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Deepa Rangachari
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OA03 - Systemic Therapies for SCLC: Novel Targets and Patients' Selection (ID 121)
- Event: WCLC 2019
- Type: Oral Session
- Track: Small Cell Lung Cancer/NET
- Presentations: 1
- Now Available
- Moderators:Christine Lee Hann, Makoto Nishio
- Coordinates: 9/08/2019, 13:30 - 15:00, Hilton Head (1978)
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OA03.07 - Immune-Related Adverse Events and Clinical Outcome to Anti PD-1 Axis Inhibition in SCLC: A Multicenter Retrospective Analysis (Now Available) (ID 2880)
13:30 - 15:00 | Author(s): Deepa Rangachari
- Abstract
- Presentation
Background
Immune-checkpoint inhibitors (ICIs) have shown promising activity in only a fraction of patients with small cell lung cancer (SCLC), and factors associated with clinical benefit are not well characterized. The development of immune-related adverse events (irAEs) may correlate with benefit from immune checkpoint inhibitors (ICIs) among patients with cancer. Whether an association exists between irAE development and improved clinical outcomes to ICIs in small cell lung cancer (SCLC) is unknown.
Method
We retrospectively analyzed data from five participating academic centers: the Dana-Farber Cancer Institute, East Carolina University, Columbia University, Beth Israel Deaconess Medical Center, and Johns Hopkins University. Patients with SCLC who received at least one dose of a programmed death (ligand) PD-(L)1 inhibitor alone or in combination with a cytotoxic T-lymphocyte associated protein 4 (CTLA-4) inhibitor were included in this study. To account for the time-dependent nature of irAE onset and clinical benefit from immunotherapy, we identified patients with early irAEs (defined as those occurring within 6 weeks of ICI treatment initiation) and performed a landmark analysis at this time point.
Result
Among 157 patients treated with ICIs, 65 (41.4%) experienced at least one irAE. Median time to the first irAE onset was 28 days (IQR:15-56). Baseline clinicopathologic characteristics were well balanced between patients who developed irAEs and those who did not. Median tumor mutational burden (TMB) was significantly higher among patients with irAEs compared to those without (14.4 vs 8.4 mutations/megabase [mut/Mb], P <0.01). Patients who developed at least one irAE had a significantly higher objective response rate (26.3% versus 3.3%, P <0.001), and significantly longer median progression-free survival (mPFS, 4.1 vs 1.3 months, HR: 0.30 [0.20-0.43, P <0.001]) and median overall survival (mOS, 14.1 vs 2.9 months, HR: 0.32 [0.21-0.48], P <0.001). The proportion of patients who were progression-free at 6, 9, and 12 weeks was significantly higher in patients who developed early irAEs compared to those who did not develop early irAEs (6 weeks: 89.5% vs 69.5%, P =0.01; 9 weeks: 71.1% vs 40%, P =0.001; 12 weeks: 65.8% vs. 31.6%, P <0.001). The median TMB was also significantly higher in patients who developed early irAEs (14.5 vs 8.7 mut/Mb, P <0.01).
Conclusion
Patients with SCLC treated with ICIs who developed early irAEs had a higher TMB and enhanced antitumor responses compared to those who did not develop irAEs. Whether a higher TMB is associated with the development of irAEs remains to be determined mechanistically.
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OA15 - Targeted Agents and Immunotherapy for Small Cell Lung Cancer (ID 152)
- Event: WCLC 2019
- Type: Oral Session
- Track: Small Cell Lung Cancer/NET
- Presentations: 1
- Now Available
- Moderators:Raffaele Califano, Charles M Rudin
- Coordinates: 9/10/2019, 14:30 - 16:00, Hilton Head (1978)
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OA15.01 - Combination Olaparib and Temozolomide in Relapsed Small Cell Lung Cancer: Updated Results from Phase 1/2 Clinical Trial (Now Available) (ID 1394)
14:30 - 16:00 | Author(s): Deepa Rangachari
- Abstract
- Presentation
Background
DNA damage repair inhibition is an emerging strategy for treating small cell lung cancer (SCLC). Combining poly(ADP-ribose) polymerase (PARP) inhibition with the DNA alkylating agent temozolomide has shown activity in both preclinical models and early phase clinical trials.
