chemotherapeutic and immunotherapeutic approaches to wild ...€¦ · press release (october 18,...

Chemotherapeutic and Immunotherapeutic Approaches to

Wild-Type NSCLC, SCLC and Mesothelioma

David R Spigel, MDProgram Director, Lung Cancer Research

Sarah Cannon Research InstituteNashville, Tennessee

Disclosures

Advisory Committee

Bristol-Myers Squibb Company, Genentech BioOncology, Novartis Pharmaceuticals Corporation, Pfizer Inc, Roche Laboratories Inc

Data and Safety Monitoring Board Merck

Reck M et al. N Engl J Med 2016;[Epub ahead of print]; Proc ESMO 2016;Abstract LBA8_PR.

Phase III KEYNOTE-024 Trial: Efficacy

Reck M et al. N Engl J Med 2016;[Epub ahead of print].

• Superior PFS with high PD-L1 expression levels• ORR = 45% (Pembro) vs 28% (Chemo); p = 0.0011• Median OS was not reached in either arm.

– 6-mo OS = 80.2% (Pembro) vs 72.4% (Chemo); HR = 0.60; p = 0.005

Median PFS (n = 154) = 10.3 mo

Median PFS (n = 151) = 6.0 mo

Hazard ratio for disease progression or death, 0.50P < 0.001

FDA Approval of Pembrolizumab as First-Line Therapy for Patients with PD-L1-Positive NSCLC

“On October 24, 2016, the US Food and Drug Administration approved pembrolizumab for the treatment of patients with metastatic non-small cell lung cancer (NSCLC) whose tumors express PD-L1 [Tumor Proportion Score ≥50%] as determined by an FDA-approved test.

This is the first FDA approval of a checkpoint inhibitor for first-line treatment of lung cancer. This approval also expands the indication in second-line treatment of lung cancer to include all patients with PD-L1-expressing NSCLC.”

http://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm526430.htm

Background• RPIII industry-sponsored trial to assess the role of

pembrolizumab in the first-line treatment of Stage IV PD-L1+ NSCLC

Study/Conduct• N = 1,934 screened in 16 countries to enroll 305 patients• Enrolled 9/14-10/15• Stage IV NSCLC• ECOG PS 0-1• Pembrolizumab 200 mg (35 cycles) vs 1 of 5 platinum

doublets x 4-6 cycles (carbo/pem, cis/pem, carbo/gem, cis/gem, carbo/pac)

• Primary Aim: PFS (central blinded review)• Trial stopped early for futility

Editorial

Results• PFS: HR 0.5, median 10.3 vs 6.0 mo• OS: HR 0.60; median OS not reached in either arm• ORR: 45 vs 28%• TRAEs lower

Editorial (continued)

Take Home• Pembrolizumab should be considered a standard

first-line treatment for eligible patients• We still do not know if a patient would do just as well

to receive chemotherapy followed by a checkpoint inhibitor (44% on chemotherapy crossed over to pembrolizumab)

• 305/1,934 (16%) patients had samples that could be assessed for PD-L1

• No comparison with a Bev regimen• ‘Negative’ patients who do not qualify for up-front

pembrolizumab are still eligible for nivolumab/atezolizumab as a later line of therapy


Langer C et al. Lancet Oncol 2016;[Epub ahead of print]; Proc ESMO 2016;Abstract LBA46_PR.

KEYNOTE-021: Efficacy of Pembro/Carbo/Pem(Pembro/CP) vs CP

Langer C et al. Lancet Oncol 2016;[Epub ahead of print]; Proc ESMO 2016;Abstract LBA46_PR.

