Comments on abstract, title, references

The authors provide a well-organized and succinct abstract which is easy to navigate. The nature of clinical population with an unmet clinical need being studied is clearly defined in the background section as well as the main aim of the study comparing the use of durvalumab with placebo in a Phase 3 clinical trial setting. The methods section provides a nice summary of the manner in which patients were assigned to treatment and received protocol therapy along with a brief overview of primary and secondary study objectives. The authors then provide an overview of the main results which were in line with defined study objectives and are supported by robust statistical findings. The conclusion then provides a brief summary of the main efficacy and safety findings and highlights a major clinically important finding that patients receiving durvalumab received a significant PFS advantage (major study endpoint) over placebo recipients.

The title is very clear and defines the therapy being evaluated in a specific patient population.

With respect to references, most of the cited papers from well known journals represented current data at the time of publication of this study and were relevant to the field of lung cancer and its respective treatment.

Comments on introduction/background

The introduction section begins by briefly mentioning the currently available SOC chemo-radiation treatment for patients with locally advanced, stage 3 NSCLC which is being evaluated in this study. It then defines the clinical problem that such treatment is associated with poor PFS and thus there is an important unmet medical need to develop new therapies that could help improve PFS outcomes in the current clinical population.

There is a concise summary of the novel treatment being evaluated that comprises of a biological explanation which explains its mechanism of action. The authors also provide a rationale supporting durvalumab’s use as an effective anti-cancer regimen by providing preclinical evidence in NSCLC and its use in clinical practice in another advanced cancer type. The study hypothesis and the nature of clinical trial design is clearly defined.

Comments on methodology

PATIENTS

All patients were enrolled using a standardized inclusion and exclusion criteria that was clearly defined, which would have helped reduced clinical heterogeneity among the clinical population being studied.

END POINTS AND ASSESSMENTS:

The authors indicate the use of RECIST v1.1 for PFS assessment. However, this method of tumor response assessment is prone to false positive disease progression following treatment with immuno-therapeutic agents which is in fact a transient inflammatory response. Hence, the study would have benefited from the additional evaluation performed using immune-related response criteria (irRC) criteria to mitigate this problem which could in fact be indicative of better treatment efficacy and thus better PFS outcomes.

However, it was great to see that radiographic assessment was performed by a blinded independent central team which would have helped reduce any potential bias during assessment of patient’s re-staging scans while evaluating study outcomes.

STUDY OVERSIGHT:

The authors demonstrated clear use of following ethical, federal and institution specific guidelines to conduct the study in a manner that would have been in the best interest of the patient’s privacy and well-being.

STATISTICAL ANALYSIS

No specific comments.

Comments on data and results

PATIENTS AND TREATMENT

The authors provide a clear breakdown of clinical background and molecular landscape of the two treatment groups. Table 1 clearly shows a well-balanced patient population in a 2 to 1 ratio as planned by the study team.

EFFICACY/SAFETY

A fair number of patients were selected for statistical analysis with a good sample size, leading to higher statistical power. The use of Cox regression models to calculate Hazard Ratios is appropriate. PFS specific outcomes seem to be reliable statistically based on the narrow width of the confidence interval, suggesting lower levels of uncertainty in the findings. The Kaplein-Meir (KM) curve and tables were clear and easy to interpret and appropriately referenced in the text. The KM curve clearly demonstrated a trend of significant improvement in PFS outcomes as claimed by the authors. However, the safety section could have been further summarized by limiting the discussion revolving around adverse events comprising of pneumonitis or radiation pneumonitis by making a direct reference to Table # 3.

All study objectives mentioned in the methods section were evaluated by the study team and discussed in the results section.

Comments on discussion and conclusions

The authors clearly highlight the main finding of the study pertaining to PFS improvement in the opening statement of the discussion section. They also help provide a potential explanation for better PFS outcomes observed in PD-L1 patients with an “unknown” status (i.e. differences in sample size when compared against patients with other PD-L1 statuses). They also highlight an important point that patients with low levels of PD-L1 expression can also be expected to derive PFS benefit with durvalumab.

The clinical impact of this drug is also re-iterated with a succinct discussion of treatment response, duration of response and reduced proclivity of developing new brain metastases. However, the discussion could have been extended further by drawing comparisons with other immuno-therapeutic agents which appears to be lacking. Additionally, the authors could have considered including a short commentary on any potential study limitations. A brief concluding statement on the topic of future research was included but appears to be fairly broad and warrants a more focused approach.