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P3.02c-032 Interstitial Pneumonitis Associated with Immune Checkpoint Inhibitors Treatment in Cancer Patients
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growth. PPD was defined as deltaTGR>50%, corresponding to an absolute increase in TGR greater than 50% per month. PDL1 expression was assessed with the SP142 clone. Results: 89 pts were eligible. 58% were male, median age 60 (41-78); 15% never smokers. 62 pts had adenocarcinoma, 21 squamous and 6 other histologies. Mutational status was unknown for 14 pts; 36% wild type, 9 pts EGFRmut, 25 pts KRASmut. PDL1 expression was positive in 25 pts, unknown in 57 pts. 52 pts (58%) received nivolumab, 25 pembrolizumab and 12 atezolizumab. Treatement was received as 1-3rd line in 52 pts, and as 4th line in 37 pts. Overall, 25 pts (28%) had a response according to RECIST 1.1 criteria, 31 (35%) a stable disease. Median OS was 14.7 months. During IC, deltaTGR was <0 in 79 pts and >0 in 20 pts. Among the 20 pts with deltaTGR>0, 9 had a PPD. Characteristics (age, sex, smoking status, pathology, number of previous line, PDL1 status) of the 9 pts were not different from other pts. None of the PPD were pseudoprogression. Median OS of PPD vs others was 3.2 and 23 months, respectively. PPD was not more frequent in tumors with high baseline TGR. Conclusion: Our results suggest that PPD is a new subset of response criteria in which IC may increase tumor progression, leading to a poorer survival. Rapidly growing disease at study entry nor RECIST criteria could predict the occurrence of PPD. Keywords: Tumor growth rate, non-small cell lung cancer, Immune checkpoint inhibitors
P3.02c-032 Interstitial Pneumonitis Associated with Immune Checkpoint Inhibitors Treatment in Cancer Patients Topic: IT Myriam Delaunay,1 Amelie Lusque,2 Nicolas Meyer,3 Jean-Marie Michot,4 Judith Raimbourg,5 Jacques Cadranel,6 Gérard Zalcman,7 Valerie Gounant,6 Denis Moro-Sibilot,8 Nicolas Girard,9 Luc Thiberville,10 David Planchard,4 Anne Cecile Metivier,11 Fabrice Barlesi,12 Eric Dansin,13 Maurice Pérol,14 Eric Pichon,15 Oliver Gautschi,16 Früh Martin,17 Samia Collot,18 Marion Jaffro,19 Gregoire Prevot,19 Julie Milia-Baron,20 Julien Mazieres21 1Thoracic Oncology, CHU Larrey, Toulouse/France, 2Institut Universitaire Du Cancer de Toulouse, Toulouse/France, 3 Dermatologist Oncology, CHU Larrey, Toulouse/France,
Journal of Thoracic Oncology
Vol. 12 No. 1S
4
Institut Gustave Roussy, Villejuif/France, 5Institut de Cancerologie de L’Ouest, Nantes/France, 6Hôpital Tenon, Paris/France, 7University Hospital Bichat, Paris/France, 8 Thoracic Oncology Unit, Chest Department, Pôle Thorax Et Vaisseaux, CHU de Grenoble, Grenoble/France, 9 Thoracic Oncology, Hospices Civils de Lyon, Lyon/France, 10 University Hospital, Rouen/France, 11Hopital Foch, Suresnes/France, 12Aix-Marseille Université, Assistance Publique Hôpitaux de Marseille, Marseille/France, 13 Département de Cancérologie Générale, Centre Oscar Lambret, Lille/France, 14Groupe Thoracique Et Orl, Centre Léon Bérard, Lyon/France, 15CHU Tours-Bretonneau, Tours/France, 16Medical Oncology, Lucerne Cantonal Hospital, Luzern/Switzerland, 17Kantonsspital St Gallen, St Gallen/Switzerland, 18CHU Larrey, Toulouse/France, 19 CHU Larrey Toulouse, Toulouse/France, 20Oncologie Thoracique, Hopital Larrey, Toulouse/France, 21University Hospital, Toulouse/France Background: Immunotherapy is now a standard of care in melanoma, lung cancer and is spreading across other tumors. Immune checkpoint inhibitors (ICI) are generally well tolerated but can also generate immune-related adverse effects. Since the first trials, pneumonitis has been identified as a rare but potentially life-threatening event. Methods: We conducted a retrospective study over a period of 5 months in centers experienced in ICI use in clinical