1 Practice changing studies in lung cancer 2017 Rolf Stahel University Hospital of Zürich Cape Town, February 16, 2018
DISCLOSURE OF INTEREST Consultant or Advisory Role in the last two years I have received honoraria as a consultant at advisory boards from Abbvie, Astra Zeneca, Boehringer Ingelheim, MSD, Pfizer, Roche and Takeda. Speaker Honoraria in the last two years I have received honoraria as a speaker from Astra Zeneca, Boehringer Ingelheim, MSD and Roche. DMC in the last two years Roche and Takeda
3 Practice changing studies in lung cancer 2017 PACIFIC Trial: Stage III NSCLC FLAURA Trial: First line advanced EGFR-mutated NSCLC ALEX Trial: First line advanced ALK-rearranged NSCLC Impower150: First line advanced NSCLC
4 Treatment of locally advanced (stage III) NSCLC In multistation N2 or N3 disease, concurrent definitive CRT is preferred [I, A]. An experienced multidisciplinary team is of paramount importance in any complex multimodality treatment strategy decision, including the role of surgery in these cases [IV, C] Concurrent CRT is the treatment of choice in patients evaluated as unresectable in stage IIIA and IIIB [I, A]. If concurrent CRT is not possible for any reason sequential ChT followed by definitive RT represents a valid and effective alternative [I, A] In the stage III disease CRT strategy, two to four cycles of concomitant ChT should be delivered [I, A]. There is no evidence for further induction or consolidation ChT Postmus, Ann Oncol 2017
5 Chemo-radiotherapy: No evidence for advantage with induction or consolidation chemotherapy in stage III Carboplatin-paclitaxel induction followed by chemo-radiotherapy Concurrent PE chemo-radiotherapy followed by docetaxel consolidation Vokes, JCO 2007 Hanna, JCO 2008
6 OS results of the phase III PROCLAIM trial: Pemetrexed, cisplatin or etoposide, cisplatin plus thoracic radiation therapy followed by consolidation chemotherapy in locally advanced NSCLC 1.0 HR (95%CI) 0.98 (0.79, 1.20) Log-rank p=0.831 Survival probability Patients at risk: Pemetrexed + cisplatin Etoposide + cisplatin 0.8 0.6 0.4 0.2 0 0 12 24 36 48 60 72 Time from randomisation (months) 30 1 29 7 28 2 27 8 26 8 26 2 Pem-CIS Censored Eto-Cis Censored 23 9 23 2 22 1 21 6 19 4 20 1 17 8 17 9 15 7 16 4 2-yr OS 14 5 14 0 52% 52% 12 6 11 3 98 97 3-yr OS 75 82 67 69 40% 37% 56 56 46 49 Median OS (95%CI), months Pemetrexed + cisplatin: 26.8 (20.4, 30.9) Etoposide + cisplatin: 25.0 (22.2, 29.8) 42 46 33 31 25 26 Median PFS 10 and 11 months 19 22 14 16 10 10 3 6 1 3 0 1 0 0 Senan, ASCO 29015
7 Randomized phase III comparison of standard-dose versus high-dose chemo-radiotherapy ± cetuximab for stage III NSCLC One-sided log-rank p=0 0042 Median PFS 11 months One-sided log-rank, p=0 2938 Bradley, Lancet Oncology 2015
8 PACIFIC: Consolidation durvalumab for 1 year after chemoradiotherapy of stage III NSCLC 713 pts with stage III NSCLC after chemo-radiotherapy 2:1 durvalumab 10 mg/kg Q2w for 12 months or placebo Paz-Ares, ESMO 2017; Antonia, NEJM 2017
