Considering specificities of non-small cell lung cancer (NSCLC) biology and corresponding treatment strategies for advanced disease, a group of experts led by Dr. Matthew Hellmann of the Department of Medicine, Memorial Sloan Kettering Cancer Centre in New York, NY, USA proposed a practical, clinical definition of acquired resistance to PD-(L)1 blockade for use in clinical reports and prospective clinical studies. According their definition, published on 3 September 2021 in the Annals of Oncology, patients should meet the following criteria: received prior treatment that includes PD-(L)1 blockade, experienced objective response on PD-(L)1 blockade, and have progressive disease occurring within 6 months of last anti-PD-(L)1 antibody treatment or rechallenge with anti-PD-(L)1 antibody, if not exposed to anti-PD-(L)1 in 6 months.

The authors wrote in the background that acquired resistance is common, but not well understood; it is in particular challenging in patients with lung cancer, as they develop acquired resistance at higher rate than those with other tumour types sensitive to PD-(L)1 blockade. Distinct considerations of acquired resistance in lung cancer suggests unique underlying determinants of durable clinical benefit and resistance and warrant disease-specific investigation.

Patterns of primary and acquired resistance may be fundamentally different. Patients with primary or acquired resistance may be sensitive to different types of subsequent therapies. