News Briefing: Advanced Predictors and Targeted TherapiesModerator: Ravi Salgia, MD, PhD, City of Hope

• Tolerability and Safety of Thoracic Radiation and Immune Checkpoint Inhibitors among Patients with Lung Cancer

Kamran Ahmed, MD, Moffitt Cancer Center

• Heterogeneity and Variation in Resistance Mechanisms among 223 EGFR-mutant NSCLC Patients With ≥ 1 Post-resistance Biopsy

Zofia Piotrowska, MD, Massachusetts General Hospital Cancer Center

• Prospective Trial of Circulating Tumor Cells as a Biomarker for Early Detection of Recurrence in Patients with Locally Advanced Non-small Cell Lung Cancer Treated with Chemoradiation

Chimbu Chinniah, Perelman School of Medicine, University of Pennsylvania

Tolerability and Safety of Thoracic Radiation and Immune Checkpoint Inhibitors among

Patients with Lung Cancer

K. A. Ahmed1, G. D. Grass1, B. Creelan2, J. Gray2, S. Kim1, T. J. Dilling1, S. J. Antonia2, and B. A. Perez1

Departments of 1Radiation Oncology and 2Thoracic Oncology; H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL

Background

• The use of immune checkpoint inhibitors (ICPIs) has become increasingly common in the management of advanced lung cancer

• Thoracic radiation therapy (TRT) has a proven role in the management of various stages of lung cancer

• We assess the risk of side effects with TRT and single agent or combined ICPIs

Method

• Data were analyzed retrospectively from our institutional database of patients treated with radiotherapy and ICPIs

• We identified 29 patients that received TRT between February 2012 and May 2016 within 6 months of ICPIs

• Toxicity information was obtained by independent review of the clinical chart by two physicians

Results: Toxicity• 3 of 29 (10%) experienced

severe pneumonitis attributable to TRT and/or ICPIs, with one grade 5 toxicity

• 2 of 29 patients experienced pneumonitis attributable to ICPIs alone and went on to receive TRT without additional toxicity

20 Gy

10 Gy

20 Gy

10 Gy

Results: Survival

Conclusions

• Treatment with ICPIs and thoracic radiation therapy carried a modest risk of side effects

• Our study indicates the risk of TRT/ICPI-related pneumonitis may be highest when TRT is delivered after ICPI therapy

• We advocate for ongoing studies to assess the synergistic effect with TRT and ICPIs and ongoing toxicity evaluations

Heterogeneity and Variation in Resistance Mechanisms among 221 EGFR-mutant NSCLC

Patients With ≥ 1 Post-resistance Biopsy

Z. Piotrowska1, K. Stirling1, R. Heist1, M. Campo1, C. Rizzo1, S. R. Digumarthy2, M. Lanuti2, F. J. Fintelmann2, I. Lennes1, A. Farago1, J. Gainor1, C. G. Azzoli1, J. Temel1, M. Mino-Kenudson2, D. Dias-Santagata2, R. Corcoran1, A. Shaw1, J. A.

Engelman3, A. Hata1, and L. V. Sequist1

1Massachusetts General Hospital Cancer Center, Boston, MA, 2Massachusetts General Hospital, Boston, MA, 3Novartis Institutes for BioMedical Research, Cambridge, MA

Background

• EGFR mutations comprise ~15% of lung adenocarcinomas. EGFR TKIs are the standard first-line treatment, but resistance typically develops after 9-13 months.

• Many patients who acquire resistance to EGFR-targeted therapy undergo a tumor biopsy at the time of progression. T790M is the most common resistance mechanism seen.

• In practice, patients rarely undergo further biopsies during treatment and are commonly categorized as “positive” or “negative” for a particular resistance mechanism (e.g. T790M) based on a single biopsy and timepoint.

• This binary positive/negative classification may underestimate the heterogeneity of resistant cancers and may prevent patients from accessing potentially effective treatment strategies.

Methods

• Retrospective analysis of 221 patients with advanced EGFR-mutant NSCLC seen at Massachusetts General Hospital (MGH) between 2008 and 2016.

