prIME LINES

October 2016

TABLE OF CONTENTS

• PHARMA NEWS • CONFERENCE NEWS FROM THE 2016 EUROPEAN SOCIETY FOR

MEDICAL ONCOLOGY CONGRESS UPCOMING prIME EVENTS

• OTHER prIME ACTIVITIES

prIME Lines – October 2016 Issue

PHARMA NEWS

Blood-Based T790M Companion Diagnostic Test for Osimertinib Approved in the

United States

On 29 September 2016, the United States (US) Food and Drug Administration (FDA)

approved cobas® EGFR Mutation Test v2 (Roche Molecular Systems), a companion

diagnostic test for osimertinib (Tagrisso®; AstraZeneca) that uses either tissue or a blood

sample to confirm the presence of the T790M resistance mutation in patients with

epidermal growth factor receptor (EGFR) mutation–positive non-small cell lung cancer

(NSCLC) who have progressed on treatment with an EGFR tyrosine kinase inhibitor

(TKI). T790M mutations occur in nearly two-thirds of patients who have progressed on a

first-line EGFR TKI. Presence of T790M was shown to be a predictive biomarker for

osimertinib, an oral irreversible third generation EGFR TKI. Blood-based genotyping is a

noninvasive method to identify T790M mutation in patients who cannot undergo tissue

biopsy. Importantly, while a positive result by blood genotyping confirms presence of a

T790M mutation, a negative blood test cannot rule out such mutation because the

sensitivity of blood-based testing is only about 70%. Thus, for T790M-negative patients

as determined by blood genotyping, biopsy and tissue testing should be reconsidered.

EMA Recommends Approval of Three Agents in September

On 15 September 2016, the European Medicines Agency (EMA) issued three positive

opinions for the approval of new agents.

• Olaratumab (Lartruvo™; Eli Lilly), a human anti-platelet derived growth factor

receptor alpha (PDGFR-α) monoclonal antibody, in combination with

doxorubicin, was recommended for approval for the treatment of patients with

advanced soft tissue sarcoma (STS) not amenable to curative treatment with

surgery or radiotherapy who have not previously received doxorubicin. PDGFR-α

is overexpressed in multiple tumor types, including STS, and expression is

associated with an increased metastatic potential. The EMA’s positive opinion

was based on results from the phase II, randomized JGDG study that compared

olaratumab in combination with doxorubicin to doxorubicin alone in 133 patients

STS, which were published in The Lancet on 9 June 2016. The median

progression free survival (PFS) was 6.6 months with the olaratumab/doxorubicin

combination, compared to 4.1 months with doxorubicin alone (hazard ratio [HR]

0.67, P = .0615). In addition, treatment with the olaratumab combination resulted

in an impressive 11.8-month improvement in median overall survival (OS; HR

0.46; P = .0003). The most common grade ≥3 adverse events (AE) of the

combination were neutropenia, anemia, fatigue, and musculoskeletal pain.

However, there was no increase in febrile neutropenia or treatment

discontinuation rate. Results from the fully accrued, phase III ANNOUNCE trial

evaluating this regimen in STS are eagerly awaited. In addition to the EMA

recommendation, on 19 October 2016 olaratumab in combination with

doxorubicin received accelerated FDA approval for the same indication.

• The cyclin-dependent kinase (CDK) 4/6 inhibitor palbociclib (Ibrance®;

Pfizer) received a positive opinion for approval for the treatment of hormone

receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-

negative, locally advanced or metastatic breast cancer, either as initial therapy in

combination with an aromatase inhibitor or in combination with fulvestrant in

women who have received prior endocrine therapy. The approval is based on

results of two phase III randomized clinical trials, PALOMA-2 and PALOMA-3.

• Finally, the EMA recommended conditional approval for the oral proteasome

inhibitor ixazomib (Ninlaro®; Takeda Oncology) in combination with

lenalidomide and dexamethasone for the treatment of patients with multiple

myeloma who have received ≥1 prior therapy. The positive opinion for approval

was based on results from the pivotal phase III TOURMALINE-MM1 trial in

which ixazomib in combination with lenalidomide plus dexamethasone

demonstrated a 6-month improvement in PFS when compared to placebo and

lenalidomide plus dexamethasone.

CONFERENCE NEWS FROM THE 2016 EUROPEAN SOCIETY FOR

MEDICAL ONCOLOGY CONGRESS

The 41st European Society for Medical Oncology (ESMO) Congress, which is one of the

largest European platforms for presenting ground-breaking data to a global audience, was

held in Copenhagen, Denmark, from 7-11 October. More than 20,500 international

delegates from 124 countries attended the 2016 Congress, which featured 194 scientific

and educational sessions. Among 1639 abstracts accepted, there were 47 late-breaking

abstracts, 12 of which were presented during three overflowing Presidential Symposia.

Several of the presented studies are practice changing. Targeted therapy and

immunotherapy were, once again, center stage at the meeting, with key presentations

across a number of tumor types. This newsletter is dedicated to summaries of some of the

most compelling abstracts presented at the ESMO Congress this year.

Breast Cancer

CDK4/6 Inhibitor in Combination With Endocrine Therapy: A Game-Changer for

Advanced HR+/HER2- Breast Cancer

Results from the phase III MONALEESA-2 trial demonstrated that the addition of the

CDK4/6 inhibitor ribociclib to letrozole significantly improved PFS compared to

letrozole alone in 668 previously untreated postmenopausal women with

HR-positive/HER2-negative advanced breast cancer. Gabriel Hortobagyi, MD (The

University of Texas, MD Anderson Cancer Center, Houston, Texas, United States),

presented results of this study, which was simultaneously published in The New England

Journal of Medicine (8 October 2016 [Epub ahead of print]). At 15.3 months follow-up,

PFS in patients receiving ribociclib plus letrozole has not been reached, compared with

14.7 months in patients receiving letrozole alone (HR 0.556, 1-sided P = .00000329). The

PFS improvement was seen in all prespecified patient subgroups. Ribociclib treatment

also resulted in significant improvements in overall response rate (ORR) in all patients

(41% vs 28%; P = .000155) and in patients with measurable disease (53% vs 37%;

P = .00028). The AEs associated with ribociclib were predictable and managed with dose

reductions. The most common grade 3/4 AEs occurring in ≥5% of patients included

neutropenia (59.6%), leukopenia (21.2%), lymphopenia (6.9%), and alanine

aminotransferase (ALT) increase (9.3%). In his discussion, Stephen Johnston, MD, PhD

(Royal Marsden NHS Foundation Trust, London, United Kingdom), declared that, based

on substantial improvements in PFS in two large randomized trials (MONALEESA and

PALOMA-2) in similar patient population, the combination of a CDK4/6 inhibitor with

endocrine therapy should be considered a “game-changer” in the treatment of advanced,

HR-positive, HER2-negative breast cancer. He indicated that the next questions to be

addressed include selecting patients for targeted combinations, biomarkers, the optimal

sequence of available agents and how to treat resistance to CDK 4/6 inhibition.

Ann Oncol. 2016;27(Suppl 6): Abstract LBA1.

Upfront Fulvestrant Superior to Anastrozole in Advanced HR+ Breast Cancer

In the phase III FALCON trial, fulvestrant (500 mg) significantly improved PFS

compared to anastrozole in 462 women with locally advanced or metastatic

HR-positive/HER2-negative breast cancer who had not previously received an endocrine

therapy. Median PFS in women receiving fulvestrant was 16.6 months, compared with

13.8 months in patients receiving anastrozole (HR 0.797, P = .0486). Treatment effects

were largely consistent across most prespecified subgroups with the largest treatment

effect seen in patients without visceral disease (22.3 months vs 13.8 months; HR 0.59).

Overall survival data are not yet mature, though there is a slight trend in favor of

fulvestrant. Overall response rates were similar in both treatment groups (46.1% vs

44.9%), though the duration of response (DoR) was longer in patients receiving

fulvestrant (20.0 months vs 13.2 months). Adverse events were generally consistent with

previous studies and health-related quality-of-life (HRQoL) was maintained in both

treatment groups. Overall these results are highly similar to those seen in the phase II

FIRST trial and confirm that fulvestrant is more efficacious than anastrozole in

postmenopausal women with HR-positive/HER-negative advanced breast cancer who

have not received prior endocrine therapy. Matthew Ellis, MD, PhD (Baylor College of

Medicine, Houston, Texas, United States), who presented these data, indicated that

fulvestrant could be a new standard of care for patients who would typically receive

endocrine therapy, such as those with nonvisceral disease or low volume disease. The

study’s discussant, Peter Schmidt, MD, PhD (Barts Cancer Institute and Queen Mary

University, London, United Kingdom), suggested that new data of adding a CDK4/6

inhibitor to endocrine therapy should also be taken into account and that a risk-stratified

approach, which incorporates disease activity (eg, disease-free interval, visceral disease

burden, symptoms) and probability of responding to endocrine therapy, may be a useful

tool to identify both patients who need a combined targeted therapy approach and those

with low-risk disease that may be controlled with endocrine therapy alone. He also

pointed out the potential role of ESR1 as a predictive biomarker for response to

fulvestrant.

Ann Oncol. 2016;27(Suppl 6): Abstract LBA14.

Gastrointestinal Cancer

Nivolumab Active in Previously Treated Hepatocellular Carcinoma

In an interim analysis of the phase I/II CheckMate-040 trial, the programmed death

receptor (PD)-1 inhibitor nivolumab demonstrated promising activity in patients with

previously treated advanced hepatocellular carcinoma (HCC), regardless of programmed

death-ligand 1 (PD-L1) expression status, viral infection, or prior sorafenib treatment.

This study consisted of two cohorts: A dose escalation cohort (n = 48), in which patients

received doses of nivolumab ranging from 0.1 mg/kg to 10 mg/kg, and a dose expansion

cohort (n = 214), in which all patients received 3 mg/kg nivolumab. Both cohorts

enrolled patients regardless of hepatitis B virus (HBV) or hepatitis C virus (HCV)

infection status. Objective responses were observed at all doselevels and in all etiologic

subtypes. In the dose escalation cohort, the ORR was 15% among all patients, with a

higher rate of 30% observed in patients with HCV infections. A similar ORR was seen in

the dose escalation cohort (16%), though HCV infections were not associated with a

higher response rate in this group. Responses were observed irrespective of PD-L1

expression (80% of patients were PD-L1 negative) on tumor cells or prior treatment with

sorafenib. The median DoR in the dose escalation cohort was 17 months and it has not

yet been reached in the dose expansion cohort, where responses are ongoing in

30 patients. Overall survival rates at 6 months and 9 months were 66% at each timepoint

For expert perspectives on these and other abstracts in breast cancer presented at the 2016 ESMO Congress, please see the

prIME Oncology Clinical Spotlight on Breast Cancer and Virtual Poster Session in Breast Cancer.

in the dose escalation cohort and 83% and 71%, respectively, in the dose expansion

cohort. Overall survival rates at 18 months were 44% in the dose escalation cohort and

have not yet been calculated for the dose expansion cohort. The safety profile of

nivolumab in advanced HCC was similar to that observed in other tumor types, with low

rates of grade 3/4 AEs and no treatment-related deaths. In his discussion, Ian Chau, MD

(Royal Marsden NHS Foundation Trust, London, United Kingdom), called the survival

data very promising when indirectly compared to previous trials of targeted agents in

second-line HCC treatment. However, he cautioned that this was an uncontrolled trial and

commented that it was a “brave move” to conduct phase III trial in the first-line setting

without justified data.

Ann Oncol. 2016;27(Suppl 6): Abstract 615O.

Genitourinary Malignancies

Adjuvant Sunitinib Delays Recurrence in Renal Cell Carcinoma

Results from the phase III S-TRAC trial, which compared one year of adjuvant sunitinib

50 mg/day to placebo in 615 patients with clear cell locoregional renal cell carcinoma

(RCC) at high risk for recurrence following nephrectomy, demonstrated a 1.2-year

disease-free survival (DFS) benefit with sunitinib. The median DFS by independent

central review was 6.8 years for patients receiving sunitinib and 5.6 years for patients

receiving placebo (HR 0.761, P = .03). In higher-risk patients, the median DFS was

6.2 years versus 4.0 years (HR 0.737; P = .04). The benefit with sunitinib was durable,

For expert perspectives on other abstracts in gastrointestinal (noncolorectal and

colorectal) cancers presented at the 2016 ESMO Congress, please see the

prIME Oncology Virtual Poster Session in Gastrointestinal Cancer.

with DFS rates favoring sunitinib at 3 years (64.9% vs 59.5%) and 5 years (59.3% vs

51.3%). Overall survival data are not yet mature and median OS has not been reached in

either arm. Sunitinib was associated with a safety profile consistent with previous

experience in RCC. Grade 3/4 treatment emergent AEs were reported in 60.5% of

sunitinib and 19.4% of placebo arm. The most common grade 3/4 treatment-related AEs

were hand-foot syndrome, hypertension, neutropenia, thrombocytopenia, and fatigue.

