Practice changing studies in lung cancer 2017

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Cameron Bradford
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1 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,

2 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 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 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 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 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 Time from randomisation (months) Pem-CIS Censored Eto-Cis Censored yr OS % 52% yr OS % 37% Median OS (95%CI), months Pemetrexed + cisplatin: 26.8 (20.4, 30.9) Etoposide + cisplatin: 25.0 (22.2, 29.8) Median PFS 10 and 11 months Senan, ASCO 29015

7 7 Randomized phase III comparison of standard-dose versus high-dose chemo-radiotherapy ± cetuximab for stage III NSCLC One-sided log-rank p= Median PFS 11 months One-sided log-rank, p= Bradley, Lancet Oncology 2015

8 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 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) (23 90) 45.1 Male, % WHO performance status score, %* 0 / / / 51.5 Smoking status, % Current / Former / Never 16.6 / 74.4 / / 75.1 / 8.9 Disease stage, % IIIA / IIIB 52.9 / / 45.1 Histology, % Squamous / Non-squamous 47.1 / / 57.0 PD-L1 status, % Known: TC <25% / TC 25% Unknown 39.3 / / Prior chemotherapy, % Induction / Definitive ccrt 25.8 / / 99.6 Prior radiotherapy, %* <54 Gy 54 to 66 Gy >66 to 74 Gy Best response to prior ccrt, % CR / PR / SD / PD 1.9 / 48.7 / 46.6 / / 46.8 / 48.1 / 0 Paz-Ares, ESMO 2017; Antonia, NEJM 2017

10 10 PACIFIC: Consolidation durvalumab for 1 year after chemoradiotherapy of stage III NSCLC: Progression-free survival Median PFS from start of 20 months Paz-Ares, ESMO 2017; Antonia, NEJM 2017

11 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 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 ( ) Male ( ) Female ( ) <65 years ( ) 65 years ( ) Smoker ( ) Non-smoker ( ) Stage IIIA ( ) Stage IIIB ( ) Squamous ( ) Non-squamous ( ) CR 9 7 PR ( ) SD ( ) 25% ( ) <25% ( ) Unknown ( ) Mutant ( ) Wild-type ( ) Unknown ( ) Favors durvalumab Favors placebo Paz-Ares, ESMO 2017; Antonia, NEJM 2017

13 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) ( ) P< Durvalumab (N=443)* ( ) Placebo (N=213)* Paz-Ares, ESMO 2017; Antonia, NEJM 2017

14 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 15 First TKI versus chemotherapy in EGFR mutated NSCLC Mok, NEJM 2009 Rosell, Lancet Oncol 2012

16 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 17 Major mechanisms of resistance to EGFR TKIs Yu, Clin Cancer Res 2013

18 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 19 EGFR TKIs Costa, Transl Lung Cancer Res 2015

20 Mok, NEJM Osimertinib or platinum-pemetrexed in EGFR TKI pretreated EGFR T790M positive NSCLC

21 21 FLAURA: First or third generation TKI inhibitors as first line therapy for patients with EGFR mutated NSCLC Ramalingam, ESMO 2017

22 22 FLAURA: Primary endpoint progression-free survival Ramalingam, ESMO 2017; Soria NEJM 2018

23 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= (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 Osimertinib SoC Time from first response (months) Ramalingam, ESMO 2017

24 24 FLAURA: Overall survival interim analysis Ramalingam, ESMO 2017

25 25 FLAURA: CNS activity Soria, NEJM 2018

26 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 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 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 29 Crizotinib in fist line: PRORILFE 1014 Salomon, NEJM 2014

30 30 First-line ceritinib versus platinum-based chemotherapy in advanced ALK-rearranged NSCLC (ASCEND-4): Soria, Lancet Oncol 2017

31 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 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 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 34 Optimal first line therapy? First line Crizotinib Ceritinib Second line Next-gen ALK TKI 11 months 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 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 36 ESMO clinical practice guidelines in metastatic non-squamous cell carcinoma: 1 st line therapy Novello et al, Ann Oncol 2016, eupdate 2017

37 Brahmer, WCLC KEYNOTE-024: Pembrolizumab vs platinum-based chemotherapy as for advanced NSCLC: Updated results

Brahmer, WCLC 2017 38 KEYNOTE-024: Pembrolizumab vs

38 Brahmer, WCLC KEYNOTE-024: Pembrolizumab vs platinum-based chemotherapy for advanced NSCLC: Updated results

NSCLC cohorts treated in first line with nivolumab alone or nivolumab combined with ipililumab according

39 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 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 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

42 Thomas Hart Benton America Today

Immune checkpoint inhibitors in NSCLC

1 Immune checkpoint inhibitors in NSCLC Rolf Stahel University Hospital of Zürich Zürich, November 3, 2017 2 What can we learn from the clinical experience of second line immunotherapy of advanced NSCLC?