9 PACIFIC: Consolidation durvalumab for 1 year after chemoradiotherapy of stage III NSCLC: Baseline characteristics Durvalumab (N=476) Placebo (N=237) Age Median (range), years 65 years, % 64 (31 84) 45.2 64 (23 90) 45.1 Male, % 70.2 70.0 WHO performance status score, %* 0 / 1 49.2 / 50.4 48.1 / 51.5 Smoking status, % Current / Former / Never 16.6 / 74.4 / 9.0 16.0 / 75.1 / 8.9 Disease stage, % IIIA / IIIB 52.9 / 44.5 52.7 / 45.1 Histology, % Squamous / Non-squamous 47.1 / 52.9 43.0 / 57.0 PD-L1 status, % Known: TC <25% / TC 25% Unknown 39.3 / 24.2 36.6 44.3 / 18.6 37.1 Prior chemotherapy, % Induction / Definitive ccrt 25.8 / 99.8 28.7 / 99.6 Prior radiotherapy, %* <54 Gy 54 to 66 Gy >66 to 74 Gy 0.6 92.9 6.3 0 91.6 8.0 Best response to prior ccrt, % CR / PR / SD / PD 1.9 / 48.7 / 46.6 / 0.4 3.0 / 46.8 / 48.1 / 0 Paz-Ares, ESMO 2017; Antonia, NEJM 2017
10 PACIFIC: Consolidation durvalumab for 1 year after chemoradiotherapy of stage III NSCLC: Progression-free survival Median PFS from start of therapy @ 20 months Paz-Ares, ESMO 2017; Antonia, NEJM 2017
11 PACIFIC: Consolidation durvalumab for 1 year after chemoradiotherapy of stage III NSCLC: Frequent side effects Durvalumab (N=475) Placebo (N=234) Event Any Grade Grade 3 or 4 Any Grade Grade 3 or 4 Any event, n (%) 460 (96.8) 142 (29.9) 222 (94.9) 61 (26.1) Cough 168 (35.4) 2 (0.4) 59 (25.2) 1 (0.4) Pneumonitis/radiation pneumonitis 161 (33.9) 16 (3.4) 58 (24.8) 6 (2.6) Fatigue 113 (23.8) 1 (0.2) 48 (20.5) 3 (1.3) Dyspnea 106 (22.3) 7 (1.5) 56 (23.9) 6 (2.6) Diarrhea 87 (18.3) 3 (0.6) 44 (18.8) 3 (1.3) Pyrexia 70 (14.7) 1 (0.2) 21 (9.0) 0 Decreased appetite 68 (14.3) 1 (0.2) 30 (12.8) 2 (0.9) Nausea 66 (13.9) 0 31 (13.2) 0 Pneumonia 62 (13.1) 21 (4.4) 18 (7.7) 9 (3.8) Arthralgia 59 (12.4) 0 26 (11.1) 0 Pruritus 58 (12.2) 0 11 (4.7) 0 Rash 58 (12.2) 1 (0.2) 17 (7.3) 0 Upper respiratory tract infection 58 (12.2) 1 (0.2) 23 (9.8) 0 Constipation 56 (11.8) 1 (0.2) 20 (8.5) 0 Hypothyroidism 55 (11.6) 1 (0.2) 4 (1.7) 0 Asthenia 51 (10.7) 3 (0.6) 31 (13.2) 1 (0.4) Back pain 50 (10.5) 1 (0.2) 27 (11.5) 1 (0.4) Paz-Ares, ESMO 2017; Antonia, NEJM 2017
12 Sex PACIFIC: Consolidation durvalumab for 1 year after chemoradiotherapy of stage III NSCLC: Subgroup analysis Age at randomization Smoking status Disease stage Histology Best response to ccrt PD-L1 status EGFR status Durvalumab Placebo Unstratified HR* No. of patients (95% CI) All patients 476 237 0.55 (0.45 0.68) Male 334 166 0.56 (0.44 0.71) Female 142 71 0.54 (0.37 0.79) <65 years 261 130 0.43 (0.32 0.57) 65 years 215 107 0.74 (0.54 1.01) Smoker 433 216 0.59 (0.47 0.73) Non-smoker 43 21 0.29 (0.15 0.57) Stage IIIA 252 125 0.53 (0.40 0.71) Stage IIIB 212 107 0.59 (0.44 0.80) Squamous 224 102 0.68 (0.50 0.92) Non-squamous 252 135 0.45 (0.33 0.59) CR 9 7 PR 232 111 0.55 (0.41 0.75) SD 222 114 0.55 (0.41 0.74) 25% 115 44 0.41 (0.26 0.65) <25% 187 105 0.59 (0.43 0.82) Unknown 174 88 0.59 (0.42 0.83) Mutant 29 14 0.76 (0.35 1.64) Wild-type 315 165 0.47 (0.36 0.60) Unknown 132 58 0.79 (0.52 1.20) 0.25 0.5 1 2 Favors durvalumab Favors placebo Paz-Ares, ESMO 2017; Antonia, NEJM 2017