• ORR = 55% (Pembro/CP) vs 29% (CP); p = 0.0016• Higher response rate (~80%) for Pembro/CP with ≥50% PD-L1 expression• 6-mo OS = 92% in both groups

Median HR

Pembro/CP (n = 60) 13.0 mo 0.53

CP (n = 63) 8.9 mo P = 0.0102

Background• RPII industry-sponsored trial to assess the role of

pembrolizumab and chemotherapy vs chemotherapy in the first-line treatment of Stage IV nonsquamousNSCLC

Study/Conduct• N = 123 enrolled in 2 countries• Enrolled 11/14-1/16• Stage IIIB/IV nonsquamous NSCLC• ECOG PS 0-1• Pembrolizumab 200 mg (2 yrs) + carbo/pemetrexed

(4 cycles + pem maintenance) vs chemotherapy alone • Primary Aim: ORR (blinded independent central

review [BICR])

Editorial

Results• ORR: 55 vs 29% (PD-L1 <1%: 57% vs 13%; ≥1%: 54%

vs ?; 1%-49%: 26% vs 39%; ≥50%: 80% vs 35%)• PFS: HR 0.53, median 13 vs 8.9 mo• OS: HR 0.9• Severe TRAEs similarTake Home• Pembrolizumab + chemotherapy appears to be more

active than chemotherapy alone• But this trial is small and PD-L1 subsets are very small • Await Phase III data (KEYNOTE-189 and 407

squamous NSCLC with carbo/pac or nab-pac trials ongoing)


CheckMate 026: A Phase 3 Trial of Nivolumab vs Investigator's Choice (IC) ofPlatinum-Based Doublet Chemotherapy (PT-DC) as First-Line Therapy for Stage IV/Recurrent Programmed Death Ligand 1 (PD-L1)-Positive NSCLC

Socinski M et al. Proc ESMO 2016;Abstract LBA7_PR.

CheckMate 026: Efficacy and Safety

Socinski M et al. Proc ESMO 2016;Abstract LBA7_PR.

• In patients with ≥5% PD-L1 expression (n = 423), nivolumab did not improve OS (HR, 1.02; p = 0.25) or ORR.

• Safety results of nivolumab were consistent with the known profile.

• Fewer Grade 3-4 AEs with nivolumab than with chemotherapy.

Background• PIII industry-sponsored trial to assess the role of

nivolumab vs chemotherapy in the first-line treatment of Stage IV NSCLC

Study/Conduct• N = 541 enrolled (global)• Enrolled 9/14-10/15• Stage IV NSCLC• PD-L1 ≥1%• Nivolumab 3 mg/kg (48 weeks) vs platinum doublet up to

6 cycles (carbo/pem, cis/pem, carbo/gem, cis/gem, carbo/pac)

• Primary Aim: PFS (PD-L1 >5%) — BICR• Crossover on the chemotherapy arm• Trial stopped early for futility

Editorial

Results• Nivo arm had fewer female patients, 32% vs 45%;

fewer patients with PD-L1 expression: ≥25%, 49% vs 61%; ≥50%, 33% vs 47%; ≥75%, 21% vs 27%

• PFS: HR 1.15, median 4.2 vs 5.9 mo• OS: HR 1.02, median OS 14 vs 13 mo• ORR: 26% vs 34%• TRAEs any/severe: 71/18 vs 92%/51%


Take Home• Nivolumab is not superior to chemotherapy —

regardless of PD-L1 expression• This trial was not designed to assess noninferiority• Nivolumab remains a drug for patients in the second

line and beyond


CheckMate 012: Safety and Efficacy of First-Line (1L) Nivolumab (nivo;N) and Ipilimumab (ipi;I) in Advanced (adv) NSCLC

Hellmann MD et al. Proc ASCO 2016;Abstract 3001.

CheckMate 012: Efficacy by Tumor PD-L1 Expression

Nivo 3 q2w + Ipi 1 q12w

(n = 38)

Nivo 3 q2w + Ipi 1 q6w(n = 39)

Nivo 3 q2w(n = 52)

ORR<1% PD-L1≥1% PD-L1≥50% PD-L1

30%57%

100%

0%57%86%

14%28%50%

Median PFS<1% PD-L1≥1% PD-L1≥50% PD-L1

4.7 mo8.1 mo

13.6 mo

2.4 mo10.6 mo

NR

6.6 mo3.5 mo8.4 mo

1-year OS rate<1% PD-L1≥1% PD-L1≥50% PD-L1

NC90%NC

NC83%

100%

79%69%83%

Hellmann MD et al. Proc ASCO 2016;Abstract 3001.