trials, access programs or following national approval. We report the main features of possibly related pneumonitis occurring in patients treated with ICI with a particular focus on clinical presentation, radiologic patterns (with a double reviewing by radiologists and pulmonologists), pathology and therapeutic strategies. Results: We identified 71 patients with possibly related pneumonitis including 54 NSCLC and 13 melanoma. They mainly received PD1 inhibitors. Pneumonitis usually occurred in male, former or current smokers with a median age of 59 years. We observed grade 2/3 (n¼ 45, 65.2%) and grade 5 (n¼ 6, 8.7%) pneumonitis. The median duration time between the introduction of immunotherapy and the pneumonitis was 2.2 months [0.1-27.4]. Ground glass opacitiy on lung CT-scan were the most predominant lesion 80.9% (n¼55), followed by consolidations 44.1% (n¼30), reticulations 36.7% (n¼25) and bronchiectasis in 20.6% (n¼14). When performed, bronchoalveolar lavage (BAL) showed a Tlymphocytic alveolitis and transbronchial biopsy an inflammatory and lymphocytic infiltration. Pneumonitis treatment was steroids (86.6%) and/or antibiotics (67.6%). Immunotherapy was stopped after the pneumonitis for 65 cases (92.9%) and reintroduced for 12
January 2017
(9.4%) cases. Twenty-four patients (34.3%) were dead at the last follow-up and 46 patients (65.7%) were still alive. Among the living patients, the pneumonitis outcome was a total recovery in 12 patients, improvement in 22 patients, stability in 10 patients, worsening evolution in 1 patient (1 unknown). Causality of immunotherapy was evaluated by investigators as “possible” for 34 patients (49.3%), “probable” for 17 (24.6%), “certain” for 15 (21.7%) other causes for 3 (4.3%) and 2 unknowns. Median overall survival from the onset of pneumonitis was 6 months. Conclusion: This series, the largest to date, of immunerelated pneumonitis demonstrates that it occurs usually during the first months and displays specific radiologic features. As there is no clearly identified risk factor, oncologists should be able to detect, diagnose (with CTscan and bronchoscopy) and treat this adverse event. An early management is usually associated with a favorable outcome and requires a close collaboration between pulmonologists, radiologists and oncologists. Keywords: Melanoma, interstitial pneumonitis, Immunotherapy, lung cancer
P3.02c-033 Patterns of Progression and Management of Acquired Resistance to Anti-PD-1 Antibodies in Advanced Non-Small Cell Lung Cancer Topic: IT Antony Mersiades,1 Megan Crumbaker,1 Bo Gao,2 Adnan Nagrial,1 Rina Hui3 1Medical Oncology, Crown Princess Mary Cancer Care Centre, Westmead Hospital, Wentworthville/NSW/Australia, 2Medical Oncology, Blacktown Cancer and Haematology Centre, Blacktown/ NSW/Australia, 3Medical Oncology, Crown Princess Mary Cancer Care Centre, Westmead Hospital, Wentworthville/ Australia Background: Anti-PD-1 antibodies (pembrolizumab and nivolumab) have shown improved overall survival in second-line treatment for metastatic non-small cell lung cancer (NSCLC) with durable responses. We aimed to assess the pattern of disease progression amongst patients who initially responded to anti-PD-1 agents and their subsequent management. Methods: We retrospectively assessed all patients who commenced single-agent anti-PD-1 antibodies between June 2012 and February 2016 at a single centre. Radiological responses were assessed by the investigator using RECIST 1.1 and irRC. Progressive disease (PD)
Abstracts