13 PACIFIC: Consolidation durvalumab for 1 year after chemoradiotherapy of stage III NSCLC: Antitumor activity Objective Response Time to death or distant metastases % patients (95% CI) 35 30 25 20 15 10 5 0 (24.28 32.89) P<0.001 28.4 16.0 Durvalumab (N=443)* (11.31 21.59) Placebo (N=213)* Paz-Ares, ESMO 2017; Antonia, NEJM 2017
14 Practice changing studies in lung cancer 2017 PACIFIC Trial: Stage III NSCLC FLAURA Trial: First line advanced EGFR-mutated NSCLC ALEX Trial: First line advanced ALK-rearranged NSCLC Impower150: First line advanced NSCLC
15 First TKI versus chemotherapy in EGFR mutated NSCLC Mok, NEJM 2009 Rosell, Lancet Oncol 2012
16 Patients with EGFR mutated NSCLC EGFR TKIs represent the standard of care as first-line treatment of advanced EGFR-mutated NSCLC [I, A] Patients with PS 3-4 may also be offered an EGFR TKI, as they are likely to receive a similar clinical benefit to patients with good PS [II, A] A phase II study has demonstrated benefit in PFS in patients who continued first-line erlotinib beyond radiological progression; therefore, this strategy could be considered in patients with asymptomatic progression There is no data to support continuation of the EGFR TKI with platinumbased chemotherapy [I, A] Novello, Ann Oncol 2016
17 Major mechanisms of resistance to EGFR TKIs Yu, Clin Cancer Res 2013
18 Patients with EGFR-mutated NSCLC Patients who progress after an EGFR TKI should undergo a rebiopsy to perform molecular analysis specifically looking for EGFR T790M mutation In patients with clinically relevant progression after previous treatment with an EGFR TKI and confirmed T790M mutation, treatment with osimertinib should be considered [III, A] Novello, Ann Oncol 2016
19 EGFR TKIs Costa, Transl Lung Cancer Res 2015
Mok, NEJM 2017 20 Osimertinib or platinum-pemetrexed in EGFR TKI pretreated EGFR T790M positive NSCLC
21 FLAURA: First or third generation TKI inhibitors as first line therapy for patients with EGFR mutated NSCLC Ramalingam, ESMO 2017
22 FLAURA: Primary endpoint progression-free survival Ramalingam, ESMO 2017; Soria NEJM 2018
23 FLAURA: Response rate and response duration Osimertinib (n=279) SoC (n=277) ORR (95% CI) 80% (75, 85) 76% (70, 81) Odds ratio # (95% CI) Complete response ǂ, n (%) Partial response ǂ, n (%) Stable disease 6 weeks, n (%) Progression, n (%) Not evaluable, n (%) Estimated remaining in response, (95% CI) 12 months 18 months 1.28 (0.85, 1.93); p=0.2335 7 (3) 216 (77) 47 (17) 3 (1) 6 (2) 64% (58, 71) 49% (41, 56) 4 (1) 206 (74) 46 (17) 14 (5) 7 (3) 37% (31, 44) 19% (13, 26) Probability of remaining in response No. at risk Osimertinib SoC 1.0 0.9 Osimertinib SoC 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 0 3 6 9 12 15 18 21 24 27 Time from first response (months) 223 210 205 180 181 136 160 95 128 69 82 39 40 17 14 4 0 1 0 0 Ramalingam, ESMO 2017
24 FLAURA: Overall survival interim analysis Ramalingam, ESMO 2017
25 FLAURA: CNS activity Soria, NEJM 2018
26 First TKIs in EGFR mutated NSCLC: Current status EURTAC: Erlotinib median PFS 9.7 months FLAURA: Osimertinib median PFS 18.9 months Rosell, Lancet Oncol 2012 Soria, NEJM 2018