* NC = not calculated when >25% of patients are censored

Press Release (October 18, 2016)Atezolizumab: First Anti-PD-L1 Immunotherapy Approved for Metastatic NSCLC

“The US FDA approved atezolizumab for the treatment of people with metastatic NSCLC who have disease progression during or following platinum-containing chemotherapy, and have progressed on an appropriate FDA-approved targeted therapy if their tumor has EGFR or ALK gene abnormalities.

“This approval is based on results from the randomized Phase III OAK and Phase II POPLAR studies…

The [OAK] study enrolled people regardless of their PD-L1 status and included both squamous and non-squamous disease types.”

https://www.gene.com/media/press-releases/14641/2016-10-18/fda-approves-genentechs-cancer-immunothe

Background• PI industry-sponsored trial to assess the role of

nivolumab + ipilimumab in the first-line treatment of Stage IV NSCLC: Cohort update

Study/Conduct• N = 77• Stage IIIB/IV NSCLC• ECOG PS 0-1• Nivo 3/ipi 1 q12wk; nivo 3/ipi 1 q6wk• Primary Aim: Safety and tolerability

Editorial

Results• ORR: 47%, 39% (PD-L1 ≥50%-92%, 50%)• PFS: Median 8.1 mo, 3.9 mo• OS: 1 year – NC/69%• TRAEs: Any grade/severe 82%/37%, 72%/33%• TRAEs leading to discontinuation: Any grade/severe

11%/5%, 13%/8%


Take Home• Nivo/ipi appears to be more active than nivo alone

(20% — second line and beyond)• PD-L1 status may not matter with the ipi combination• Await Phase III trials• Toxicity is high (but manageable) — may be a serious

barrier to development (or use over pembrolizumabalone)


Primary Analysis from OAK, A Randomized Phase III Study Comparing Atezolizumabwith Docetaxel in 2L/3L NSCLC

Barlesi F et al. Proc ESMO 2016;Abstract LBA44_PR.

OAK: Efficacy Results

Barlesi F et al. Proc ESMO 2016;Abstract LBA44_PR.

• OS was improved regardless of PD-L1 expression levels. • There was pronounced benefit in patients with ≥50% PD-L1 expression. • OS benefit was observed in all subgroups except EGFR-mutant disease.

OS (nonsquamous)HR, 0.73P = 0.0015Minimum follow up = 19 months

Background• PIII industry-sponsored trial to assess the role of

atezolizumab vs chemotherapy in the second-line treatment of Stage IV NSCLC

Study/Conduct• N = 850 enrolled (global)• Enrolled 9/14-10/15• Stage IV NSCLC• Any PD-L1 status• Atezolizumab 1,200 mg q3wk vs docetaxel 75• Primary Aim: OS (ITT), OS (PD-L1 >1% TC or IC) —

BICR• Crossover on the chemotherapy arm• Trial stopped early for futility

Editorial

Results• PFS: HR 1.15, median 4.2 vs 5.9 mo• OS: HR 0.73, median OS 13.8 vs 9.6 mo• OS PD-L1 ≥1% TC or IC: HR 0.74; median OS 15.7 vs

