INTRODUCTION
Despite extensive clinical investigations, lung cancer remains the leading cause of
cancer-related deaths worldwide,([1]) illustrating the need for novel approaches to reduce lung cancer incidence and
mortality. Lately, significant progress has been achieved for clinical management
of lung cancers, including screening strategies, use of immunotherapy-based approaches
to treat locally advanced and metastatic disease, and development of novel targeted
agents for molecularly defined subgroups. Much of the data that support these strategies
became available just within the past year. In this review, we summarize the studies
published/presented in 2018 that form the basis for new standard-of- care management
options for lung cancers. These practice-changing studies exemplify the importance
of multidisciplinary, evidence-based care to improve outcomes for lung cancer patients.
Computerized tomography (CT) scans for lung cancer screening
The role of lung cancer screening with low dose chest CT scans was evaluated by the
NELSON trial.([2]) NELSON was a randomized clinical trial from The Netherlands and Leuven that compared,
in a high-risk population, the lung cancer mortality reduction associated with CT-screening
versus no screening. An important feature of the NELSON trial was the fact that investigators
utilized a nodule volume management strategy in contrast with nodule diameter, used
in previous studies like NLST.([3])
The study population was selected based on the answers of a mail questionnaire sent
to 606,409 persons aged 50-74, of which 15,822 eligible participants gave informed
consent and were eventually randomized (1:1). Eligibility criteria included smokers
with a smoking history of >10 cigarettes/day for >30 years or >15 cigarettes/day for
>25 years, and, in former smokers, smoking cessation in =10 years. CT-screening was
offered to study arm participants at baseline and 1, 3 and 5.5 years after randomization.
Participants' records were linked to national registries and an expert panel blinded
to study arm reviewed medical files for deceased lung cancer patients. CT screening
compliance was 94% on average. In 9.1% of the participants, additional CT scans within
2 months were performed to estimate nodule volume doubling time, leading to an overall
referral rate of 2.1% for suspicious nodules. Detection rates across the rounds varied
between 0.8- 1.0%, and 69% of screen-detected lung cancers were detected at stage
IA or B. There were 214 lung cancer deaths in the control arm and 157 in the screen
arm. The lung cancer mortality rate ratio at Year 10 was 0.74 (0.60-0.91). The lung
cancer mortality rate ratio observed at Year 10 was 0.61 in the small subset of female
patients. NELSON confirmed previous NLST findings by demonstrating the capacity of
CT screening to reduce lung cancer mortality in a high-risk population of smokers.
Moreover, it also suggested that the nodule volume management strategy was associated
with less false positives as well as the fact that lung cancer screening might be
more effective in females.
Overall survival with durvalumab after chemoradiotherapy in stage III non-small cell
lung cancer (NSCLC)
Approximately one third of NSCLC patients present with stage III disease. The standard
treatment for the past several years has been concurrent platinum- based chemoradiation
therapy, resulting in a median progression-free survival of 8 months and 5-year overall
survival of 15%. PACIFIC was the first phase III study to evaluate consolidation immunotherapy
for patients with stage III, unresectable NSCLC. In 2017, the initial results of the
PACIFIC trial demonstrated that consolidation therapy with the anti-PD-L1 antibody
durvalumab tripled the median progression-free survival (5.6 months versus 16.8 months)
in stage III, unresectable NSCLCs who had not progressed after concurrent chemoradiation
therapy.([4]) Response rates were also higher in the durvalumab group (28% versus 16%). Toxicity
was similar between the two groups, but the main causes of treatment interruption
were pneumonia and pneumonitis, underscoring the importance of radiation therapy delivery
quality. Based on these results, the FDA and ANVISA approved durvalumab consolidation
therapy, now considered a new standard of care. In November 2018, updates on the PACIFIC
trial were published, with a median follow-up time of 25.2 months.([5]) There were improvements in the 24-month overall survival in favor of the durvalumab
arm (34.7 months versus 28.7 months), as well as a lower incidence of distant metastases,
including a 50% reduction in the development of new brain lesions. The benefits in
progression-free, and overall survival occurred in all subgroups, irrespective of
histology or PD-L1 expression levels (< or = 25%). Controversies on the use of durvalumab
still remain, such as the optimal timing for initiation of therapy. In PACIFIC, durvalumab
was started 1-42 days after completion of chemoradiation; a subgroup analysis demonstrated
improved progression-free, and overall survival, and time to distant metastases when
durvalumab was initiated within 14 days of chemoradiation therapy. The PACIFIC trial
results provide evidence for pivotal interactions between radiation therapy and immunotherapy,
and support an important change in the standard treatment of stage III NSCLC, after
a decade's time without significant advances in this field.