27 Practice changing studies in lung cancer 2017 PACIFIC Trial: Stage III NSCLC FLAURA Trial: First line advanced EGFR-mutated NSCLC ALEX Trial: First line advanced ALK-rearranged NSCLC Impower150: First line advanced NSCLC
28 Patients with ALK-rearranged NSCLC First-line treatment with crizotinib is the preferred treatment of patients with ALK-rearranged NSCLC [I, A] Several alternative ALK inhibitors are currently in clinical development, with broader activity against a number of mutated ALK genes and mainly characterised by higher brain activity In patients who progress after an ALK TKI, second-generation ALK inhibitors such ceritinib are recommended [III, A] Novello, Ann Oncol 2016
29 Crizotinib in fist line: PRORILFE 1014 Salomon, NEJM 2014
30 First-line ceritinib versus platinum-based chemotherapy in advanced ALK-rearranged NSCLC (ASCEND-4): Soria, Lancet Oncol 2017
31 Alectinib vs crizotinib in treatment-naïve advanced ALK+ NSCLC: primary results of the global phase III ALEX study Shaw, ASCO 2017; Peters, NEJM 2017
32 Alectinib vs crizotinib in treatment-naïve advanced ALK+ NSCLC: primary results of the global phase III ALEX study Shaw, ASCO 2017; Peters, NEJM 2017
33 Alectinib vs crizotinib in treatment-naïve advanced ALK+ NSCLC: primary results of the global phase III ALEX study: CNS activity Shaw, ASCO 2017; Peters, NEJM 2017
34 Optimal first line therapy? First line Crizotinib Ceritinib Second line Next-gen ALK TKI 11 months 18 20 months (combined PFS) First line 16.6 months (single PFS) Other ALK TKI Chemotherapy Immunotherapy? Other ALK TKI Chemotherapy Immunotherapy? Alectinib brigatinib/lorlatinib? 25.7 months (single PFS) Other ALK TKI Chemotherapy Immunotherapy?
35 Practice changing studies in lung cancer 2017 PACIFIC Trial: Stage III NSCLC FLAURA Trial: First line advanced EGFR-mutated NSCLC ALEX Trial: First line advanced ALK-rearranged NSCLC Impower150: First line advanced NSCLC
36 ESMO clinical practice guidelines in metastatic non-squamous cell carcinoma: 1 st line therapy Novello et al, Ann Oncol 2016, eupdate 2017
Brahmer, WCLC 2017 37 KEYNOTE-024: Pembrolizumab vs platinum-based chemotherapy as for advanced NSCLC: Updated results
Brahmer, WCLC 2017 38 KEYNOTE-024: Pembrolizumab vs platinum-based chemotherapy for advanced NSCLC: Updated results
39 Combination therapies: Early results in first line therapy of advanced NSCLC Randomized phase-2 study of first line chemotherapy with or without pembrolizumab (no restriction regarding PD-L1 expression) NSCLC cohorts treated in first line with nivolumab alone or nivolumab combined with ipililumab according to PD-L1 expression Langer, Lancet Oncol 2016 Hellmann, Lancet Oncol 2016 Phase III KEYNOTE-189 CheckMate 227
40 Primary PFS analyses of a randomized phase III study of carboplatin and paclitaxel +/ bevacizumab, with or without atezolizumab in 1L non-squamous metastatic NSCLC (IMpower150) Reck, ESMO IO 2017
41 Primary PFS analyses of a randomized phase III study of carboplatin and paclitaxel +/ bevacizumab, with or without atezolizumab in 1L non-squamous metastatic NSCLC (IMpower150) Reck, ESMO IO 2017
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