10.3 mo• OS PD-L1 <1% TC or IC: HR 0.75; median OS 12.6 vs

8.9 mo• OS PD-L1 ≥50% TC or IC: HR 0.41; median OS 20.5 vs

8.9 mo• PFS PD-L1 any PD-L1 TC or IC: HR 0.95; median OS

2.8 vs 4 mo• ORR: 52 vs 18%• TRAEs any/severe: 64/15 vs 86%/43%


Take Home• Atezolizumab is superior to docetaxel in refractory

NSCLC — regardless of PD-L1 status or histology• Atezolizumab may be preferred over nivolumab in the

community due to q3wk dosing• No (yet) known difference between PD-1 and PD-L1

inhibitors


www.thelancet.com/oncology Vol 17 March 2016 299

Articles

Lancet Oncol 2016; 17: 299–308

Published OnlineFebruary 5, 2016http://dx.doi.org/10.1016/S1470-2045(15)00544-6

See Comment page 259

*Joint first authors

H Lee Moffitt Cancer Center, Tampa, FL, USA (Prof S Antonia MD); Yale University, Yale Cancer Center, New Haven, CT, USA (S B Goldberg MD); The Angeles Clinic and Research Institute, Los Angeles, CA, USA (A Balmanoukian MD); Memorial Sloan-Kettering Cancer Center and Weill Cornell Medical College, New York, NY, USA (J E Chaft MD); Earle A Chiles Research Institute, Providence Cancer Center, Portland, OR, USA (R E Sanborn MD); MedImmune, Gaithersburg, MD, USA (A Gupta MD, R Narwal PhD, K Steele PhD, Y Gu PhD, J J Karakunnel MD); and Columbia University Medical Center, New York, NY, USA (Prof N A Rizvi MD)

Correspondenceto:Prof Naiyer Rizvi, Columbia University Medical Center, Division of Hematology-Oncology, New York, NY 10032, [email protected]

Safety and antitumour activity of durvalumab plus tremelimumab in non-small-cell lung cancer: a multicentre, phase 1b studyScott Antonia*, Sarah B Goldberg*, Ani Balmanoukian, Jamie E Chaft, Rachel E Sanborn, Ashok Gupta, Rajesh Narwal, Keith Steele, Yu Gu, Joyson J Karakunnel, Naiyer A Rizvi

SummaryBackground PD-L1 and CTLA-4 immune checkpoints inhibit antitumour T-cell activity. Combination treatment with the anti-PD-L1 antibody durvalumab and the anti-CTLA-4 antibody tremelimumab might provide greater antitumour activity than either drug alone. We aimed to assess durvalumab plus tremelimumab in patients with advanced squamous or non-squamous non-small-cell lung cancer (NSCLC).

Methods We did a multicentre, non-randomised, open-label, phase 1b study at fi ve cancer centres in the USA. We enrolled immunotherapy-naive patients aged 18 years or older with confi rmed locally advanced or metastatic NSCLC. We gave patients durvalumab in doses of 3 mg/kg, 10 mg/kg, 15 mg/kg, or 20 mg/kg every 4 weeks, or 10 mg/kg every 2 weeks, and tremelimumab in doses of 1 mg/kg, 3 mg/kg, or 10 mg/kg every 4 weeks for six doses then every 12 weeks for three doses. The primary endpoint of the dose-escalation phase was safety. Safety analyses were based on the as-treated population. The dose-expansion phase of the study is ongoing. This study is registered with ClinicalTrials.gov, number NCT02000947.

