- Email: [email protected]
Phase I Trial of Pembrolizumab and Radiation Therapy after Induction Chemotherapy for Extensive-Stage Small Cell Lung Cancer
Journal Pre-proof Phase I Trial of Pembrolizumab and Radiation Therapy after Induction Chemotherapy for Extensive-Stage Small Cell Lung Cancer James W. Welsh, John V. Heymach, Dawei Chen, Vivek Verma, Taylor R. Cushman, Kenneth R. Hess, Girish Shroff, Chad Tang, Ferdinandos Skoulidis, Melenda Jeter, Hari Menon, Quynh-Nhu Nguyen, Joe Y. Chang, Mehmet Altan, Vassiliki A. Papadimitrakopoulou, George R. Simon, Uma Raju, Lauren Byers, Bonnie Glisson PII:
S1556-0864(19)33525-7
DOI:
https://doi.org/10.1016/j.jtho.2019.10.001
Reference:
JTHO 1605
To appear in:
Journal of Thoracic Oncology
Received Date: 26 August 2019 Revised Date:
27 September 2019
Accepted Date: 1 October 2019
Please cite this article as: Welsh JW, Heymach JV, Chen D, Verma V, Cushman TR, Hess KR, Shroff G, Tang C, Skoulidis F, Jeter M, Menon H, Nguyen Q-N, Chang JY, Altan M, Papadimitrakopoulou VA, Simon GR, Raju U, Byers L, Glisson B, Phase I Trial of Pembrolizumab and Radiation Therapy after Induction Chemotherapy for Extensive-Stage Small Cell Lung Cancer, Journal of Thoracic Oncology (2019), doi: https://doi.org/10.1016/j.jtho.2019.10.001. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2019 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.
Phase I Trial of Pembrolizumab and Radiation Therapy after Induction Chemotherapy for Extensive-Stage Small Cell Lung Cancer James W. Welsh1, John V. Heymach4, Dawei Chen1,2, Vivek Verma3, Taylor R. Cushman1, Kenneth R. Hess5, Girish Shroff,6 Chad Tang1, Ferdinandos Skoulidis4, Melenda Jeter1, Hari Menon1, Quynh-Nhu Nguyen1, Joe Y. Chang1, Mehmet Altan4, Vassiliki A. Papadimitrakopoulou4, George R. Simon4, Uma Raju1, Lauren Byers,4 and Bonnie Glisson4
Departments of 1 Radiation Oncology, 4Thoracic Head & Neck Oncology, 5Biostatistics, 6
Diagnostic Radiology, The University of Texas MD Anderson Cancer Center, Houston, TX;
2
Department of Radiation Oncology, Shandong Cancer Hospital affiliated to Shandong
University, JN, CN and 3Department of Radiation Oncology, Allegheny General Hospital, Pittsburgh, PA
Support: Merck provided funding for and access to pembrolizumab; other support was provided by the Cancer Center Support (Core) Grant P30 CA016672 from the National Cancer Institute, National Institutes of Health.
Correspondence to: James W. Welsh, MD, Department of Radiation Oncology, Unit 97, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030. Tel 713-563-2447; Fax 713-745-1417; Email [email protected]
Short Title: Combination of Pembrolizumab and RT for ES-SCLC Presented at: ASTRO 2018 (Oct 21, 2018; San Antonio, TX, USA)
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Disclaimers: JWW, JVH, JYC, and DRG have received research grants from Bristol-Myers Squibb. JWW and DRG have received grants from Merck. JVH also received research funding from AstraZeneca and Spectrum Pharmaceuticals. JWW reported receiving research support from GlaxoSmithKline, Bristol-Meyers Squibb, Merck, Nanobiotix, Mavu Pharmaceuticals, and Checkmate Pharmaceuticals; serving on the scientific advisory board for RefleXion Medical, MolecularMatch, OncoResponse, CheckMate, Mavu Pharmaceuticals, and Alpine Immune Sciences; being cofounder of Helios Oncology, MolecularMatch, and OncoResponse; serving as an advisor to AstraZeneca, Merck, MolecularMatch, Incyte, Aileron, and Nanobiotix; and holding patents for MP470 (amuvatinib), MRX34 regulation of PDL1, and XRT technique to overcome immune resistance (MD Anderson Cancer Center has a trademark for RadScopal). No other disclosures were reported.
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ABSTRACT PURPOSE Radiation and immunotherapy have separately been shown to confer survival advantages to patients with extensive-stage small cell lung cancer (ES-SCLC), but failure rates remain high and combination therapy has been understudied. In this single-arm phase I trial (NCT02402920), we assessed the safety of combining pembrolizumab with thoracic radiation therapy (TRT) after induction chemotherapy for SCLC. METHODS ES-SCLC patients who had completed chemotherapy received TRT with pembrolizumab. The maximum tolerated dose of pembrolizumab was assessed by 3+3 dose-escalation; doses began at 100 mg and increased in 50 mg increments to 200 mg. Pembrolizumab was given every 3 weeks for up to 16 cycles; TRT was prescribed as 45 Gy in 15 daily fractions. Toxicity was evaluated with the Common Terminology Criteria for Adverse Events v4.0. The primary endpoint was safety of the combined therapy based on the incidence of dose-limiting toxicity (DLTs) in the 35 days following initiation of treatment. RESULTS Thirty-eight ES-SCLC patients (median age 65 years, range, 37–79) were enrolled from September 2015 through September 2017; 33 received per-protocol treatment, and all tolerated pembrolizumab at 100-200 mg with no DLTs in the 35-day window. There were no grade 4-5 toxicities; two (6%) experienced grade 3 events (n=1 rash, n=1 asthenia/paresthesia/autoimmune disorder) that were unlikely/doubtfully related to protocol therapy. The median follow-up time was 7.3 months (range 1–13); median progression-free and overall survival were 6.1 months (95% confidence interval [CI] 4.1–8.1) and 8.4 months (95% CI 6.7-10.1).
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CONCLUSIONS Concurrent pembrolizumab-TRT was tolerated well, with few high-grade adverse events in the short-term; progression-free and overall survival rates are difficult to interpret due to heterogeneity in eligibility criteria (e.g. enrolling progressors on induction chemotherapy). Although randomized studies have illustrated benefits to TRT alone and immunotherapy alone, the safety of the combined regimen supports further investigation as a foundational approach for future prospective studies.