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patterns were defined as solitary, oligometastatic (2-3 lesions), generalized (>3 lesions), enlargement of existing or new lesions, visceral or non-visceral. Management and survival after progression were examined. Results: A total of 81 patients received single-agent pembrolizumab (n¼43) or nivolumab (n¼38). Of the seventeen (21.3%) patients achieving partial response, three were treatment-naïve, fifteen (88.2%) were former or current smokers, none had EGFR mutation or ALK translocation. The median number of disease sites at baseline was three, and two patients had stable brain metastases after radiotherapy at the commencement of anti-PD1 treatment. Ten (58.8%) responders developed acquired resistance, with a median time to progression of 20.2 months. Nine (90%) had solitary (n¼4) or oligometastatic (n¼5) progression. Five (50%) progressed only at existing sites, three (30%) developed new lesions only, and two (20%) progressed at both existing and new sites. Four (40%) progressed at non-visceral sites only, and one progressed in the brain at a previously treated site. Five (50%) patients underwent local treatment to solitary (n¼2) or oligoprogressive disease (n¼3) with all five achieving local control with radiotherapy. Seven(70%) continued anti-PD-1 agents beyond progression, while the three (30%) remaining patients did not receive any further therapy. With a median follow-up of 24.8 months, five (50%) of the patients had died, one from an infective exacerbation of COPD, one from type 1 respiratory failure, and three from disease progression. The median duration of treatment was 4.35 months (1.96 to 11.46) and the median overall survival after progression was 11.44 months. Conclusion: This study suggested that acquired resistance to anti-PD1 agents could often result in solitary or oligometastatic progression, and that CNS progression was uncommon. In a subset of patients, treatment beyond progression with or without local therapy to oligometastatic disease may provide ongoing and durable clinical benefit. Keywords: non-small cell lung cancer, Acquired resistance, anti-PD1
P3.02c-034 A Single Institution Experience with Immunotherapy as an Effective Therapy Approach of Advance Non-Small Cell Lung Cancer (NSCLC) Topic: IT Julia Martínez Pérez, Inmaculada Sanchez, Alejandro Falcon Gonzalez, Miriam Alonso,
growth. PPD was defined as deltaTGR>50%, corresponding to an absolute increase in TGR greater than 50% per month. PDL1 expression was assessed with the SP142 clone. Results: 89 pts were eligible. 58% were male, median age 60 (41-78); 15% never smokers. 62 pts had adenocarcinoma, 21 squamous and 6 other histologies. Mutational status was unknown for 14 pts; 36% wild type, 9 pts EGFRmut, 25 pts KRASmut. PDL1 expression was positive in 25 pts, unknown in 57 pts. 52 pts (58%) received nivolumab, 25 pembrolizumab and 12 atezolizumab. Treatement was received as 1-3rd line in 52 pts, and as 4th line in 37 pts. Overall, 25 pts (28%) had a response according to RECIST 1.1 criteria, 31 (35%) a stable disease. Median OS was 14.7 months. During IC, deltaTGR was <0 in 79 pts and >0 in 20 pts. Among the 20 pts with deltaTGR>0, 9 had a PPD. Characteristics (age, sex, smoking status, pathology, number of previous line, PDL1 status) of the 9 pts were not different from other pts. None of the PPD were pseudoprogression. Median OS of PPD vs others was 3.2 and 23 months, respectively. PPD was not more frequent in tumors with high baseline TGR. Conclusion: Our results suggest that PPD is a new subset of response criteria in which IC may increase tumor progression, leading to a poorer survival. Rapidly growing disease at study entry nor RECIST criteria could predict the occurrence of PPD. Keywords: Tumor growth rate, non-small cell lung cancer, Immune checkpoint inhibitors