Findings Between Oct 28, 2013, and April 1, 2015, 102 patients were enrolled into the dose-escalation phase and received treatment. At the time of this analysis (June 1, 2015), median follow-up was 18·8 weeks (IQR 11–33). The maximum tolerated dose was exceeded in the cohort receiving durvalumab 20 mg/kg every 4 weeks plus tremelimumab 3 mg/kg, with two (30%) of six patients having a dose-limiting toxicity (one grade 3 increased aspartate aminotransferase and alanine aminotransferase and one grade 4 increased lipase). The most frequent treatment-related grade 3 and 4 adverse events were diarrhoea (11 [11%]), colitis (nine [9%]), and increased lipase (eight [8%]). Discontinuations attributable to treatment-related adverse events occurred in 29 (28%) of 102 patients. Treatment-related serious adverse events occurred in 37 (36%) of 102 patients. 22 patients died during the study, and three deaths were related to treatment. The treatment-related deaths were due to complications arising from myasthenia gravis (durvalumab 10 mg/kg every 4 weeks plus tremelimumab 1 mg/kg), pericardial eff usion (durvalumab 20 mg/kg every 4 weeks plus tremelimumab 1 mg/kg), and neuromuscular disorder (durvalumab 20 mg/kg every 4 weeks plus tremelimumab 3 mg/kg). Evidence of clinical activity was noted both in patients with PD-L1-positive tumours and in those with PD-L1-negative tumours. Investigator-reported confi rmed objective responses were achieved by six (23%, 95% CI 9–44) of 26 patients in the combined tremelimumab 1 mg/kg cohort, comprising two (22%, 95% CI 3–60) of nine patients with PD-L1-positive tumours and four (29%, 95% CI 8–58) of 14 patients with PD-L1-negative tumours, including those with no PD-L1 staining (four [40%, 95% CI 12–74] of ten patients).

Interpretation Durvalumab 20 mg/kg every 4 weeks plus tremelimumab 1 mg/kg showed a manageable tolerability profi le, with antitumour activity irrespective of PD-L1 status, and was selected as the dose for phase 3 studies, which are ongoing.

Funding MedImmune.

IntroductionDrugs that block the PD-L1/PD-1 pathway act in the tumour microenvironment and prevent inhibition of T-cell function, whereas drugs that block the CTLA-4 pathway act in the lymphoid compartment to expand the number and repertoire of tumour-reactive T cells.1,2 Thus, combined blockade of both pathways targets both compartments. The clinical benefi t of PD-L1/PD-1 pathway inhibition has been shown in roughly 10–30% of PD-L1 unselected patients with non-small-cell lung cancer (NSCLC).3 However, fewer than half of NSCLC patients

express PD-L1 on their tumour cells,4 and most patients (including PD-L1-positive and PD-L1-negative) do not respond to PD-1 pathway blockade alone, representing an opportunity for combination treatments. In studies of nivolumab plus ipilimumab for melanoma5 and NSCLC,6 durable responses were reported in both PD-L1-positive and PD-L1-negative patients. Tolerability of this treat ment combination seemed to be dose-dependent and schedule-dependent, highlighting the need for optimum dose selection to minimise the toxic eff ects of combination regimens while maintaining clinical activity.

Lancet Oncol 2016;17(3):299-308.

Response to Durvalumab (D) / Tremelimumab (T)

• Clinical activity observed both in patients with PD-L1+ and PD-L1- tumors• Dose selected for Phase III studies: D 20 mg/kg + T 1 mg/kg

Antonia S et al. Lancet Oncol 2016;17(3):299-308.

ORR (T 1 mg/kg cohort, n = 26): 23%

• Dose escalation: D 3-20 mg/kg q4wk or 10 mg/kg q2wk plusT 1-10 mg/kg q4wk

Background• PIb industry-sponsored trial to assess the role of

durvalumab/tremelimumab in Stage IV NSCLCStudy/Conduct• N = 102• Enrolled 10/13-4/15• Stage IIIB/IV NSCLC• 0-4+ prior lines of therapy• Durva 3 mg/kg, 10 mg/kg, 15 mg/kg, 20 mg/kg q4wk or

10 mg/kg q2wk + Trem 1 mg/kg, 3 mg/kg or 10 mg/kg q4wk

• Primary Aim: Safety and tolerability

Editorial

Results• RP2D: Durva 20 mg/kg q4wk + Trem 1 mg/kg; ORR:

47%, 39% (PD-L1 ≥50%-92%, 50%)• ORR: 0%-23%• TRAEs: Severe, diarrhea 7%-18%, pneumonitis 6%,

transaminitis 3%-4%• TRAEs leading to discontinuation: 28%


Take Home• Durva/Trem is an active regimen — with ORRs that

appear higher with Durva alone• Benefit not clearly associated with PD-L1 expression• Diarrhea/colitis and TRAEs leading to discontinuation

are of concern• Phase III trials in first line pending (NEPTUNE and

MYSTIC)


E1505: Adjuvant chemotherapy +/-bevacizumab for early stage NSCLC —Outcomes based on chemotherapy subsets

Wakelee HA et al. Proc ASCO 2016;Abstract 8507.