Sunitinib was associated with a clinically meaningful reduction in QoL related to appetite

loss and diarrhea. Results from S-TRAC were simultaneously published in The New

England Journal of Medicine (10 October 2016 [Epub ahead of print]). In his discussion,

Axel Bex, MD, PhD (The Netherlands Cancer Institute, Amsterdam, the Netherlands),

highlighted that the S-TRAC trial is the first positive trial ever for adjuvant treatment in

RCC. However, he questioned whether the “weak” 1.2-year median delay in recurrence

with sunitinib is worth “the harm” associated with treatment, particularly given the

generally asymptomatic nature of recurrences. Citing discordant results from the

similarly designed ASSURE trial and opinions from European Association for Urology

(EAU) Guidelines Panel, Dr Bex indicated that before changing practice he would need

more evidence, including OS data from this and other trials.

Ann Oncol. 2016;27(Suppl 6): Abstract LBA11.

Front-Line Cabozantinib Superior to Sunitinib in Metastatic RCC

Results from the phase III CABOSUN trial demonstrated a significant benefit, including

a 2.6-month increase in PFS and an 8.5-month increase in OS, for cabozantinib 60 mg

daily over sunitinib 50 mg daily in 157 previously untreated patients with poor-risk or

intermediate-risk metastatic RCC. Median PFS with cabozantinib was 8.2 months

compared to 5.6 months with sunitinib (HR 0.69, P = .012). Cabozantinib provided

superior outcomes regardless of patient risk group (poor or intermediate) or presence of

bone metastases. More patients receiving cabozantinib responded to treatment (46% vs

18%) and experienced greater tumor reduction (87.3% vs 43.6%). Median OS favored

cabozantinib (30.3 months vs 21.8 months; HR 0.80). The safety profiles of the two

agents were highly similar, with equal rates of high-grade AEs and similar proportions of

patients discontinuing due to AEs. Grade 3/4 AEs occurring more frequently with

cabozantinib include hypertension (28%), ALT increase (5%), anorexia (5%), hand-foot

syndrome (8%), and weight loss (4%). Presenter Toni Choueiri, MD (Dana-Farber

Cancer Institute, Boston, Massachusetts, United States), concluded by saying these

results support use of cabozantinib in previously untreated patients with metastatic RCC,

particularly in patients with intermediate-risk or poor-risk disease for whom sunitinib

offers little benefit. The discussant, Bernard Escudier, MD (Gustave Roussy, Villejuif,

France), highlighted that cabozantinib is a potent VEGF inhibitor, superior to sunitinib,

and is probably also active in patients with a more favorable risk profile. He also pointed

out that results of ongoing phase III trials in first-line setting will need to be re-examined

in light of these new data.

Ann Oncol. 2016;27(Suppl 6): Abstract LBA30.

Pembrolizumab Effective for Cisplatin-Ineligible Urothelial Cancer

In an analysis of the first 100 patients enrolled in the KEYNOTE-052 study in cisplatin-

ineligible recurrent or metastatic urothelial cancer, pembrolizumab 200 mg every 3 weeks

resulted in a 24% ORR, with greatest benefit observed in patients with a PD-L1

combined proportion score (CPS) ≥10% and those without visceral disease. The ORR in

all patients included 6 complete responses (CR) and 18 partial responses (PR). Responses

are ongoing at ≥6 months in 83% of responders. A planned subgroup analysis revealed

differential treatment effects in patients with lymph node only disease (ORR 40%) and

patients with upper respiratory tract disease (ORR 10%). Patients expressing higher

levels of PD-L1 had more favorable outcomes. A CPS ≥10% resulted in an ORR of 37%,

while CPS <1% and CPS ≥1% to <10% were associated with ORRs of 18% and 15%,

respectively. Pembrolizumab-related AEs were similar to those previously seen in

urothelial cancer, with primarily lower grade AEs. Immune-related (IR) AEs of interest