Pembrolizumab plus chemotherapy in metastatic, non-squamous, NSCLC
The combination of chemotherapy and immunotherapy for treatment-naïve non- squamous,
NSCLC was investigated in the KEYNOTE-189 trial.([6]) In this study, 616 patients with EGFR wild-type, ALK-negative cancers were stratified
according to PD-L1 expression levels, platinum compound, and smoking history, and
were randomized to receive platinum (carboplatin or cisplatin), pemetrexed, and placebo
for up to 4 cycles, followed by maintenance pemetrexed and placebo, versus platinum,
pemetrexed, pembrolizumab for up to 4 cycles, followed by maintenance pemetrexed and
pembrolizumab. Crossover from the placebo to the pembrolizumab arm was allowed at
the time of disease progression. The primary endpoints of the study (progression-free
and overall survival) were met. The 12-month overall survival was 69.2% in the pembrolizumab
arm versus 49.4% in the placebo arm (hazard ratio [HR] 0.49, 95% CI 0.38-0.64, P<0.001).
The median progression-free survival was 8.8 months versus 4.9 months for the pembrolizumab
and placebo groups, respectively (HR 0.52, 95% CI 0.43-0.64, P<0.001). Response rates
were also higher in the pembrolizumab arm (47.6% versus 18.9%, P<0.0001). Improvements
in overall survival, progression-free survival and response rates occurred in all
three subgroups defined by PD-L1 status (i.e., tumor proportion score [TPS] <1%, 1-49%,
and =50%). Nonetheless, greatest benefits were observed among the patients whose tumors
had higher PD-L1 levels - HR (95% CI) for overall survival in PD-L1 TPS <1%, 1-49%,
and =50% were 0.59 (0.38-0.92), 0.55 (0.34-0.90), and 0.42 (0.260.68), respectively.
Grade 3-5 adverse events were observed in 67.2% and 65.8% of patients assigned to
the pembrolizumab and placebo groups, respectively. Acute kidney injury (all grades)
happened in 5.2% of pembrolizumab-treated patients versus 0.5% of placebo-treated
patients, and should be carefully screened for in routine clinical practice. Taken
together, these data confirmed the hypothesis that the combination of chemotherapy
and anti-PD1 antibodies improves outcomes in metastatic NSCLCs, and defined platinum,
pemetrexed, and pembrolizumab as a new standard of care for treatment naïve, EGFR
wild-type, and ALK-negative non-squamous NSCLCs, irrespective of PD-L1 expression
levels.
Pembrolizumab plus chemotherapy for squamous NSCLC
Squamous cell carcinomas correspond to 20% of lung cancers and is associated with
a shorter survival. Treatment for this disease has not greatly improved in the last
15 years. The KEYNOTE-407 trial randomized 559 stage IV squamous NSCLC patients with
measurable disease and ECOG performance status 0 or 1, to receive carboplatin plus
paclitaxel/ nab-paclitaxel every 21 days for 4 cycles associated with pembrolizumab
or placebo every 21 days for 35 cycles or until disease progression or unacceptable
toxicity. Patients with symptomatic central nervous system metastasis, pneumonitis
requiring corticosteroids, systemic immunosuppressive treatment, or active auto-immune
disease were excluded. Patients in the placebo arm were allowed to cross over to receive
pembrolizumab after confirmed disease progression. The trial had two co-primary endpoints:
overall survival and progression-free survival.([7]) The median follow-up time was 7.8 months. PD-L1 TPS =1% was observed in 63% of
patients. Median overall survival was 15.8 months in the pembrolizumab arm and 11.3
months in the placebo group (HR for death 0.64; 95% CI, 0.49-0.85; p<0.001). Median
progression-free survival was 6.4 months in the pembrolizumab arm and 4.8 months in
the placebo arm (HR for progression or death 0.56; 95% CI, 0.45-0.70; p<0.001). The
combination with pembrolizumab was also associated with improved overall response
rate (ORR) (57.9% versus 38.4%) and duration of response (7.7 months versus 4.8 months).