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Introduction Small cell lung cancer (SCLC) is an aggressive malignancy; most patients present with extensive disease, and survival times remain short.1 The standard of care includes chemotherapy with or without consolidative thoracic radiotherapy (TRT) or prophylactic cranial irradiation (PCI).2 Recent results from the IMPower133 trial have shown a survival benefit with the addition of atezolizumab to chemotherapy, but did not allow TRT3. Findings from a previous randomized trial (which did not include immunotherapy) demonstrated that consolidative TRT for patients with extensive-stage (ES) SCLC who responded to chemotherapy led to improved 2-year progression-free survival (PFS) and overall survival (OS) rates, but did not meet the primary endpoint at 1 year.4 However, for either approach of immunotherapy alone or TRT alone, both local and distant failure rates remain high, highlighting the need for improved disease control. Combined radiation and immunotherapy is promising for SCLC for several reasons. First, SCLC has a high mutational burden5 which correlates with response to programmed cell death-1 (PD-1) inhibition. 6 Although a high mutational burden may result in more aggressive disease, it also leads to increased antigenicity and thus better detection by the immune system, which can be further enhanced by PD-1 inhibition. Additionally, evidence also suggests that radiation complements immunotherapy by reducing tumor burden,7 inducing neoantigens, and enhancing T-cell infiltration of tumors.8 Moreover, the addition of adjuvant immunotherapy to chemoradiotherapy prolonged overall survival in a randomized trial of durvalumab, a PD-L1 inhibitor, in patients with stage III non-small cell lung cancer.9 For these reasons, combined radiation and immunotherapy may provide advantages over either modality alone; however, this approach has largely not been prospectively evaluated. We
5
thus performed a phase I trial of the safety and preliminary efficacy of pembrolizumab in combination with concurrent TRT for patients with ES-SCLC.
Patients and Methods Patients Eligible patients for this phase I study (NCT02402920) were ≥18 years old with ESSCLC or large cell neuroendocrine cancer (LCNEC); had received 1-6 cycles of induction chemotherapy before enrollment; and had Zubrod performance status < 3. Recurrent or progressive disease was allowed. Exclusion criteria included the presence of any autoimmune disorder or other malignancy or central nervous system involvement at enrollment; and receipt of any form of immunosuppressive therapy within 7 days of enrollment. A history of other cancer was not a basis for exclusion. This study was approved by the U.T. M. D. Anderson Cancer Center institutional review board, and written informed consent was obtained from all patients. PCI (25 Gy in 10 fractions) was allowed at the treating physician’s discretion but was encouraged to be completed before trial enrollment. If PCI was given during the trial, then TRT and pembrolizumab were delayed by one cycle (21 days). Dose-limiting toxicities (DLTs) were defined as grade ≥3 nonhematologic/laboratory events or grade ≥4 hematologic/laboratory toxicity that was possibly, probably, or definitely related to the combined pembrolizumab and TRT. Toxicity was scored with the Common Terminology Criteria for Adverse Events (CTCAE) v4.0.
Study Design and Treatment
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All patients received up to 6 induction cycles of chemotherapy before beginning concurrent pembrolizumab and TRT; baseline positron emission tomography (PET) or computed tomography (CT) scans were obtained within 4 weeks before beginning concurrent therapy. Notably, neither PD-1 nor PD-L1 was tested, and no threshold criteria were applied. This open-label study had a standard 3+3 dose-escalation design, with pembrolizumab dose levels of 100 mg, 150 mg, and 200 mg. Pembrolizumab was given starting on day 1 and given every 21 days for up to 16 cycles. No patients were replaced during the escalation process, and no dose adjustments were to be made (instead, cessation was recommended for excessive toxicities). This trial was to enroll roughly 40 patients, based on protocol calculations that with 40 enrolled patients, the probability of observing at least 1 patient with toxicity (and a reference “true toxicity rate” of 0.1) would be 88%. Intensity modulated radiation therapy (IMRT) was begun on day 1 and given in 15 daily fractions to 45 Gy. A simultaneous integrated boost (SIB) to the gross tumor volume (GTV) of up to 52.5 Gy was allowed, as long as the dose to the planning target volume (PTV) remained at 45 Gy. This dose parallels our institutional procedure for consolidative TRT, and was also the dose utilized by the RTOG 0937 trial.10 Follow-up scans with CT, PET, or PET/CT were obtained every 12 weeks (± 4 weeks) to evaluate response to therapy. The primary objective was to determine the safety of the concurrent pembrolizumab-TRT combination; a secondary objective was to assess progression-free survival. Time of initiation was determined as the date of starting pembrolizumab or RT, whichever came first. Response and progression were evaluated and rated with the Immune-Related Response Criteria (irRC)11: briefly, complete response (irCR) requires complete elimination of all tumors, partial response (irPR) is defined as a ≥50% reduction in total tumor burden, and stable disease (irSD) is defined
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as no progression but neither irPR nor irCR. Overall response rate (ORR) referred to irPR or irCR.
Statistical Analysis All statistical analysis was performed with IBM Statistical Package for the Social Sciences (SPSS) v24 (Chicago, IL) and GraphPad Prism v7 (La Jolla, CA). PFS and OS intervals were defined as the time from trial enrollment to date of progression/death/censor (PFS) or death/censor (OS). Confidence intervals (CIs) were calculated for the ORR by using the binomial exact method. The Kaplan-Meier product limit method was used to estimate OS and PFS distributions. Because this was a single-arm phase I trial with the primary goal of assessing the safety of pembrolizumab with TRT, no other statistical evaluations were performed.
Results Patient Characteristics Thirty-eight patients were screened for enrollment from September 2015 through September 2017. Of those, 33 (87%) initiated treatment per protocol; the other 5 patients were taken off the study prior to initiation of treatment because of rapid disease progression (n=3), withdrawal of consent (n=1), and screening failure (n=1). The CONSORT diagram was shown in Figure 1. The median number of pembrolizumab cycles received was 4 (range 1–16), with 2 patients (6%) discontinuing due to toxicity and 30 (91%) discontinuing early to due progression or death. Thirty-two patients (97%) completed the full course of TRT. Five patients (15%) received PCI during the protocol. When this report was written, 32 patients (97%) who received any treatment on protocol had been removed from the study; 28 for disease progression or death,
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and 2 for toxicity which were unrelated to treatment. Details of the 32 off-study patients were shown in S. Table 1.
Thirty patients (91%) had SCLC and the remaining 3 patients (9%) had LCNEC. The median age was 62 years (range 37–80); 20 (61%) were men and 13 (39%) were women (Table 1). All patients had received induction chemotherapy before trial enrollment. The median number of chemotherapy cycles was 4 (range 2–6); the most common regimens were carboplatin and etoposide (n=21) and cisplatin/etoposide (n=12). No patients had received chemotherapy before the diagnosis; 10 (30%) had received prior RT, 1 to the liver, 1 to the lung, and 8 as PCI before trial enrollment. No patient had received prior immunotherapy. Dosimetric details of the population were shown in S. Table 2. Safety No DLTs were observed in the first 35 days or through continued follow-up until data cutoff was performed. None of the six patients in the first two dose groups experienced DLTs, so the rest of the patients received 200 mg. Toxic effects attributable to protocol therapy are shown in Table 2. No patient experienced grade 4 or 5 treatment-related toxicity, and most adverse events were self-limiting and could be managed on an outpatient basis. Among the 33 patients evaluable for toxicity, two (6%) experienced grade 3 treatment-related events (rash in one patient and asthenia, paresthesia, and autoimmune disorder in the other), but both of them were unlikely or doubtfully related to pembrolizumab and TRT (S. Table 3). Notably, no patient experienced pneumonitis and five (15%) experienced grade 2 esophagitis. The patient with autoimmune disorder was a 58-year-old female who experienced grade 1 fatigue and worsening peripheral neuropathy which began during pre-trial cisplatin and etoposide treatment. She was started on gabapentin and received the second cycle of
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pembrolizumab. Two weeks later, she presented to the emergency department for worsening peripheral neuropathy, proximal and distal weakness and sensory loss of light touch in all extremities. Magnetic resonance imaging did not show any central nervous system disease and cerebrospinal fluid protein was elevated, but cytology was negative for malignancy. Paraneoplastic autoantibody panel in serum was positive for anti-neuronal nuclear antibody, type 1 titer of 1:15,360, suggesting autoimmune etiology. It was assumed that the patient’s autoimmune paraneoplastic syndrome had been unmasked by pembrolizumab and the patient was taken off trial. She was started on methylprednisolone (1mg/kg/day); neurologic symptoms improved, and she was discharged nine days after admission. The patient was lost to follow-up.