E1505: Overall Survival by Chemotherapy Group

Wakelee HA et al. Proc ASCO 2016;Abstract 8507.

Nonsquamous

Nonsquamous HR, p-value*Cis/Docetaxel 1.3, 0.09Cis/Gemcitabine 1.14, 0.45Cis/Pemetrexed 0.97, 0.83

No differences in overall survival were observed between chemotherapy regimens in the squamous cell population

*Cis/Vinorelbine as reference

Background• RPIII cooperative group pivotal trial to assess the role

of bevacizumab (Bev) in the adjuvant NSCLC settingStudy/Conduct• N = 1,501 — Enrolled 7/07 – 9/13• Stage IB (4 cm/+- IIIA)• Any NSC histology• Choice of chemotherapy platform regimen

(cisplatin/vinorelbine [V], docetaxel [D], gemcitabine [G], pemetrexed [P])

• Primary Aim: Overall survival (OS)• Trial stopped early for futility• Not designed to allow meaningful chemotherapy

subset comparisons

Editorial

Results• 475 OS events (70% of planned)• IB 26%, II 44%, IIIA 30%• V 25%, D 23%, G 19%, P 33%• OS: HR 0.99; median OS chemo alone NR,

Bev 86 mo• DFS: HR 0.99• Pooled analyses: No differences• Safety: Neutropenia and HTN higher with Bev


Take Home• There is no role for Bev in the adjuvant treatment of

NSCLC• The enthusiasm for any adjuvant therapy has waned

since the original pivotal trials. We now focus on Stage II-IIIA. Carboplatin is frequently used at some point in care. RT is used judiciously in node positive settings. The next big questions (and ongoing trials are addressing) are in EGFR and ALK settings —with perhaps the biggest question being around the role of immunotherapy in the early stage setting (including recent limited data with nivolumab in the preop setting (Forde, ESMO 2016)


PROCLAIM: Results Summary

Adverse events (Grade 3/4)

Overall study

Pem-Cis (n = 283) Eto-Cis (n = 272)Neutropenia 24.4% 44.5%

Febrile neutropenia 5.3% 9.6%

Thrombocytopenia 6.7% 10.7%

Pneumonitis 1.8% 2.6%

• No significant difference in OS between Pem-Cis and Eto-Cis arms (p = 0.831)• Enrollment was stopped early because of futility• Incidence of drug-related Grade 3/4 events was significantly lower in the Pem-

Cis arm versus the Eto-Cis arm (64% vs 76.8%) during the overall study period.

Senan S et al. J Clin Oncol 2016;34(9):953-62.

Background• RPIII industry-sponsored trial to assess the role of

pemetrexed (Pem) in the management of Stage III nonsquamous NSCLC

Study/Conduct• N = 598• Enrolled 10/08 – 8/12• Stage IIIA/B• Cisplatin/Pem x 3 cycles with Pem consolidation (4

cycles) vs cisplatin/etoposide x 2 cycles + RT with chemotherapy consolidation

• Primary Aim: OS• Trial stopped early for futility• Not designed for noninferiority comparison

Editorial

Results• OS: HR 0.98; median OS 27 vs 25 mo• Pem with fewer dose-reducing-SAEs (neutropenia)Take Home• Pem is not better than etoposide for Stage III disease• This trial does not justify the use of Pem in Stage III

disease• Carboplatin/paclitaxel still commonly used in the

community• Immunotherapy (durvalumab — the Pacific trial) is

the next big trial that can impact care (no consolidation therapy used)


chemotherapeutic and immunotherapeutic approaches to wild ...€¦ · press release (october 18,...

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