A snapshot of lung cancer after ASCO 2018

An event organised by the Roy Castle Lung Cancer Foundation and the British Thoracic Oncology Group (BTOG) aimed to summarise the key take-home messages and studies of interest regarding lung cancer from the 2018 American Society of Clinical Oncology (ASCO) Annual Meeting. No small feat with any ASCO, but an even greater venture for an ASCO in which lung cancer was the talk of the conference, particularly the ground-breaking advances with respect to immunotherapy. With Dr Jason Lester acting as Chair and Speaker, accompanied by Dr Riyaz Shah and Dr Martin Forster, the meeting tackled early lung cancer treatment, metastatic non-small cell lung cancer (NSCLC), and small cell lung cancer and thymoma. In this snapshot, you will find top-line results and key interpretations from the trials of greatest interest discussed during these engaging and informative talks. A full video of the meeting is due to be uploaded to the BTOG website – worth keeping your eyes peeled for this.

Early lung cancer (Dr Jason Lester)

LUN14-149 Phase II trial (Abstract 8523)

Result: 6/93 (6.5%) patients experienced Grade 3–5 pneumonitis with consolidation pembrolizumab following concurrent chemoradiation in patients with unresectable stage III NSCLC.

Interpretation: The risk of pneumonitis during consolidation chemotherapy in patients with inoperable or unresectable stage III NSCLC is an important concern which limits treatment for many patients. Considering 10% Grade 3 pneumonitis as a benchmark for clinically acceptable incidence, this result indicates that most patients can tolerably receive consolidation pembrolizumab following concurrent chemoradiation. Of note, the population assessed are considered high programmed death-ligand 1 (PD-L1) expressers (PD-L1 >50%). Further investigations are required and efficacy data are maturing.

ETOP NICOLAS Phase II trial (Abstract 8510)

Result: 6/58 (10.3%) patients experienced Grade 3 pneumonitis with consolidation nivolumab started concurrently with first-line chemoradiation in patients with stage III NSCLC. 

Interpretation: As per the clinical benchmark of 10%, this result suggests acceptable incidence of pneumonitis in this patient group – consisting of patients with Eastern Cooperative Oncology Group performance status 0 or 1. Additionally, the time of pneumonitis occurrence was found to be inconsistent, indicating it is immune-related. As per the trial design, efficacy data will be evaluated and reported next.

Unanswered questions

• Do all programmed cell death-1 (PD-1)/PD-L1 inhibitors have the same efficacy and toxicity?
  
• What is the optimal duration of consolidation immunotherapy?
• Is consolidation with combination immunotherapy feasible?

In addition to the above, Dr Jason Lester discussed results from trials assessing lung cancer screening (Abstract 12021), smoking cessation (Abstract 6559) and stereotactic radiotherapy (Abstract 8511 and 8512).

Metastatic NSCLC (Dr Riyaz Shah)

KEYNOTE-189 PHASE III TRIAL (ABSTRACT 9021 AND ORIGINAL ARTICLE)

Result: Compared with placebo + chemotherapy, pembrolizumab + chemotherapy yielded superior overall survival (OS) and progression-free survival, higher objective response rate, durable response and generally expected toxicity in patients with non-squamous metastatic NSCLC. Health-related quality of life (HRQoL) in patients in the pembrolizumab arm was shown to maintain or improve compared with the placebo arm, despite a higher Grade 3–5 treatment-related adverse event rate.

KEYNOTE-407 PHASE III TRIAL (ABSTRACT 105)

Result: Similar results to KEYNOTE-189 have been reported for KEYNOTE-407, which compared combination pembrolizumab + chemotherapy with placebo + chemotherapy in patients with squamous metastatic NSCLC.

Interpretation: Practice-changing results have been reported for the KEYNOTE-189 and KEYNOTE-407 studies, particularly the OS results which showed dramatic improvements in the overall group and statistically significant improvement in all subgroups by programmed death-ligand 1 (PD-L1) status. The additional analysis on HRQoL for KEYNOTE-189 adds to the body of evidence that this treatment approach is applicable in clinical practice. Taken together, the results from KEYNOTE-189 and KEYNOTE-407 establish pembrolizumab + chemotherapy as the new standard of care for first-line treatment in NSCLC; although monotherapy with pembrolizumab has also shown excellent results in patients expressing high levels of PD-L1 (≥50%; KEYNOTE-024). The question yet to be answered by the data available is how to select between monotherapy or combination therapy with pembrolizumab – physicians are eagerly awaiting a rationale and resolution of this practice-changing query.

KEYNOTE-042 PHASE III TRIAL (ABSTRACT LBA4)

Result: Pembrolizumab monotherapy significantly improved OS in patients with squamous or non-squamous metastatic NSCLC compared with chemotherapy in ≥1%, ≥20% and ≥50% PD-L1 expression subgroups. Exploratory analysis of OS in patients with PD-L1 expression ≥1–49% reported a hazard ratio of 0.92 (95% confidence interval [CI]: 0.77–1.11).

Interpretation: While these results are positive as per the trial endpoints, the reporting of an upper CI which crosses 1 in the exploratory analysis of OS in patients with PD-L1 expression ≥1–49% indicates that the positive results seen for OS in the ≥1% and ≥20% subgroups are skewed by the result for the ≥50% subgroup. Dr Riyaz Shah indicated that this trial is negative in terms of clinical applicability and that current practice will remain unchanged.

“We don’t know why this happens…we should maybe consider that the size of the tumour and prognosis may not be related when giving immuno-oncology (IO) therapy…it may be an inflammatory response. A lot of people are scratching their heads.” Dr Riyaz Shah, on the topic of crossing Kaplan–Meier curves seen in study results with IO therapies

“I don’t think all these drugs are the same…they have slightly different half-lives and molecular targets…A lot of granularity we do not know yet…there is no answer for it.” Dr Riyaz Shah, on the topic of the conflicting trial results reported between PD-L1 inhibitors

SCLC (Dr Martin Forster)

The studies discussed in this session included the reports on combinations nivolumab + ipilimumab, durvalumab + tremelimumab and monotherapy pembrolizumab in SCLC. Take-home messages on immunotherapy in SCLC include:

• Immunotherapy agents targeting programmed cell death 1 (PD-1)/programmed death-ligand 1 (PD-L1) with and without cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitors showed reproducible evidence of efficacy in relapsed SCLC
• Benefit appears to be limited to a subset of patients
• PD-L1 is a suboptimal marker of efficacy but helps to select patient groups for improved activity of pembrolizumab
• High tumour mutational burden is associated with strong efficacy of nivolumab + ipilimumab

In conclusion, it appears that immunotherapy has a role in the management of SCLC; however, confirmation of the initial signal of benefit observed is awaited from ongoing pivotal studies.

Succinct invests in their teams’ knowledge by regularly attending international congresses and national study days to ensure we are up to date with the latest knowledge and trends. If you are interested in how our oncology expertise can help you with your communications needs, please contact Louise Carrington at Louise.Carrington@succinctcomms.com or +44 (0)7468 714548.