• For each patient, we collected data for all biopsies obtained after resistance, including results of clinical molecular testing, treatment history and biopsy complications.

Resistance mechanisms upon initial resistance to EGFR TKI therapy(n=221)

Overall T790M-positive:

61%

• Among 83 patients with two post-resistance biopsies, 41 (49%) had variations in the resistance mechanisms identified between biopsy 1 and 2.

• 20% patients “lost” T790M between biopsy 1 and 2

• 11% “gained” T790M

• Of the 17 patients who lost T790M, three had a new resistance mechanism identified on the second biopsy.

Results

T790-WT T790-positive METamp123

T790M“Loss”(20%)T790M“Gain”(11%)

Bx1

Bx2

BRAF SCLCTransformation

Conclusions

• Our data suggest that resistance to EGFR-targeted therapy is heterogeneous and that the dominant drivers of resistance can fluctuate over time

• As much as half of the time, the dominant resistance mechanisms observed on one biopsy may no longer be relevant on a second biopsy, and a second biopsy may uncover a new, potentially targetable, resistance mechanism

• We hope that these findings will prompt clinicians to consider repeat biopsy when selecting a new therapy

• While we observed that biopsies were generally safe and feasible, noninvasive testing methods, such as liquid biopsies, may provide another method to more easily characterize resistance over time

Prospective Trial of Circulating Tumor Cells as a Biomarker for Early Detection of Recurrence in

Patients with Locally Advanced Non-small Cell Lung Cancer Treated with Chemoradiation

C. Chinniah1, L. Aguarin1, P. Cheng1, C. DeCesaris1, A. Cutillo1, A. T. Berman1, M. Frick1, W. P. Levin1, K. A. Cengel1, S. M. Hahn2, J. F. Dorsey1, G. D. Kao1, and C. B.

Simone II1

1Department of Radiation Oncology, University of Pennsylvania, Philadelphia, PA, 2Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX

Background

• Assays identifying circulating tumor cells (CTCs) may allow for noninvasive and sequential monitoring of lung cancer.

• Data assessing CTC use for monitoring treatment response and tumor recurrence in non-metastatic lung cancer patients are sparse.

• This study is the largest prospective clinical trial to date of CTCs as biomarkers for locally advanced lung cancer.

Trial Eligibility Criteria

• Locally advanced non-small cell lung cancer (LA-NSCLC) (stage II-III)

• Concurrent chemotherapy; patients who were planning to get surgery were ineligible

• No prior active malignancy in the last 5 years

• Age 18 years or older

Trial Diagram

Treatment (Tx) Plan: 6660 cGy in 37 fractions (180 cGy/frac)

Consent Patient

Simulation

Tx Start Tx End

Weeks 1-2

Weeks 3-4

Weeks 5-6

Pre-Tx On-Tx Post-Tx

1 Mo

3 Mo

6 Mo

12 Mo

18 Mo

24 Mo

Follow-Up: PET/CT or CT scans ordered prior to each of these time points

Pre-Tx

Results

• 48 patients enrolled. 22 recurred. Acquired samples from 20 of 22.

Rise in CTC counts post-RT: 15 of 20

CTC counts negative on initial post-RT draw and rose prior to radiographic evidence of recurrence: 10 of 15

• Two-thirds of recurrent patients demonstrated a rise in CTC counts an average of 6 months (182 days) before PET/CT or CT scans detected the recurrence

Example Case

Pre-txCTCs: +

4 month post-txCTCs: -

6 month post-tx

10/17/14 4/21/15 1/25/16 4/8/16 6/24/15

CTCs: +

12/29/14

Dec’d

Recurrence

Tx End

CTCs: -

Conclusions

• CTC monitoring in patients undergoing chemoradiation for locally advanced NSCLC is feasible

• CTC elevations in many patients meaningfully precede radiologic evidence of disease recurrence

• CTCs may be a promising biomarker of progressive or recurrent disease may help guide early salvage therapeutic strategies

• Future research is needed to test whether the early detection of disease recurrence afforded by CTC analysis translates to improved outcomes

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