Method
This is a single-arm phase 1/2 study combining the PARP inhibitior olaparib (tablet formulation) with temozolomide in patients with SCLC. Key eligibility criteria include histologically or cytologically confirmed incurable SCLC which progressed following ≥ 1 platinum-based chemotherapy. In cohort 1, olaparib and temozolomide are administered orally on days 1-7 of 21-day cycles. After cohort 1 completed enrollment, cohort 2 was added in a protocol amendment, in which olaparib is administered continuously days 1-21 and temozolomide is administered days 1-7 of 21-day cycles. For each cohort, the phase 1 portion is a conventional 3+3 design, with the primary objective to determine the maximum tolerated dose (MTD) or recommended phase 2 dose (RP2D). The primary objective of the phase 2 dose expansion portion is to determine the objective response rate (ORR). Response assessments are performed every 6 weeks, with treatment continued until progression, unacceptable toxicity, or investigator’s discretion. Treatment post-progression is allowed for patients with ongoing clinical benefit.
Result
Between October 2015 and April 2018, 50 patients were enrolled to cohort 1. The median age was 63 (range 39-85), median number of prior therapies was 2 (range 1-7), and 72% were platinum sensitive. The RP2D was olaparib 200 mg PO BID d1-7 and T 75 mg/m2 QD d1-7. The confirmed ORR was 41.7%. After a median follow-up of 7.1 months among 22 surviving patients, the median progression-free survival (mPFS) was 4.2 months, median overall survival (mOS) was 8.5 months, and median duration of response (mDoR) was 4.3 months. The ORR among platinum-sensitive and platinum-resistant patients was 47.1% and 28.6%, respectively, with no significant differences in mPFS, mOS or mDOR. The most common grade 3/4 treatment related adverse events were neutropenia (38%), anemia (28%) and thrombocytopenia (26%). Among 41 pts treated at the RP2D, dose reductions occurred in 44% overall and 64% of those who received at least 3 cycles. Enrollment to the phase 1 portion of cohort 2 began in November 2018 and is ongoing. Updated results from cohorts 1 and 2 will be presented at the meeting.
Conclusion
Combination olaparib and temozolomide has an acceptable tolerability profile and shows promising clinical activity in relapsed SCLC. Clinical trials identifier NCT02446704.
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P1.04 - Immuno-oncology (ID 164)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Immuno-oncology
- Presentations: 1
- Moderators:
- Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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P1.04-73 - Small Cell Transformation of Non-Small Cell Lung Cancer (NSCLC) on Immune Checkpoint Inhibitors: Case Report and Literature Review (ID 1510)
09:45 - 18:00 | Author(s): Deepa Rangachari
- Abstract
Background
Histological transformation of oncogene-driven lung adenocarcinoma to small cell lung cancer (SCLC) following treatment with tyrosine kinase inhibitors (TKI) is a well-described phenomenon. However, it is unknown whether a similar transformation may drive acquired resistance to immune checkpoint inhibitors (ICPi) in NSCLC by altering tumor-related immune evasion.
Method
We present a case of a patient with NSCLC treated at our institution with transformation to SCLC during second line therapy with nivolumab. We conducted a review of the literature to identify similar cases and patient outcomes.
Result
This is a case of a 69 year-old woman with a 35 pack-year tobacco history presenting with stage IV squamous cell lung cancer (figure 1A). Her disease progressed within 4 weeks of first line carboplatin/gemcitabine and she was transitioned to next line nivolumab with sustained partial response lasting 18 months. She then developed rapid, bulky progression of mediastinal disease. Biopsy showed transformation to SCLC (figure 1B). Comparison of genomic profiling results from the initial NSCLC diagnosis and SCLC transformation revealed similar tumor profiles (TP53 R283fs*62). Absence of RB1 loss and initial protracted response to nivolumab suggested that transformation likely occurred as a result of treatment-induced selection pressure. The patient had a near complete response following 4 cycles of carboplatin/etoposide and remained alive 7 months post-transformation. Review of the literature revealed 7 reported cases where SCLC transformation was thought to result from acquired resistance to ICPi (Table 1).
Conclusion
We add to the emerging evidence of transformed SCLC as an acquired resistance mechanism following ICPi treatment in advanced NSCLC. Although only a few reports are available at this time, the real-world frequency may well be under-estimated due to relative infrequency of post-progression biopsies in NSCLC patients not being treated with TKIs. The underlying genomic/epigenetic mechanisms that may explain acquired resistance with neuro-endocrine transformation remain to be elucidated.