Treatment Response The median follow-up time was 7.3 months (range, 1–13). The median PFS was 6.1 months (95% CI 4.1–8) and median OS was 8.4 months (95%; CI: 6.7–10.1) (Fig. 2A, B). The PFS and OS rates at 6 months were 50.3% (95%; CI: 31.5–66.6) and 76.5% (95%, CI: 52.3– 85.3). The median PFS time for patients who experienced any response to induction chemotherapy (n=25) was 6.1 months (95%, CI: 4.0-8.2) versus 4.8 months for non-responders (n=8; 95%, CI: 1.1-7.5). Corresponding median OS intervals were 8.4 months for responders (95%, CI: 5.8-11.1) and 5.1 months for non-responders (95%, CI: 1.7-8) By irRC, best responses were irCR for 1 patient (3%), irPR for 4 (12%), irSD for 6 (18%), and irPD for 22 (67%); for the purposes of this study, stable disease was not required to persist for ≥6 months. Of the 8 patients who progressed on chemotherapy prior to per-protocol treatment, all had irPD as best response on trial. The ORR was found to be 5/33 (15%, CI: 5.131.9%).
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Three patients experienced mild-to-moderate enlargement of the overall tumor burden before a decrease, otherwise known as pseudoprogression (Fig. 3A). Best irRC responses according to tumor volume and time are displayed in Figure 3B and 3C. The average time to response among responders was 130 days (range 37–245). Of the 22 patients with irPD, all had growth of unirradiated tumors and development of new metastatic lesions. Only 3 patients (9%) had progression of the irradiated lesion. Treatment response for a representative patient is shown in S. Figure 1, for whom baseline imaging revealed involvement of a right paratracheal lymph node. Images obtained at 2 months after therapy revealed marked enlargement of the lymph node; however, the size of the node had greatly decreased by 4 months after therapy. The primary irradiated lesion remained stable throughout this time.
Discussion To our knowledge, this is the first prospective study of concurrent pembrolizumab and TRT for ES-SCLC, a highly aggressive neoplasm for which therapeutic options remain limited. This novel regimen was tolerated well, with few high-grade adverse events, and no DLTs in the 35 day period. The safety of this approach supports its further study as a foundational regimen on which to evaluate combined-modality management to reverse immune resistance. The safety of this combination, the primary endpoint of this trial, was supported by the lack of observed DLTs and low incidence of grade ≥3 toxicity (2 patients, 6%) during an admittedly short follow-up interval. By comparison, a phase 3 trial of consolidative TRT reported by Slotman and colleagues4 revealed that 26 of 247 patients (10%) experienced some type of grade 3 event, most commonly fatigue. Although direct comparisons are problematic owing to the differing doses and follow-up times in these trials, one possible conclusion is that
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concurrent immunotherapy and TRT does not overtly increase toxicity. This is important because combined immunotherapy and TRT, especially in concurrent schedules, has been understudied, in large part because of toxicity concerns; however, evidence from patients with non-small cell lung cancer corroborates the encouraging safety profiles.12,13 Our clinical outcomes, although limited by short follow-up time and lack of statistical power, were also comparable to those reported in a European phase 3 trial with consolidative TRT alone.4 Our median PFS time was 6.1 months versus 4 months in the phase 3 trial; the median OS time was 8.4 months versus 8 months; and the 6-month PFS was 50.3% versus 24%. Notable differences also include that our study was not restricted to patients who responded to induction chemotherapy or to those with newly diagnosed disease; thus, it included patients who had had disease progression on induction. These factors likely explain the high rate of clinical progression (PD by irRC standards) after combined-modality therapy in our study. Patients with PD after induction chemotherapy would be expected to have poorer survival than patients without PD. Perhaps, a “purer” population of patients who did not progress on induction chemotherapy could experience important benefits from the addition of concurrent or adjuvant immunotherapy to TRT. Further, outcomes may have been influenced by the absence of selection for patients whose tumors express PD-L1, which does appear to increase the probability of response to anti-PD-1 antibodies in SCLC based on experience with pembrolizumab and nivolumab.12, 13 Based on these results, further trials aimed at integrating immunotherapy and TRT are recommended. Given the success of immunotherapy alone for ES-SCLC as seen in the IMpower 133 and CASPIAN trials3,6,14-16, efforts to increase the ORRs of immunotherapy for ES-SCLC should now commence. Although maintenance immunotherapy has been attempted for this
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purpose, the results have been disappointing.17 Instead, the rationale for combined TRT and immunotherapy to further enhance ORRs is based on well-studied biological principles; radiation can assist in tumor debulking, increase antigen presentation, promote T cell infiltration, and favorably modulate the tumor microenvironment.18-20 Phase II trials powered to evaluate the efficacy of a combined regimen may be an excellent step forward with which to preliminarily gauge whether combined-modality therapy may eventually prove to be superior to singlemodality management. This trial had several limitations aside from the aforementioned issues of patient heterogeneity, short follow-up, and small sample size. Although prospective trials minimize retrospective-type selection biases, enrollment biases are often overlooked. Indeed, the population selected for this trial may have had higher-risk disease that warranted additional intervention (as opposed to standard TRT alone for more “standard-risk” cases). We further included patients regardless of response to induction chemotherapy and with unknown PD1/PDL1 status. Additionally, standardized follow-up imaging techniques (e.g. PET) and timing thereof could not be mandated, since some outside facilities may not have these capabilities; this may have affected response rates and PFS. Finally, analysis of treatment-related toxicity is influenced strongly by numerous other factors, including receipt of full-course RT and immunotherapy, prior therapies, tumor extent, location, or volume, dosimetric factors, and supportive management. In light of these caveats, our findings should be tested in other prospective trials; however, we also wish to emphasize the conservative interpretation that no obvious increase in toxicity (especially high-grade events) was observed in this study. In summary, concurrent pembrolizumab with TRT for ES-SCLC was tolerated well with few high-grade events and no DLTs. Clinical outcomes should be investigated further, with
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longer follow-up, with larger and more homogeneous sets of patients preceded by combination immunotherapy/chemotherapy, in efforts to improve outcomes compared to either immunotherapy or TRT alone.