included 6 patients with grade 2 hypothyroidism, 2 patients with grade 3 pneumonitis,

and one patient each with grade 2 pneumonitis, grade 3 nephritis, and grade 3 colitis. The

discussant, Laurence Albiges, MD (Gustave Roussy, Villejuif, France), said that these

data in combination with previously reported results from the IMvigor 210 trial of

atezolizumab, confirm that immunotherapy will soon be “the option” for first-line

urothelial cancer. Several phase III trials of PD-1 and PD-L1 inhibitors are currently

ongoing that may provide further support for immunotherapy in urothelial cancer and

help answer remaining questions, including best strategies for patient selection and the

optimal sequencing of available agents.

Ann Oncol. 2016;27(suppl 6): Abstract LBA32.

Gynecologic Malignancies

Niraparib Maintenance: New Option for Relapsed Platinum-Sensitive Ovarian

Cancer

Results from a randomized, double-blind, placebo-controlled phase III trial showed that

maintenance therapy with the selective PARP1/2 inhibitor niraparib significantly

improved PFS in women with recurrent, platinum-sensitive ovarian cancer regardless of

the germline BRCA (gBRCA) mutation and homologous recombination deficiency (HRD)

status. Patients (N = 553) with platinum-sensitive, recurrent, high-grade serous ovarian

cancer who responded to 4-6 cycles of platinum-based chemotherapy were divided in two

cohorts based on results of central BRCA testing; cohort gBRCA mutant (n = 203) and

non-gBRCA mutant cohort (n = 350). Patients in each cohort were then randomized to

receive maintenance therapy with either niraparib 300 mg daily or placebo. In the non-

gBRCA cohort patients were further grouped based on result of HRD testing into HRD-

positve and HRD-negative. At 16.9 months follow-up, gBRCA mutated patients receiving

niraparib had a median PFS of 21 months, compared with 5.5 months in patients

receiving placebo (HR 0.27, P<.0001). The 18-month PFS rate was 50% with niraparib

versus 16% with placebo. Non-gBRCA mutant patients also received significant benefit

from niraparib maintenance (9.3 months vs 3.9 months; HR 0.45, P<.0001). In the

subgroup analysis, benefit was observed regardless of HRD status, though larger benefit

was seen in patients with HRD-positive tumors. Hematologic lab abnormalities were the

most common side effect and were managed primarily with dose adjustments. Grade 3/4

AEs occurring in ≥5% of patients included thrombocytopenia (33.8%), anemia (25.3%),

neutropenia (19.6%), and fatigue and hypertension (8.2% each). These data were

presented during the first Presidential Symposium and simultaneously published in The

New England Journal of Medicine (8 October 2016 [Epub ahead of print]). The

discussant, Sandro Pignata, MD (Istituto Nazionale Tumori di Napoli, Naples, Italy),

acknowledged the practice-changing nature of these “extraordinary” results, indicating

they have opened the door for PARP inhibitor therapy in patients without BRCA

mutations.

Ann Oncol. 2016;27(Suppl 6): Abstract LBA3.

Head and Neck Cancer

Nivolumab Improves Survival, Tolerability, and QoL in Advanced Head and Neck

Cancer

In an analysis of patient reported outcomes (PROs) from the phase III CheckMate-141

trial in patients with squamous cell carcinoma of the head and neck (SCCHN), nivolumab

treatment resulted in stable PROs across three separate QoL instruments, while

investigator’s choice chemotherapy was consistently associated with worsening of PROs.

The previously reported phase III CheckMate-141 trial compared nivolumab 3 mg/kg IV

every two weeks to investigator’s choice therapy in 361 patients with relapsed or

metastatic SCCHN who had progressed on platinum therapy. Treatment with nivolumab

resulted in a significant improvement in OS compared with investigator’s choice therapy

(7.5 months vs 5.1 months; HR 0.70, P = .0101). In this analysis, PROs were analyzed

using cancer-specific, head and neck cancer–specific, and generic health status

instruments to determine the impact of nivolumab treatment on patient QoL, which was

assessed at baseline, week 9, and every 6 weeks thereafter. As measured by the EORTC

Quality of Life Questionnaire-Core 30 module (EORTC QLQ-C30), patients treated with

nivolumab experienced stable PROs for functional domains and symptom burden, while

patients receiving investigator’s choice therapy had statistically significant and clinically

meaningful worsening in physical, role, and social functioning and symptom burden.

