COMMENTARY

How the 2018 World Conference on Lung Cancer Data Change Clinical Practice

H. Jack West, MD

Disclosures

October 04, 2018

The 19th World Conference on Lung Cancer (WCLC), held September 23-26 in Toronto, featured a remarkable presidential session that included multiple practice-changing results.

Just 1 year ago, the phase 3 PACIFIC trial overcame one of the most challenging impasses in lung cancer, demonstrating that maintenance durvalumab after concurrent chemoradiation for stage III unresectable non–small cell lung cancer (NSCLC) significantly improves progression-free survival (PFS).

Along with updated data on overall survival (OS) from PACIFIC, the presidential session at WCLC 2018 included a positive trial showing a huge benefit for brigatinib as a first-line treatment for ALK rearrangement–positive NSCLC; a remarkable improvement in OS in a European trial of CT screening for lung cancer; and the most elusive result of all: a trial positive for an OS benefit in first-line treatment of extensive-stage small cell lung cancer (ES-SCLC) that warrants a change in the standard of care.

PACIFIC Trial

The first presentation was the update of the PACIFIC trial, which included 713 patients with stage 3 unresectable NSCLC who had not demonstrated disease progression after receiving concurrent chemoradiation with at least two cycles of platinum-based chemotherapy and approximately 6-7 weeks of chest radiation. They were randomly assigned in a 2:1 fashion to either 1 year of maintenance durvalumab 10 mg/kg IV every 2 weeks or placebo for the same duration.[1] As highlighted in a publication of the early results, the dramatic improvement in PFS (median PFS 16.8 vs 5.6 months; hazard ratio [HR] 0.52; P < .0001), with only a very limited increase in side effects, led to US Food and Drug Administration (FDA) approval for durvalumab in this setting[2] and generally broad acceptance of this strategy as a new standard of care. Still, we have awaited OS data for this trial, with some oncologists contending that we need to see updated data before recommending maintenance durvalumab.

Dr Scott Antonia reported the updated results at the live session[3] with a simultaneous publication in the New England Journal of Medicine (NEJM),[4] which demonstrated that durvalumab was also associated with a significant OS benefit (median not reached [NR] vs 28.7 months; HR 0.68; P = .00251). The relatively favorable OS seen even in the control arm provided some reassurance against the occasional criticism that the control arm had demonstrated a relatively weak PFS. Despite these favorable results for the broad population, however, subset analyses from PACIFIC demonstrated that patients with either tumor PD-L1 expression < 1% at initial diagnosis or those with a tumor harboring an activating EGFR mutation did not appear to benefit. We are left with the open question of whether these patients should receive durvalumab on the basis of their inclusion in the trial or whether they should be viewed as distinct populations that should not receive consolidation immunotherapy. In the absence of more clinical data, my view is that we should discuss this option with patients who would have been eligible for PACIFIC, including the potential for no benefit (or even harm) on the basis of their biomarker features, and then make a decision on an individualized basis.

ALTA-1L Trial

Dr Ross Camidge presented the early results of the ALTA-1L trial of the second-generation ALK inhibitor brigatinib compared with prior standard-of-care crizotinib in 275 ALK inhibitor-naive patients,[5] which were also published simultaneously in the NEJM.[6] As was widely expected, brigatinib demonstrated a significantly longer PFS (median PFS not reached vs 9.8 months; HR 0.49; P = .0007), though results remain relatively immature, with a median follow-up of 11.0 and 9.3 months for the brigatinib and crizotinib arms, respectively. Among the approximately 30% of enrolled patients with brain metastases at baseline, the benefits favoring brigatinib were even more pronounced (intracranial response rate 67% vs 17%; odds ratio (OR) 13.0; P < .001; intracranial PFS not reached vs 5.6 months; HR 0.27; P < .0001).

Though these positive trial results are clearly impressive, the findings are limited by the immaturity of the data and the fact that crizotinib has been overwhelmingly supplanted by alectinib, which is now FDA-approved as first-line treatment for ALK-positive NSCLC[7] on the basis of the ALEX trial of alectinib versus crizotinib.[8] Though the data with brigatinib are arguably especially compelling for ALK-positive patients with brain metastases, its place as a first-line therapy remains to be defined in the absence of an FDA approval for brigatinib in this setting or evidence to support its superiority over alectinib as the current standard of care.

NELSON Trial

A more surprising result came in the NELSON trial, a study conducted in Belgium and the Netherlands on the benefits of chest CT screening and presented by Dr Harry de Koning.[9] The trial randomly assigned 15,792 reasonably fit men and women aged 54-70 years with a significant and relatively recent smoking history to either chest CT screening at years 1, 2, 4, and 6.5, or to no screening on the control arm. There was high adherence to this schedule on the screening arm (96%, 92%, 88%, and 67% at these intervals, respectively).

Indeterminate results were seen in only 9.3% of scans; 2.2% of scans were noted as positive and lung cancer was detected in 0.9%, for a positive predictive value of 41% with a positive scan result. This was associated with a dramatically higher proportion of diagnoses at an earlier stage compared with a cancer registry in the Netherlands. More important, it was associated with a significant improvement in lung cancer mortality at year 10 in men (HR 0.74; P = .003) that was even more pronounced in women (HR 0.61; P = .0543). Despite previously demonstrated survival benefits in the National Lung Screening Trial,[10] there has been very poor adoption of chest CT screening.[11] We can only hope that the results of the NELSON trial help rectify the egregious underscreening for lung cancer in eligible patient populations.

IMpower 133 Trial

Finally, just in time to refute the last bastion of therapeutic nihilism in thoracic oncology, we saw Dr Stephen Liu present the IMpower 133 trial,[12] also paired with a NEJM publication.[13] The trial randomly assigned 403 patients with advanced ES-SCLC in a 1:1 fashion to carboplatin/etoposide with either atezolizumab or placebo. This trial demonstrated a significant improvement in OS (median OS 12.3 vs 10.3 months; HR 0.70; P = .0069) as well as PFS (median PFS 5.2 vs 4.3 months; HR 0.77; P = .017), with no significant or surprising safety issues. Though clearly an advance, the somewhat underwhelming magnitude of benefit led some to question whether this should be adopted as a new standard of care.

My perspective is that it is quite likely that any of a number of currently ongoing studies of immunotherapy, along with or instead of platinum/etoposide chemotherapy, are likely to displace this regimen on the basis of more impressive efficacy as first-line treatment for ES-SCLC. However, this work represents enough of an advance to serve as at least an interim first-line standard. After a couple of decades of desperate effort, we have reached a point where it is time to move beyond platinum/etoposide alone.

Somewhere, a pig got off the ground briefly, even if he hasn't quite learned to fly.

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