References 1. Govindan R, Page N, Morgensztern D, et al: Changing Epidemiology of Small-Cell Lung Cancer in the United States Over the Last 30 Years: Analysis of the Surveillance, Epidemiologic, and End Results Database. Journal of Clinical Oncology 24:4539-4544, 2006 2. National Comprehensive Cancer Network. Small Cell Lung Cancer. Cancer Version 1.2018, March 22, 2018 3. Horn L, Mansfield AS, Szczęsna A, et al: First-Line Atezolizumab plus Chemotherapy in Extensive-Stage Small-Cell Lung Cancer. New England Journal of Medicine, 2018 4. Slotman BJ, van Tinteren H, Praag JO, et al: Use of thoracic radiotherapy for extensive stage small-cell lung cancer: a phase 3 randomised controlled trial. The Lancet 385:36-42, 2015 5. Peifer M, Fernandez-Cuesta L, Sos ML, et al: Integrative genome analyses identify key somatic driver mutations of small-cell lung cancer. Nat Genet 44:1104-10, 2012 6. Ricciuti B, Kravets S, Dahlberg SE, et al: Use of targeted next generation sequencing to characterize tumor mutational burden and efficacy of immune checkpoint inhibition in small cell lung cancer. J Immunother Cancer 7:87, 2019 7. Huang AC, Postow MA, Orlowski RJ, et al: T-cell invigoration to tumour burden ratio associated with anti-PD-1 response. Nature 545:60, 2017 8. Demaria S, Golden EB, Formenti SC: Role of local radiation therapy in cancer immunotherapy. JAMA Oncology 1:1325-1332, 2015 9. Antonia SJ, Villegas A, Daniel D, et al: Overall Survival with Durvalumab after Chemoradiotherapy in Stage III NSCLC. N Engl J Med 379:2342-2350, 2018 10. Gore EM, Hu C, Sun AY, et al: Randomized Phase II Study Comparing Prophylactic Cranial Irradiation Alone to Prophylactic Cranial Irradiation and Consolidative Extracranial Irradiation for Extensive-Disease Small Cell Lung Cancer (ED SCLC): NRG Oncology RTOG 0937. J Thorac Oncol 12:1561-1570, 2017 11. Wolchok JD, Hoos A, O'Day S, et al: Guidelines for the evaluation of immune therapy activity in solid tumors: immune-related response criteria. Clin Cancer Res 15:7412-20, 2009 12. Verma V, Cushman TR, Selek U, et al: Safety of Combined Immunotherapy and Thoracic Radiation Therapy: Analysis of 3 Single-Institutional Phase I/II Trials. Int J Radiat Oncol Biol Phys 101:1141-1148, 2018 13. Verma V, Cushman TR, Tang C, et al: Toxicity of radiation and immunotherapy combinations. Adv Radiat Oncol 3:506-511, 2018 14. Paz-Ares LG, Jiang H, Huang Y, et al: Overall survival with durvalumab plus etoposideplatinum in fist-line extensive-stage SCLC: results from the caspian study. J Thorac Oncol 2019;PL02.11. 15. Ready N, Owonikoko TK, Postmus PE, et al: CheckMate 451: A randomized, doubleblind, phase III trial of nivolumab (nivo), nivo plus ipilimumab (ipi), or placebo as maintenance therapy
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in patients (pts) with extensive-stage disease small cell lung cancer (ED-SCLC) after first-line platinumbased doublet chemotherapy (PT-DC). Journal of Clinical Oncology 34:TPS8579-TPS8579, 2016 16. Rudin C, Shen L, Pietanza MC: P2.04-007 KEYNOTE-604: Phase 3 Randomized, Double-Blind Trial of Pembrolizumab/Placebo plus Etoposide/Platinum for Extensive Stage-SCLC. Journal of Thoracic Oncology 12:S2400, 2017 17. Gadgeel SM, Pennell NA, Fidler MJ, et al: Phase II Study of Maintenance Pembrolizumab in Patients with Extensive-Stage Small Cell Lung Cancer (SCLC). J Thorac Oncol 13:1393-1399, 2018 18. Huang AC, Postow MA, Orlowski RJ, et al: T-cell invigoration to tumour burden ratio associated with anti-PD-1 response. Nature 545:60-65, 2017 19. Menon H, Ramapriyan R, Cushman TR, et al: Role of Radiation Therapy in Modulation of the Tumor Stroma and Microenvironment. Front Immunol 10:193, 2019 20. Demaria S, Golden EB, Formenti SC: Role of Local Radiation Therapy in Cancer Immunotherapy. JAMA Oncol 1:1325-32, 2015
Figure Legends Fig. 1. CONSORT diagram. Fig. 2. Progression-free survival (A) and overall survival (B) estimates for the 33 patients treated per protocol. Fig. 3. Antitumor response categories by irRC. (A) Best response (change in volume) of overall tumor burden during the protocol. (B) Longitudinal best response (change in volume). (C) Times to and durability of response. Abbreviations: irPD, progressive disease (per the Immune-Related Response Criteria definition); irSD, immune-related stable disease; irPR, immune-related partial response; irCR, immune-related complete response. S. Fig. 1. Pseudoprogression example. Irradiated (top) and unirradiated (bottom) lesions illustrate pseudoprogression of a right paratracheal node. The node had grown at the 2-month follow-up scan but had shrunk considerably by the 4-month scan.
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Table 1. Patient Characteristics Characteristic Sex Male Female Median age, years
No. of Patients (%) or Median (Range) 20 (61) 13 (39) 62 (37-80)
Histology SCLC LCNEC
30 (91) 3(9)
Ethnicity White Asian African American
32 (97) 1 (3) 0
Prior therapy Radiation therapy Induction systemic therapy Immunotherapy
10 (30) 33 (100) 0
Response to induction chemotherapy Complete response Partial response Stable disease Progressive disease Intrathoracic disease after chemotherapy
2 (6) 21 (64) 7 (21) 3 (9) 27 (82)
Completed per-protocol radiation therapy Cycles of pembrolizumab Received prophylactic cranial irradiation
32 (97) 4 (1-16) 5 (15)
Table 2. Adverse Events possibly/probably/definitely related to protocol therapy among 33 Patients Evaluable for Toxicity No. (%) Adverse Event Grade 1 Grade 2 Grade 3 Grade 4 General Headache 1 (3) 0 0 0 Fatigue 6 (18) 2 (6) 0 0 Radiation dermatitis 1 (3) 0 0 0 Anorexia 1 (3) 0 0 0 Pruritus 1 (3) 1 (3) 0 0 Rash, maculopapular 0 1 (3) 0 0 Muscle weakness 1 (3) 0 0 0 Pain 2 (6) 1 (3) 0 0 Respiratory Dyspnea 1 (3) 1 (3) 0 0 Cough 0 2 (6) 0 0 Pneumonitis 0 0 0 0 Gastrointestinal Constipation 2 (6) 0 0 0 Dysphagia 4 (12) 3 (9) 0 0 Esophagitis 3 (9) 5 (15) 0 0 Hematologic Anemia WBC count decrease Platelet count decrease
0 1 (3) 1(3)
2 (6) 0 0
0 0 0
0 0 0
Abbreviations: WBC, white blood cell Footnote: The 100 mg pembrolizumab patients experienced fatigue (G1, n=1; G2, n=1), pain (G1, n=1), dysphagia (G1, n=1; G2, n=1), and esophagitis (G1, n=1; G2, n=1). For the 150 mg cohort, toxicities were fatigue (G1, n=2), esophagitis (G2, n=1) and anemia (G2, n=2). All other adverse events were in the 200 mg group.
S1556-0864(19)33525-7
DOI:
https://doi.org/10.1016/j.jtho.2019.10.001
Reference:
JTHO 1605
To appear in:
Journal of Thoracic Oncology
Received Date: 26 August 2019 Revised Date:
27 September 2019
Accepted Date: 1 October 2019
Please cite this article as: Welsh JW, Heymach JV, Chen D, Verma V, Cushman TR, Hess KR, Shroff G, Tang C, Skoulidis F, Jeter M, Menon H, Nguyen Q-N, Chang JY, Altan M, Papadimitrakopoulou VA, Simon GR, Raju U, Byers L, Glisson B, Phase I Trial of Pembrolizumab and Radiation Therapy after Induction Chemotherapy for Extensive-Stage Small Cell Lung Cancer, Journal of Thoracic Oncology (2019), doi: https://doi.org/10.1016/j.jtho.2019.10.001. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2019 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.
Phase I Trial of Pembrolizumab and Radiation Therapy after Induction Chemotherapy for Extensive-Stage Small Cell Lung Cancer James W. Welsh1, John V. Heymach4, Dawei Chen1,2, Vivek Verma3, Taylor R. Cushman1, Kenneth R. Hess5, Girish Shroff,6 Chad Tang1, Ferdinandos Skoulidis4, Melenda Jeter1, Hari Menon1, Quynh-Nhu Nguyen1, Joe Y. Chang1, Mehmet Altan4, Vassiliki A. Papadimitrakopoulou4, George R. Simon4, Uma Raju1, Lauren Byers,4 and Bonnie Glisson4
Departments of 1 Radiation Oncology, 4Thoracic Head & Neck Oncology, 5Biostatistics, 6
Diagnostic Radiology, The University of Texas MD Anderson Cancer Center, Houston, TX;
2
Department of Radiation Oncology, Shandong Cancer Hospital affiliated to Shandong
University, JN, CN and 3Department of Radiation Oncology, Allegheny General Hospital, Pittsburgh, PA
Support: Merck provided funding for and access to pembrolizumab; other support was provided by the Cancer Center Support (Core) Grant P30 CA016672 from the National Cancer Institute, National Institutes of Health.
Correspondence to: James W. Welsh, MD, Department of Radiation Oncology, Unit 97, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030. Tel 713-563-2447; Fax 713-745-1417; Email [email protected]
Short Title: Combination of Pembrolizumab and RT for ES-SCLC Presented at: ASTRO 2018 (Oct 21, 2018; San Antonio, TX, USA)
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Disclaimers: JWW, JVH, JYC, and DRG have received research grants from Bristol-Myers Squibb. JWW and DRG have received grants from Merck. JVH also received research funding from AstraZeneca and Spectrum Pharmaceuticals. JWW reported receiving research support from GlaxoSmithKline, Bristol-Meyers Squibb, Merck, Nanobiotix, Mavu Pharmaceuticals, and Checkmate Pharmaceuticals; serving on the scientific advisory board for RefleXion Medical, MolecularMatch, OncoResponse, CheckMate, Mavu Pharmaceuticals, and Alpine Immune Sciences; being cofounder of Helios Oncology, MolecularMatch, and OncoResponse; serving as an advisor to AstraZeneca, Merck, MolecularMatch, Incyte, Aileron, and Nanobiotix; and holding patents for MP470 (amuvatinib), MRX34 regulation of PDL1, and XRT technique to overcome immune resistance (MD Anderson Cancer Center has a trademark for RadScopal). No other disclosures were reported.
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ABSTRACT PURPOSE Radiation and immunotherapy have separately been shown to confer survival advantages to patients with extensive-stage small cell lung cancer (ES-SCLC), but failure rates remain high and combination therapy has been understudied. In this single-arm phase I trial (NCT02402920), we assessed the safety of combining pembrolizumab with thoracic radiation therapy (TRT) after induction chemotherapy for SCLC. METHODS ES-SCLC patients who had completed chemotherapy received TRT with pembrolizumab. The maximum tolerated dose of pembrolizumab was assessed by 3+3 dose-escalation; doses began at 100 mg and increased in 50 mg increments to 200 mg. Pembrolizumab was given every 3 weeks for up to 16 cycles; TRT was prescribed as 45 Gy in 15 daily fractions. Toxicity was evaluated with the Common Terminology Criteria for Adverse Events v4.0. The primary endpoint was safety of the combined therapy based on the incidence of dose-limiting toxicity (DLTs) in the 35 days following initiation of treatment. RESULTS Thirty-eight ES-SCLC patients (median age 65 years, range, 37–79) were enrolled from September 2015 through September 2017; 33 received per-protocol treatment, and all tolerated pembrolizumab at 100-200 mg with no DLTs in the 35-day window. There were no grade 4-5 toxicities; two (6%) experienced grade 3 events (n=1 rash, n=1 asthenia/paresthesia/autoimmune disorder) that were unlikely/doubtfully related to protocol therapy. The median follow-up time was 7.3 months (range 1–13); median progression-free and overall survival were 6.1 months (95% confidence interval [CI] 4.1–8.1) and 8.4 months (95% CI 6.7-10.1).
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CONCLUSIONS Concurrent pembrolizumab-TRT was tolerated well, with few high-grade adverse events in the short-term; progression-free and overall survival rates are difficult to interpret due to heterogeneity in eligibility criteria (e.g. enrolling progressors on induction chemotherapy). Although randomized studies have illustrated benefits to TRT alone and immunotherapy alone, the safety of the combined regimen supports further investigation as a foundational approach for future prospective studies.
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Introduction Small cell lung cancer (SCLC) is an aggressive malignancy; most patients present with extensive disease, and survival times remain short.1 The standard of care includes chemotherapy with or without consolidative thoracic radiotherapy (TRT) or prophylactic cranial irradiation (PCI).2 Recent results from the IMPower133 trial have shown a survival benefit with the addition of atezolizumab to chemotherapy, but did not allow TRT3. Findings from a previous randomized trial (which did not include immunotherapy) demonstrated that consolidative TRT for patients with extensive-stage (ES) SCLC who responded to chemotherapy led to improved 2-year progression-free survival (PFS) and overall survival (OS) rates, but did not meet the primary endpoint at 1 year.4 However, for either approach of immunotherapy alone or TRT alone, both local and distant failure rates remain high, highlighting the need for improved disease control. Combined radiation and immunotherapy is promising for SCLC for several reasons. First, SCLC has a high mutational burden5 which correlates with response to programmed cell death-1 (PD-1) inhibition. 6 Although a high mutational burden may result in more aggressive disease, it also leads to increased antigenicity and thus better detection by the immune system, which can be further enhanced by PD-1 inhibition. Additionally, evidence also suggests that radiation complements immunotherapy by reducing tumor burden,7 inducing neoantigens, and enhancing T-cell infiltration of tumors.8 Moreover, the addition of adjuvant immunotherapy to chemoradiotherapy prolonged overall survival in a randomized trial of durvalumab, a PD-L1 inhibitor, in patients with stage III non-small cell lung cancer.9 For these reasons, combined radiation and immunotherapy may provide advantages over either modality alone; however, this approach has largely not been prospectively evaluated. We
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thus performed a phase I trial of the safety and preliminary efficacy of pembrolizumab in combination with concurrent TRT for patients with ES-SCLC.
