single-agent tyrosine kinase inhibitor use) women with metastatic, non-squamous NSCLC (NCT 01664754). We plan to enroll 12-15 participants divided into two dose-escalation cohorts of exemestane. All participants receive standard chemotherapy with pemetrexed (500 mg/m[2]) and carboplatin (AUC 6), both given intravenously every 3 weeks. Cohort 1, which added exemestane 25 mg orally daily, has completed enrollment without any dose-limiting toxicities. Cohort 2, for which enrollment started in December of 2013, evaluates exemestane at 50 mg orally daily. Our primary aim is to evaluate safety and tolerability of the indicated regimen. Secondary objectives are tumor response rate, quality of life, pharmacokinetics/pharmacodynamics, and correlative studies of biomarkers (such as blood estrogens, tumor ERs, aromatase, and apoptosis) with tumor response.
Results:
Not applicable
Conclusion:
Not applicable