The benefit of the addition of pembrolizumab to chemotherapy in overall survival,
progression-free survival and response rates was observed for all the prespecified
PD-L1 TPS subgroups, and increased with every increment of PD- L1 expression. Adverse
events of grade =3 occurred in 69.8% in the pembrolizumab group and 68.2% in the placebo
group, leading to death in 8.3% and 6.8% of patients, respectively. Immune mediated
adverse events or infusion reactions of grade =3 were observed in 10.8% and 3.2% of
the pembrolizumab and placebo-treated patients, respectively. In view of the dismal
outcomes with current treatment for metastatic squamous NSCLCs, the results of KEYNOTE-407
confirmed the rationale to combine pembrolizumab with carboplatin and paclitaxel or
nab-paclitaxel and established a new paradigm in the treatment of this disease.
Brigatinib for frontline treatment of ALK positive NSCLC
Brigatinib is a next-generation ALK inhibitor that targets a broad range of ALK mutations.
ALTA-1L was an open-label, multicenter, randomized, phase 3 trial comparing the efficacy
and safety of brigatinib with crizotinib in patients with ALK-positive NSCLC who had
not received previous treatment with an ALK inhibitor.([8]) Patients with asymptomatic, untreated CNS metastases were not excluded. In the
crizotinib group, crossover to brigatinib was permitted after progression. The primary
endpoint was progression-free survival. In this study, 275 patients were enrolled.
Brigatinib showed superior efficacy against extra- and intra-cranial disease. With
a median follow-up of 11.0 months in the brigatinib group and 9.3 months in the crizotinib
group, brigatinib was associated with a 51% lower risk of disease progression or death
than crizotinib (HR 0.49; P<0.001). The 12-month progression-free survival was 67%
in the brigatinib group (median not reached) and 43% in the crizotinib group. The
confirmed objective response rate was 71% (95% CI, 62 to 78) with brigatinib and 60%
(95% CI, 51 to 68) with crizotinib; the confirmed intracranial response rate among
patients with measurable lesions was 78% (95% CI, 52 to 94) and 29% (95% CI, 11 to
52), respectively.([9]) No new safety concerns were noted. Despite shorter follow-up, these initial ALTA-1L
results appear similar to results from the phase 3 ALEX trial, which compared alectinib
versus crizotinib. A key strength of this trial is that a blinded independent review
committee assessed progression-free survival, and ALK was assessed locally, increasing
the applicability of these data. A limitation is that overall survival data will be
confounded by crossover of patients and subsequent use of other tyrosine kinase inhibitors
after trial. In conclusion, brigatinib is a new first line option to treat ALK-positive
NSCLC.
First-line atezolizumab plus chemotherapy in extensive small-cell lung cancer (SCLC)
The combination of chemotherapy and immunotherapy for treatment-naïve advanced SCLC
was investigated in the IMpower-133 trial.([10]) In this double- blind, placebo-controlled, phase 3 study, a total of 403 ECOG PS
0-1 patients with extensive SCLC were randomized to receive carboplatin and etoposide
with either atezolizumab (an anti-PD-L1 inhibitor) or placebo for four 21-day cycles
(induction phase), followed by a maintenance phase during which they received either
atezolizumab or placebo. Crossover was not allowed. Patients with treated asymptomatic
brain metastases were eligible. During the maintenance phase, prophylactic cranial
irradiation was permitted, but thoracic radiation therapy was not. PD-L1 testing was
not performed during screening. Median follow-up was 13.9 months. The primary endpoints
of the study, overall survival and progression-free survival, were met. The median
overall survival was 12.3 months in the atezolizumab group and 10.3 months in the
placebo group (HR 0.70; 95% CI: 0.54 to 0.91; p=0.007). The median progression-free
survival was 5.2 months and 4.3 months, respectively (HR 0.77; 95% CI: 0.62 to 0.96;
p=0.02). Objective response rate (60.2% versus 64.4%) and duration of response were
similar in the two groups. The benefit was consistent across key evaluated subgroups
(sex, age, ECOG PS, brain and liver metastases, blood- based tumor mutational burden).
The safety profile was consistent with previously reported data for each individual
agent, with no new findings. Immune-related adverse events occurred in 39.9% in the
atezolizumab group and in 24.5% in the placebo group, with rash and hypothyroidism
being the most common. Despite some criticism related to the magnitude of the benefit,
this was the first trial, in more than two decades, to show a survival improvement
with the addition of a new drug to advanced SCLC first-line treatment. These data
are likely to establish the combination of platinum, etoposide and atezolizumab as
a new standard of care for this population.