P3.02c-032 Interstitial Pneumonitis Associated with Immune Checkpoint Inhibitors Treatment in Cancer Patients Topic: IT Myriam Delaunay,1 Amelie Lusque,2 Nicolas Meyer,3 Jean-Marie Michot,4 Judith Raimbourg,5 Jacques Cadranel,6 Gérard Zalcman,7 Valerie Gounant,6 Denis Moro-Sibilot,8 Nicolas Girard,9 Luc Thiberville,10 David Planchard,4 Anne Cecile Metivier,11 Fabrice Barlesi,12 Eric Dansin,13 Maurice Pérol,14 Eric Pichon,15 Oliver Gautschi,16 Früh Martin,17 Samia Collot,18 Marion Jaffro,19 Gregoire Prevot,19 Julie Milia-Baron,20 Julien Mazieres21 1Thoracic Oncology, CHU Larrey, Toulouse/France, 2Institut Universitaire Du Cancer de Toulouse, Toulouse/France, 3 Dermatologist Oncology, CHU Larrey, Toulouse/France,
Journal of Thoracic Oncology
Vol. 12 No. 1S
4
Institut Gustave Roussy, Villejuif/France, 5Institut de Cancerologie de L’Ouest, Nantes/France, 6Hôpital Tenon, Paris/France, 7University Hospital Bichat, Paris/France, 8 Thoracic Oncology Unit, Chest Department, Pôle Thorax Et Vaisseaux, CHU de Grenoble, Grenoble/France, 9 Thoracic Oncology, Hospices Civils de Lyon, Lyon/France, 10 University Hospital, Rouen/France, 11Hopital Foch, Suresnes/France, 12Aix-Marseille Université, Assistance Publique Hôpitaux de Marseille, Marseille/France, 13 Département de Cancérologie Générale, Centre Oscar Lambret, Lille/France, 14Groupe Thoracique Et Orl, Centre Léon Bérard, Lyon/France, 15CHU Tours-Bretonneau, Tours/France, 16Medical Oncology, Lucerne Cantonal Hospital, Luzern/Switzerland, 17Kantonsspital St Gallen, St Gallen/Switzerland, 18CHU Larrey, Toulouse/France, 19 CHU Larrey Toulouse, Toulouse/France, 20Oncologie Thoracique, Hopital Larrey, Toulouse/France, 21University Hospital, Toulouse/France Background: Immunotherapy is now a standard of care in melanoma, lung cancer and is spreading across other tumors. Immune checkpoint inhibitors (ICI) are generally well tolerated but can also generate immune-related adverse effects. Since the first trials, pneumonitis has been identified as a rare but potentially life-threatening event. Methods: We conducted a retrospective study over a period of 5 months in centers experienced in ICI use in clinical trials, access programs or following national approval. We report the main features of possibly related pneumonitis occurring in patients treated with ICI with a particular focus on clinical presentation, radiologic patterns (with a double reviewing by radiologists and pulmonologists), pathology and therapeutic strategies. Results: We identified 71 patients with possibly related pneumonitis including 54 NSCLC and 13 melanoma. They mainly received PD1 inhibitors. Pneumonitis usually occurred in male, former or current smokers with a median age of 59 years. We observed grade 2/3 (n¼ 45, 65.2%) and grade 5 (n¼ 6, 8.7%) pneumonitis. The median duration time between the introduction of immunotherapy and the pneumonitis was 2.2 months [0.1-27.4]. Ground glass opacitiy on lung CT-scan were the most predominant lesion 80.9% (n¼55), followed by consolidations 44.1% (n¼30), reticulations 36.7% (n¼25) and bronchiectasis in 20.6% (n¼14). When performed, bronchoalveolar lavage (BAL) showed a Tlymphocytic alveolitis and transbronchial biopsy an inflammatory and lymphocytic infiltration. Pneumonitis treatment was steroids (86.6%) and/or antibiotics (67.6%). Immunotherapy was stopped after the pneumonitis for 65 cases (92.9%) and reintroduced for 12
January 2017
(9.4%) cases. Twenty-four patients (34.3%) were dead at the last follow-up and 46 patients (65.7%) were still alive. Among the living patients, the pneumonitis outcome was a total recovery in 12 patients, improvement in 22 patients, stability in 10 patients, worsening evolution in 1 patient (1 unknown). Causality of immunotherapy was evaluated by investigators as “possible” for 34 patients (49.3%), “probable” for 17 (24.6%), “certain” for 15 (21.7%) other causes for 3 (4.3%) and 2 unknowns. Median overall survival from the onset of pneumonitis was 6 months. Conclusion: This series, the largest to date, of immunerelated pneumonitis demonstrates that it occurs usually during the first months and displays specific radiologic features. As there is no clearly identified risk factor, oncologists should be able to detect, diagnose (with CTscan and bronchoscopy) and treat this adverse event. An early management is usually associated with a favorable outcome and requires a close collaboration between pulmonologists, radiologists and oncologists. Keywords: Melanoma, interstitial pneumonitis, Immunotherapy, lung cancer