Patients and Methods Patients Eligible patients for this phase I study (NCT02402920) were ≥18 years old with ESSCLC or large cell neuroendocrine cancer (LCNEC); had received 1-6 cycles of induction chemotherapy before enrollment; and had Zubrod performance status < 3. Recurrent or progressive disease was allowed. Exclusion criteria included the presence of any autoimmune disorder or other malignancy or central nervous system involvement at enrollment; and receipt of any form of immunosuppressive therapy within 7 days of enrollment. A history of other cancer was not a basis for exclusion. This study was approved by the U.T. M. D. Anderson Cancer Center institutional review board, and written informed consent was obtained from all patients. PCI (25 Gy in 10 fractions) was allowed at the treating physician’s discretion but was encouraged to be completed before trial enrollment. If PCI was given during the trial, then TRT and pembrolizumab were delayed by one cycle (21 days). Dose-limiting toxicities (DLTs) were defined as grade ≥3 nonhematologic/laboratory events or grade ≥4 hematologic/laboratory toxicity that was possibly, probably, or definitely related to the combined pembrolizumab and TRT. Toxicity was scored with the Common Terminology Criteria for Adverse Events (CTCAE) v4.0.
Study Design and Treatment
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All patients received up to 6 induction cycles of chemotherapy before beginning concurrent pembrolizumab and TRT; baseline positron emission tomography (PET) or computed tomography (CT) scans were obtained within 4 weeks before beginning concurrent therapy. Notably, neither PD-1 nor PD-L1 was tested, and no threshold criteria were applied. This open-label study had a standard 3+3 dose-escalation design, with pembrolizumab dose levels of 100 mg, 150 mg, and 200 mg. Pembrolizumab was given starting on day 1 and given every 21 days for up to 16 cycles. No patients were replaced during the escalation process, and no dose adjustments were to be made (instead, cessation was recommended for excessive toxicities). This trial was to enroll roughly 40 patients, based on protocol calculations that with 40 enrolled patients, the probability of observing at least 1 patient with toxicity (and a reference “true toxicity rate” of 0.1) would be 88%. Intensity modulated radiation therapy (IMRT) was begun on day 1 and given in 15 daily fractions to 45 Gy. A simultaneous integrated boost (SIB) to the gross tumor volume (GTV) of up to 52.5 Gy was allowed, as long as the dose to the planning target volume (PTV) remained at 45 Gy. This dose parallels our institutional procedure for consolidative TRT, and was also the dose utilized by the RTOG 0937 trial.10 Follow-up scans with CT, PET, or PET/CT were obtained every 12 weeks (± 4 weeks) to evaluate response to therapy. The primary objective was to determine the safety of the concurrent pembrolizumab-TRT combination; a secondary objective was to assess progression-free survival. Time of initiation was determined as the date of starting pembrolizumab or RT, whichever came first. Response and progression were evaluated and rated with the Immune-Related Response Criteria (irRC)11: briefly, complete response (irCR) requires complete elimination of all tumors, partial response (irPR) is defined as a ≥50% reduction in total tumor burden, and stable disease (irSD) is defined
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as no progression but neither irPR nor irCR. Overall response rate (ORR) referred to irPR or irCR.
Statistical Analysis All statistical analysis was performed with IBM Statistical Package for the Social Sciences (SPSS) v24 (Chicago, IL) and GraphPad Prism v7 (La Jolla, CA). PFS and OS intervals were defined as the time from trial enrollment to date of progression/death/censor (PFS) or death/censor (OS). Confidence intervals (CIs) were calculated for the ORR by using the binomial exact method. The Kaplan-Meier product limit method was used to estimate OS and PFS distributions. Because this was a single-arm phase I trial with the primary goal of assessing the safety of pembrolizumab with TRT, no other statistical evaluations were performed.
Results Patient Characteristics Thirty-eight patients were screened for enrollment from September 2015 through September 2017. Of those, 33 (87%) initiated treatment per protocol; the other 5 patients were taken off the study prior to initiation of treatment because of rapid disease progression (n=3), withdrawal of consent (n=1), and screening failure (n=1). The CONSORT diagram was shown in Figure 1. The median number of pembrolizumab cycles received was 4 (range 1–16), with 2 patients (6%) discontinuing due to toxicity and 30 (91%) discontinuing early to due progression or death. Thirty-two patients (97%) completed the full course of TRT. Five patients (15%) received PCI during the protocol. When this report was written, 32 patients (97%) who received any treatment on protocol had been removed from the study; 28 for disease progression or death,
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and 2 for toxicity which were unrelated to treatment. Details of the 32 off-study patients were shown in S. Table 1.
Thirty patients (91%) had SCLC and the remaining 3 patients (9%) had LCNEC. The median age was 62 years (range 37–80); 20 (61%) were men and 13 (39%) were women (Table 1). All patients had received induction chemotherapy before trial enrollment. The median number of chemotherapy cycles was 4 (range 2–6); the most common regimens were carboplatin and etoposide (n=21) and cisplatin/etoposide (n=12). No patients had received chemotherapy before the diagnosis; 10 (30%) had received prior RT, 1 to the liver, 1 to the lung, and 8 as PCI before trial enrollment. No patient had received prior immunotherapy. Dosimetric details of the population were shown in S. Table 2. Safety No DLTs were observed in the first 35 days or through continued follow-up until data cutoff was performed. None of the six patients in the first two dose groups experienced DLTs, so the rest of the patients received 200 mg. Toxic effects attributable to protocol therapy are shown in Table 2. No patient experienced grade 4 or 5 treatment-related toxicity, and most adverse events were self-limiting and could be managed on an outpatient basis. Among the 33 patients evaluable for toxicity, two (6%) experienced grade 3 treatment-related events (rash in one patient and asthenia, paresthesia, and autoimmune disorder in the other), but both of them were unlikely or doubtfully related to pembrolizumab and TRT (S. Table 3). Notably, no patient experienced pneumonitis and five (15%) experienced grade 2 esophagitis. The patient with autoimmune disorder was a 58-year-old female who experienced grade 1 fatigue and worsening peripheral neuropathy which began during pre-trial cisplatin and etoposide treatment. She was started on gabapentin and received the second cycle of
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pembrolizumab. Two weeks later, she presented to the emergency department for worsening peripheral neuropathy, proximal and distal weakness and sensory loss of light touch in all extremities. Magnetic resonance imaging did not show any central nervous system disease and cerebrospinal fluid protein was elevated, but cytology was negative for malignancy. Paraneoplastic autoantibody panel in serum was positive for anti-neuronal nuclear antibody, type 1 titer of 1:15,360, suggesting autoimmune etiology. It was assumed that the patient’s autoimmune paraneoplastic syndrome had been unmasked by pembrolizumab and the patient was taken off trial. She was started on methylprednisolone (1mg/kg/day); neurologic symptoms improved, and she was discharged nine days after admission. The patient was lost to follow-up.