Table 1. Summary of literature on NSCLC cases transformed to SCLC on ICPi Serial No. (Reference) Original histology Original genomic profile ICPi details Genomic profile of transformed SCLC Outcome post SCLC transformation 1 (Index case)
Squamous cell carcinoma TP53 mutation Nivolumab (2nd line, 47 cycles) TP53 R283fs*62 mutation Alive 7 months post SCLC 2 (Iams et al, JTO 2018) Adeno-carcinoma KRAS G12C mutation Nivolumab (2nd line, 33 cycles) KRAS G12C mutation, TP53 R273C mutation Died 16 months post SCLC 3 (Iams et al, JTO 2018) Adeno-carcinoma KRAS G12C mutation Nivolumab (2nd line, 36 cycles) TP53 S315S mutation, RB1 splice site mutation Died 11 months post SCLC 4 (Imakita et al, Respir Med Case Rep. 2017) Poorly differentiated carcinoma Neg for EGFR / Alk Nivolumab (2nd line, 3 cycles) Not described Died 2 months post SCLC 5 (Abdallah et al, Lung Cancer [Auckl]. 2018) Adeno-carcinoma Neg for EGFR / Alk Nivolumab (2nd line, 5 cycles) Not described Response after 2 chemotherapy cycles 6 (Abdallah et al, Lung Cancer [Auckl]. 2018) Squamous cell carcinoma Not described Pembrolizumab (1st line, 30 cycles) Not described Alive 18 months post SCLC 7 (Bar et al, JCO 2018) Squamous cell carcinoma Not described ICPi (16 months) Not described Poor response to chemotherapy 8 (Bar et al, JCO 2018) Squamous cell carcinoma Not described ICPi (6 months) Not described Poor response to chemotherapy
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P2.04 - Immuno-oncology (ID 167)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Immuno-oncology
- Presentations: 1
- Moderators:
- Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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P2.04-60 - Pembrolizumab-Based Regimens Administered at Non-Standard Frequency in Non-Small Cell Lung Cancer (NSCLC) (ID 1463)
10:15 - 18:15 | Author(s): Deepa Rangachari
- Abstract
Background
Pembrolizumab (P) administered every 3 weeks ± chemotherapy is a standard treatment option for advanced NSCLC. However, other than modeling and simulation-based analysis, there have been no post-approval studies to determine the optimal administration frequency or if longer intervals between administrations are effective.
Method
We retrospectively reviewed medical charts of 81 patients with advanced NSCLC treated with P for at least 4 cycles at a single academic center (02/2016-3/2019). 2 patients groups were selected: those who received 3 or more P-based regimens at non-standard frequency intervals between cycles longer than 3 weeks ± 3 days (group A), or those who received P-based regimens at standard frequency or up to 2 non-standard cycles (group B). Descriptive tables of demographic details, tumor characteristics, treatment details, and immune-related adverse events (irAEs) were generated. Kaplan-Meier survival analysis and Cox proportional hazards model for multivariable regression analysis were utilized.
Result
Of 81 P-treated patients, 47 (58%) had received at least 4 cycles (group A: 14, B: 33). There were no significant differences between groups in sex, stage at diagnosis, smoking status, driver oncogene mutations, PD-L1 expression, tumor mutation burden, line of therapy, performance status or grade 3 irAEs. Patients in group B were more likely to receive P + chemotherapy (group A: 0%, B: 33.3%, p = 0.02). Patients in group A were more likely to have any grade irAEs (groups A: 78.6%, B: 33.3%, p = 0.024). The reasons for any non-standard cycles in group A were: irAEs (14.3% patients), non-irAE medical issues (35.7% patients) and solely non-medical patient-physician preference (50% patients). Median time to treatment discontinuation (TTD) was significantly longer in group A than group B (24 months vs 5 months, p <0.0001), as was median overall survival (OS) (Not reached vs 14 months, p=0.0029). Patients in group A continued to show significantly longer overall survival when adjusted for confounding variables (Hazard Ratio 5.6, p=0.029).
Conclusion
Our data, though limited by sample size and single institution design, shows that a significant proportion of patients receive P at extended intervals in routine clinical practice and with no worse outcomes than would be expected for those with advanced NSCLC receiving P at label-specified 3-week intervals. Given the durability of benefit seen in such patients, this requires confirmation in larger datasets and prospective trials so as to maximize patient experience and clinical outcomes while minimizing financial toxicity.
Group A
(≥ 3 Non-standard cycles)
Group B
(Standard or ≤ 2 non-standard cycles)
p-value
(chi-square
log-rank test)
N = 14 N = 33 Median OS, months (95% CI) Not reached (14 - not reached) 14 (8 - not reached) 0.0029 Median TTD, months (95% CI) 24 (17 - not reached) 5 (4-6) <0.0001