P3.02c-033 Patterns of Progression and Management of Acquired Resistance to Anti-PD-1 Antibodies in Advanced Non-Small Cell Lung Cancer Topic: IT Antony Mersiades,1 Megan Crumbaker,1 Bo Gao,2 Adnan Nagrial,1 Rina Hui3 1Medical Oncology, Crown Princess Mary Cancer Care Centre, Westmead Hospital, Wentworthville/NSW/Australia, 2Medical Oncology, Blacktown Cancer and Haematology Centre, Blacktown/ NSW/Australia, 3Medical Oncology, Crown Princess Mary Cancer Care Centre, Westmead Hospital, Wentworthville/ Australia Background: Anti-PD-1 antibodies (pembrolizumab and nivolumab) have shown improved overall survival in second-line treatment for metastatic non-small cell lung cancer (NSCLC) with durable responses. We aimed to assess the pattern of disease progression amongst patients who initially responded to anti-PD-1 agents and their subsequent management. Methods: We retrospectively assessed all patients who commenced single-agent anti-PD-1 antibodies between June 2012 and February 2016 at a single centre. Radiological responses were assessed by the investigator using RECIST 1.1 and irRC. Progressive disease (PD)
Abstracts
S1293
patterns were defined as solitary, oligometastatic (2-3 lesions), generalized (>3 lesions), enlargement of existing or new lesions, visceral or non-visceral. Management and survival after progression were examined. Results: A total of 81 patients received single-agent pembrolizumab (n¼43) or nivolumab (n¼38). Of the seventeen (21.3%) patients achieving partial response, three were treatment-naïve, fifteen (88.2%) were former or current smokers, none had EGFR mutation or ALK translocation. The median number of disease sites at baseline was three, and two patients had stable brain metastases after radiotherapy at the commencement of anti-PD1 treatment. Ten (58.8%) responders developed acquired resistance, with a median time to progression of 20.2 months. Nine (90%) had solitary (n¼4) or oligometastatic (n¼5) progression. Five (50%) progressed only at existing sites, three (30%) developed new lesions only, and two (20%) progressed at both existing and new sites. Four (40%) progressed at non-visceral sites only, and one progressed in the brain at a previously treated site. Five (50%) patients underwent local treatment to solitary (n¼2) or oligoprogressive disease (n¼3) with all five achieving local control with radiotherapy. Seven(70%) continued anti-PD-1 agents beyond progression, while the three (30%) remaining patients did not receive any further therapy. With a median follow-up of 24.8 months, five (50%) of the patients had died, one from an infective exacerbation of COPD, one from type 1 respiratory failure, and three from disease progression. The median duration of treatment was 4.35 months (1.96 to 11.46) and the median overall survival after progression was 11.44 months. Conclusion: This study suggested that acquired resistance to anti-PD1 agents could often result in solitary or oligometastatic progression, and that CNS progression was uncommon. In a subset of patients, treatment beyond progression with or without local therapy to oligometastatic disease may provide ongoing and durable clinical benefit. Keywords: non-small cell lung cancer, Acquired resistance, anti-PD1
P3.02c-034 A Single Institution Experience with Immunotherapy as an Effective Therapy Approach of Advance Non-Small Cell Lung Cancer (NSCLC) Topic: IT Julia Martínez Pérez, Inmaculada Sanchez, Alejandro Falcon Gonzalez, Miriam Alonso,