Treatment Response The median follow-up time was 7.3 months (range, 1–13). The median PFS was 6.1 months (95% CI 4.1–8) and median OS was 8.4 months (95%; CI: 6.7–10.1) (Fig. 2A, B). The PFS and OS rates at 6 months were 50.3% (95%; CI: 31.5–66.6) and 76.5% (95%, CI: 52.3– 85.3). The median PFS time for patients who experienced any response to induction chemotherapy (n=25) was 6.1 months (95%, CI: 4.0-8.2) versus 4.8 months for non-responders (n=8; 95%, CI: 1.1-7.5). Corresponding median OS intervals were 8.4 months for responders (95%, CI: 5.8-11.1) and 5.1 months for non-responders (95%, CI: 1.7-8) By irRC, best responses were irCR for 1 patient (3%), irPR for 4 (12%), irSD for 6 (18%), and irPD for 22 (67%); for the purposes of this study, stable disease was not required to persist for ≥6 months. Of the 8 patients who progressed on chemotherapy prior to per-protocol treatment, all had irPD as best response on trial. The ORR was found to be 5/33 (15%, CI: 5.131.9%).
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Three patients experienced mild-to-moderate enlargement of the overall tumor burden before a decrease, otherwise known as pseudoprogression (Fig. 3A). Best irRC responses according to tumor volume and time are displayed in Figure 3B and 3C. The average time to response among responders was 130 days (range 37–245). Of the 22 patients with irPD, all had growth of unirradiated tumors and development of new metastatic lesions. Only 3 patients (9%) had progression of the irradiated lesion. Treatment response for a representative patient is shown in S. Figure 1, for whom baseline imaging revealed involvement of a right paratracheal lymph node. Images obtained at 2 months after therapy revealed marked enlargement of the lymph node; however, the size of the node had greatly decreased by 4 months after therapy. The primary irradiated lesion remained stable throughout this time.
Discussion To our knowledge, this is the first prospective study of concurrent pembrolizumab and TRT for ES-SCLC, a highly aggressive neoplasm for which therapeutic options remain limited. This novel regimen was tolerated well, with few high-grade adverse events, and no DLTs in the 35 day period. The safety of this approach supports its further study as a foundational regimen on which to evaluate combined-modality management to reverse immune resistance. The safety of this combination, the primary endpoint of this trial, was supported by the lack of observed DLTs and low incidence of grade ≥3 toxicity (2 patients, 6%) during an admittedly short follow-up interval. By comparison, a phase 3 trial of consolidative TRT reported by Slotman and colleagues4 revealed that 26 of 247 patients (10%) experienced some type of grade 3 event, most commonly fatigue. Although direct comparisons are problematic owing to the differing doses and follow-up times in these trials, one possible conclusion is that
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concurrent immunotherapy and TRT does not overtly increase toxicity. This is important because combined immunotherapy and TRT, especially in concurrent schedules, has been understudied, in large part because of toxicity concerns; however, evidence from patients with non-small cell lung cancer corroborates the encouraging safety profiles.12,13 Our clinical outcomes, although limited by short follow-up time and lack of statistical power, were also comparable to those reported in a European phase 3 trial with consolidative TRT alone.4 Our median PFS time was 6.1 months versus 4 months in the phase 3 trial; the median OS time was 8.4 months versus 8 months; and the 6-month PFS was 50.3% versus 24%. Notable differences also include that our study was not restricted to patients who responded to induction chemotherapy or to those with newly diagnosed disease; thus, it included patients who had had disease progression on induction. These factors likely explain the high rate of clinical progression (PD by irRC standards) after combined-modality therapy in our study. Patients with PD after induction chemotherapy would be expected to have poorer survival than patients without PD. Perhaps, a “purer” population of patients who did not progress on induction chemotherapy could experience important benefits from the addition of concurrent or adjuvant immunotherapy to TRT. Further, outcomes may have been influenced by the absence of selection for patients whose tumors express PD-L1, which does appear to increase the probability of response to anti-PD-1 antibodies in SCLC based on experience with pembrolizumab and nivolumab.12, 13 Based on these results, further trials aimed at integrating immunotherapy and TRT are recommended. Given the success of immunotherapy alone for ES-SCLC as seen in the IMpower 133 and CASPIAN trials3,6,14-16, efforts to increase the ORRs of immunotherapy for ES-SCLC should now commence. Although maintenance immunotherapy has been attempted for this
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purpose, the results have been disappointing.17 Instead, the rationale for combined TRT and immunotherapy to further enhance ORRs is based on well-studied biological principles; radiation can assist in tumor debulking, increase antigen presentation, promote T cell infiltration, and favorably modulate the tumor microenvironment.18-20 Phase II trials powered to evaluate the efficacy of a combined regimen may be an excellent step forward with which to preliminarily gauge whether combined-modality therapy may eventually prove to be superior to singlemodality management. This trial had several limitations aside from the aforementioned issues of patient heterogeneity, short follow-up, and small sample size. Although prospective trials minimize retrospective-type selection biases, enrollment biases are often overlooked. Indeed, the population selected for this trial may have had higher-risk disease that warranted additional intervention (as opposed to standard TRT alone for more “standard-risk” cases). We further included patients regardless of response to induction chemotherapy and with unknown PD1/PDL1 status. Additionally, standardized follow-up imaging techniques (e.g. PET) and timing thereof could not be mandated, since some outside facilities may not have these capabilities; this may have affected response rates and PFS. Finally, analysis of treatment-related toxicity is influenced strongly by numerous other factors, including receipt of full-course RT and immunotherapy, prior therapies, tumor extent, location, or volume, dosimetric factors, and supportive management. In light of these caveats, our findings should be tested in other prospective trials; however, we also wish to emphasize the conservative interpretation that no obvious increase in toxicity (especially high-grade events) was observed in this study. In summary, concurrent pembrolizumab with TRT for ES-SCLC was tolerated well with few high-grade events and no DLTs. Clinical outcomes should be investigated further, with
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longer follow-up, with larger and more homogeneous sets of patients preceded by combination immunotherapy/chemotherapy, in efforts to improve outcomes compared to either immunotherapy or TRT alone.