Nivolumab treatment resulted in a more than doubling of time to deterioration for most

functional domains and for fatigue, dyspnea, and insomnia. Similar results were seen

with the SCCHN-specific module (EORTC QLQ-HN35), where nivolumab resulted in

stable PROs for symptom burden and investigator’s choice therapy resulted in statically

significant worsening of symptoms. According to this scale, nivolumab delayed the time

to deterioration for pain, sensory problems, and mouth opening problems. Finally,

nivolumab treatment resulted in stable health status on the European Quality of Life-5

Dimensions questionnaire (EQ-5D-VAS), while investigator’s choice resulted in

worsening health status that reached statistical significance at week 15. Across all three

scales, higher levels of PD-L1 expression led to numerically greater but not statistically

significant improvements in PROs. The presenter concluded that nivolumab is the first

PD-1 inhibitor to demonstrate a statistically significant improvement in OS, with better

tolerability and QoL benefit than standard therapy, in SCCHN. Full results from the

CheckMate-141 trial, including these data, were simultaneously published in The New

England Journal of Medicine (9 October 2016 [Epub ahead of print]).

Ann Oncol. 2016;27(Suppl 6): Abstract LBA4.

For expert perspectives on other abstracts in head and neck cancer presented at the

2016 ESMO Congress, please see the prIME Oncology Virtual Poster Session in

Head and Neck Cancer.

Lung Cancer

Immunotherapy Continues to Take Center Stage in Advanced NSCLC

New data on immunotherapy in NSCLC was at center stage of the 2016 ESMO Congress,

with abstracts covering updated studies on second-line immunotherapy, new

immunotherapy combinations, and the first presentations of trials investigating PD-1

inhibitors as first-line treatments in NSCLC. Key data of 4 abstracts presented during the

second Presidential Symposium are summarized.

• Moving PD-1 Inhibitors Into First-line Therapy of Advanced NSCLC. Across

three presentations, first-line PD-1 inhibition was met with varying success, with

pembrolizumab improving patient outcomes as both a single agent and in

combination with chemotherapy, while single agent nivolumab failed to

demonstrate clinical benefit when compared to chemotherapy.

Pembrolizumab first-line therapy, new standard of care for high PD-L1–

positive NSCLC. Martin Reck, MD, PhD (Lung Clinic Grosshansdorf,

Grosshansdorf, Germany), presented results from the phase III KEYNOTE-024

trial, which compared pembrolizumab 200 mg every three weeks to platinum-

based chemotherapy in 305 patients with advanced NSCLC with a PD-L1 tumor

proportion score (TPS) ≥50%. Pembrolizumab significantly improved PFS

compared to chemotherapy (median PFS 10.3 months vs 6.0 months; HR 0.50,

P<.001). The 12-month rate of PFS was 48% in the pembrolizumab arm versus

15% in the chemotherapy arm. Overall survival was also significantly improved

in patients receiving pembrolizumab (median OS was not reached for either arm;

HR 0.60, P = .005), with 12-month OS rates of 70% versus 54%. Based on the

significant improvements in PFS and OS associated with pembrolizumab, the

Data Safety Monitoring Committee recommended stopping the trial and allowing

patients in the chemotherapy arm to cross over. First-line pembrolizumab was

associated with a manageable toxicity profile, with fewer all grade and grade 3/4

AEs than seen with chemotherapy. The most common IRAEs included

hypothyroidism, hyperthyroidism, pneumonitis, infusion reactions, and severe

skin toxicity. Dr Reck concluded that these data support pembrolizumab as a new

standard of care for untreated high PD-L1–positive advanced NSCLC. Data from

this presentation were simultaneously published in The New England Journal of

Medicine (9 October 2016 [Epub ahead of print]). While results from the

KEYNOTE-024 trial support first-line immunotherapy, the similarly designed

CheckMate-026 trial investigating first-line nivolumab failed to demonstrate any

benefit over chemotherapy in either PFS or OS with nivolumab. A key difference

between these two trials is the PD-L1 cut-off. KEYNOTE-024 was restricted to

only patients with high (≥50%) PD-L1 expression, while the CheckMate-026 trial

enrolled also patients with low (≥1%) PD-L1 expression, suggesting PD-L1

expression level may be more important as a biomarker when selecting PD-1

inhibitors for first-line therapy of NSCLC than it is in the second-line setting.

Impressive activity of pembrolizumab in combination with chemotherapy.

Corey Langer, MD (University of Pennsylvania, Philadelphia, Pennsylvania,

United States), presented results from Cohort G of the phase II KEYNOTE-021

trial, which evaluated the addition of pembrolizumab 200 mg every 3 weeks to

carboplatin plus pemetrexed in advanced NSCLC. This trial enrolled 123 patients

with varying levels of PD-L1 expression, including PD-L1 nonexpressers. The

addition of pembrolizumab to chemotherapy resulted in an almost doubled

response rate (confirmed ORR 55% vs 29%; P = .006), including greatly reduced

rates of progressive disease (3% vs 17%). Overall response rates varied based on

PD-L1 expression, but were highest (80%) in the population of patients with

≥50% PD-L1 expression. Six-month PFS rates were also significantly higher with

the addition of pembrolizumab (77% vs 63%; HR 0.53, P = .002), but no OS

benefit was observed at 12 months (HR 0.90). However, pembrolizumab plus

chemotherapy was associated with higher rates of grade 3/4 AEs (39% vs 26%),

including more chemotherapy-related AEs. Results from this study were

simultaneously published in Lancet Oncology (9 October 2016 [Epub ahead of

print]). In his discussion of the two trials of first-line pembrolizumab, Jean-

Charles Soria, MD, PhD (Gustave Roussy, Villejuif, France), commented that

while these results are exciting, they will likely only benefit a small population of

first-line patients due to the restricted enrollment criteria. Dr Soria indicated that

for immunotherapy to become truly meaningful in the first-line treatment of

NSCLC, the pool of patients to whom it is available must be widened.

Ann Oncol. 2016;27(Suppl 6): Abstract LBA8.

Ann Oncol. 2016;27(Suppl 6): Abstract LBA7.

Ann Oncol. 2016;27(Suppl 6): Abstract LBA46.

• Survival Benefit With Atezolizumab in Second-Line NSCLC. Results of the

randomized, phase III OAK trial in patients with previously treated advanced

NSCLC showed a significant improvement in OS with the PD-L1 inhibitor

atezolizumab compared to the OS with docetaxel, with the greatest benefit seen in

patients expressing higher levels of PD-L1. Patients in the intent-to-treat

population (ITT; N = 850) receiving atezolizumab had an average 4.2-month

improvement in OS (13.8 months vs 9.6 months; HR 0.73, P =.003). While OS

favored atezolizumab regardless of PD-L1 expression level, patients with PD-L1

expression ≥50% on tumor cells (TC3) or ≥10% on immune cells (IC3), had the

largest OS benefit from atezolizumab (20.5 months vs 8.9 months; HR 0.41,

P<.0001). Atezolizumab resulted in longer OS in all patient subgroups evaluated,

including squamous and nonsquamous histology and never smokers, with the

exception of patients with EGFR mutations (HR 1.24). There was no PFS benefit

for atezolizumab in the ITT population, but higher PD-L1 expression

corresponded to longer PFS (HR 0.63 in TC3 PD-L1 expression group). Likewise,

though ORR was similar between the treatment arms in the ITT population (14%

vs 13%), increasing levels of PD-L1 expression corresponded with increasing

response rates. In the highest PD-L1 expression group, ORR was 31% with

atezolizumab compared to 11% with chemotherapy. Atezolizumab was associated

with lower rates of AEs than docetaxel, including extremely low rates of IRAEs.

The presenter, Fabrice Barlesi, MD, PhD (Aix-Marseille University, Marseille,

France), concluded that OAK represents the first phase III trial of a PD-L1

inhibitor to show a survival benefit in NSCLC, regardless of PD-L1 expression,

and that these data support the use of atezolizumab in the second-line treatment of

NSCLC.

Ann Oncol. 2016;27(Suppl 6): Abstract LBA44.

Melanoma

Adjuvant Ipilimumab Significantly Improves OS in Stage III Melanoma

According to the final analysis of the phase III EORTC 18071 trial, adjuvant ipilimumab

therapy after complete resection of stage III melanoma prolonged OS, distant metastasis-

free survival (DMFS), and relapse-free survival (RFS) compared to placebo, including a

28% reduction in the risk of death. In this trial, 951 patients with stage III melanoma

were randomized to ipilimumab 10 mg/kg or placebo every 3 weeks for 4 doses, then

every 3 months for up to 3 years or disease recurrence or unacceptable toxicity.