References 1. Govindan R, Page N, Morgensztern D, et al: Changing Epidemiology of Small-Cell Lung Cancer in the United States Over the Last 30 Years: Analysis of the Surveillance, Epidemiologic, and End Results Database. Journal of Clinical Oncology 24:4539-4544, 2006 2. National Comprehensive Cancer Network. Small Cell Lung Cancer. Cancer Version 1.2018, March 22, 2018 3. Horn L, Mansfield AS, Szczęsna A, et al: First-Line Atezolizumab plus Chemotherapy in Extensive-Stage Small-Cell Lung Cancer. New England Journal of Medicine, 2018 4. Slotman BJ, van Tinteren H, Praag JO, et al: Use of thoracic radiotherapy for extensive stage small-cell lung cancer: a phase 3 randomised controlled trial. The Lancet 385:36-42, 2015 5. Peifer M, Fernandez-Cuesta L, Sos ML, et al: Integrative genome analyses identify key somatic driver mutations of small-cell lung cancer. Nat Genet 44:1104-10, 2012 6. Ricciuti B, Kravets S, Dahlberg SE, et al: Use of targeted next generation sequencing to characterize tumor mutational burden and efficacy of immune checkpoint inhibition in small cell lung cancer. J Immunother Cancer 7:87, 2019 7. Huang AC, Postow MA, Orlowski RJ, et al: T-cell invigoration to tumour burden ratio associated with anti-PD-1 response. Nature 545:60, 2017 8. Demaria S, Golden EB, Formenti SC: Role of local radiation therapy in cancer immunotherapy. JAMA Oncology 1:1325-1332, 2015 9. Antonia SJ, Villegas A, Daniel D, et al: Overall Survival with Durvalumab after Chemoradiotherapy in Stage III NSCLC. N Engl J Med 379:2342-2350, 2018 10. Gore EM, Hu C, Sun AY, et al: Randomized Phase II Study Comparing Prophylactic Cranial Irradiation Alone to Prophylactic Cranial Irradiation and Consolidative Extracranial Irradiation for Extensive-Disease Small Cell Lung Cancer (ED SCLC): NRG Oncology RTOG 0937. J Thorac Oncol 12:1561-1570, 2017 11. Wolchok JD, Hoos A, O'Day S, et al: Guidelines for the evaluation of immune therapy activity in solid tumors: immune-related response criteria. Clin Cancer Res 15:7412-20, 2009 12. Verma V, Cushman TR, Selek U, et al: Safety of Combined Immunotherapy and Thoracic Radiation Therapy: Analysis of 3 Single-Institutional Phase I/II Trials. Int J Radiat Oncol Biol Phys 101:1141-1148, 2018 13. Verma V, Cushman TR, Tang C, et al: Toxicity of radiation and immunotherapy combinations. Adv Radiat Oncol 3:506-511, 2018 14. Paz-Ares LG, Jiang H, Huang Y, et al: Overall survival with durvalumab plus etoposideplatinum in fist-line extensive-stage SCLC: results from the caspian study. J Thorac Oncol 2019;PL02.11. 15. Ready N, Owonikoko TK, Postmus PE, et al: CheckMate 451: A randomized, doubleblind, phase III trial of nivolumab (nivo), nivo plus ipilimumab (ipi), or placebo as maintenance therapy
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in patients (pts) with extensive-stage disease small cell lung cancer (ED-SCLC) after first-line platinumbased doublet chemotherapy (PT-DC). Journal of Clinical Oncology 34:TPS8579-TPS8579, 2016 16. Rudin C, Shen L, Pietanza MC: P2.04-007 KEYNOTE-604: Phase 3 Randomized, Double-Blind Trial of Pembrolizumab/Placebo plus Etoposide/Platinum for Extensive Stage-SCLC. Journal of Thoracic Oncology 12:S2400, 2017 17. Gadgeel SM, Pennell NA, Fidler MJ, et al: Phase II Study of Maintenance Pembrolizumab in Patients with Extensive-Stage Small Cell Lung Cancer (SCLC). J Thorac Oncol 13:1393-1399, 2018 18. Huang AC, Postow MA, Orlowski RJ, et al: T-cell invigoration to tumour burden ratio associated with anti-PD-1 response. Nature 545:60-65, 2017 19. Menon H, Ramapriyan R, Cushman TR, et al: Role of Radiation Therapy in Modulation of the Tumor Stroma and Microenvironment. Front Immunol 10:193, 2019 20. Demaria S, Golden EB, Formenti SC: Role of Local Radiation Therapy in Cancer Immunotherapy. JAMA Oncol 1:1325-32, 2015
Figure Legends Fig. 1. CONSORT diagram. Fig. 2. Progression-free survival (A) and overall survival (B) estimates for the 33 patients treated per protocol. Fig. 3. Antitumor response categories by irRC. (A) Best response (change in volume) of overall tumor burden during the protocol. (B) Longitudinal best response (change in volume). (C) Times to and durability of response. Abbreviations: irPD, progressive disease (per the Immune-Related Response Criteria definition); irSD, immune-related stable disease; irPR, immune-related partial response; irCR, immune-related complete response. S. Fig. 1. Pseudoprogression example. Irradiated (top) and unirradiated (bottom) lesions illustrate pseudoprogression of a right paratracheal node. The node had grown at the 2-month follow-up scan but had shrunk considerably by the 4-month scan.
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Table 1. Patient Characteristics Characteristic Sex Male Female Median age, years
No. of Patients (%) or Median (Range) 20 (61) 13 (39) 62 (37-80)
Histology SCLC LCNEC
30 (91) 3(9)
Ethnicity White Asian African American
32 (97) 1 (3) 0
Prior therapy Radiation therapy Induction systemic therapy Immunotherapy
10 (30) 33 (100) 0
Response to induction chemotherapy Complete response Partial response Stable disease Progressive disease Intrathoracic disease after chemotherapy
2 (6) 21 (64) 7 (21) 3 (9) 27 (82)
Completed per-protocol radiation therapy Cycles of pembrolizumab Received prophylactic cranial irradiation
32 (97) 4 (1-16) 5 (15)
Table 2. Adverse Events possibly/probably/definitely related to protocol therapy among 33 Patients Evaluable for Toxicity No. (%) Adverse Event Grade 1 Grade 2 Grade 3 Grade 4 General Headache 1 (3) 0 0 0 Fatigue 6 (18) 2 (6) 0 0 Radiation dermatitis 1 (3) 0 0 0 Anorexia 1 (3) 0 0 0 Pruritus 1 (3) 1 (3) 0 0 Rash, maculopapular 0 1 (3) 0 0 Muscle weakness 1 (3) 0 0 0 Pain 2 (6) 1 (3) 0 0 Respiratory Dyspnea 1 (3) 1 (3) 0 0 Cough 0 2 (6) 0 0 Pneumonitis 0 0 0 0 Gastrointestinal Constipation 2 (6) 0 0 0 Dysphagia 4 (12) 3 (9) 0 0 Esophagitis 3 (9) 5 (15) 0 0 Hematologic Anemia WBC count decrease Platelet count decrease
0 1 (3) 1(3)
2 (6) 0 0
0 0 0
0 0 0
Abbreviations: WBC, white blood cell Footnote: The 100 mg pembrolizumab patients experienced fatigue (G1, n=1; G2, n=1), pain (G1, n=1), dysphagia (G1, n=1; G2, n=1), and esophagitis (G1, n=1; G2, n=1). For the 150 mg cohort, toxicities were fatigue (G1, n=2), esophagitis (G2, n=1) and anemia (G2, n=2). All other adverse events were in the 200 mg group.