Ipilimumab treatment was associated with a 10.5-month improvement in RFS

(27.6 months vs 17.1 months; HR 0.76, P = .0008). Five-year OS rates were significantly

higher in patients receiving ipilimumab (65% vs 54%; HR 0.72, P = .001). Overall

survival favored ipilimumab in most patient subgroups, with the exception of patients

with stage IIIA disease. Distant metastasis-free survival rates at 5 years were 48% in

ipilimumab treated patients compared to 39% in patients receiving placebo (HR 0.76).

For expert perspectives on these and other abstracts in lung cancer presented at the

2016 ESMO Congress, please see the

prIME Oncology Virtual Poster Session in Lung Cancer.

The safety results in this long-term follow-up were consistent with the primary report.

There were higher rates of AEs in the ipilimumab group, including higher rates of grade

3/4 AEs (54.1% vs 26.2%) and grade 3/4 IRAEs (41.6% vs 2.7%) The most common

grade 3/4 IRAEs were gastrointestinal (16.2%), hepatic (10.9%), and endocrine (7.8%).

Adverse events were managed according established algorithms and usually resolved

within 4-8 weeks said Alexander Eggermont, MD, PhD (Gustave Roussy, Villejuif,

France) who presented the data. However, endocrine AEs took longer to resolve or

required permanent hormonal replacement therapies. Final results from EORTC 18071

were simultaneously published in The New England Journal of Medicine (8 October 2016

[Epub ahead of print]). In the discussion, Olivier Michielin, MD, PhD (Lausanne

University Hosptial, Lausanne, Switzerland), complemented the investigators for their

intelligent study design, saying that this trial provides great insight into how immune

responses form in the presence of only residual disease and identifies potential patient

subgroups that may be more sensitive to immunotherapy in the adjuvant setting.

Ann Oncol. 2016;27(Suppl 6): Abstract LBA2.

For expert perspectives on this and other abstracts in melanoma presented at the

2016 ESMO Congress, please see the

prIME Oncology Virtual Poster Session in Melanoma.

UPCOMING prIME EVENTS

prIME News: Updates from the Annual European Oncology Conference 8 November 2016 | Live Broadcast Anticipating the Promise of Immunotherapy in Glioblastoma 19 November 2016 | Scottsdale, Arizona, United States

West Cancer Center Oncology Conference—Collaboration for the Future Cure: Precision Medicine & Immuno-Oncology 18-19 November 2016 | Memphis, Tennessee, United States

How I Treat Hodgkin Lymphoma: Optimal Decisions for Every Fork in the Road 2 December 2016 | San Diego, California, United States

Expert Practice℠ in Colorectal Cancer 2 December 2016 | Guangzhou, China Expert Practice℠ in Head & Neck Cancer 3 December 2016 | Guangzhou, China

Reaching New Heights in the Management of Non-Small Cell Lung Cancer: Focus on EGFR-Targeted Therapy 5 December 2016 | Vienna, Austria

Cancer cachexia: Early Intervention and Improving Patient Outcomes 6 December 2016 | Vienna, Austria

Tackling Hard to Treat Breast Cancer Subtypes: New Opportunities in Triple-Negative and HER2-Positive Disease 8 December 2016 | San Antonio, Texas, United States

OTHER prIME ACTIVITIES

Virtual Poster Session: Practical Application of Key Data Presented During the 2016 European Oncology Congress in Copenhagen

Clinical Spotlight in Breast Cancer From the 2016 European Oncology Congress in Copenhagen—Combination Strategies for ER-Positive, HER2-Negative Metastatic Breast Cancer

Downloadable Slides—Choosing the Right Treatment for My Patients With Gastrointestinal Neuroendocrine Tumors: The Devil Is in the Detail Downloadable Slides—Finding Solutions to Difficult Problems in HER2-Positive Breast Cancer

Downloadable Slides—Management of Advanced Renal Cell Carcinoma in the Spotlight: Important Changes Are Occurring

prIME News Webcast—NSCLC Immunotherapy in Practice: The Asian Perspective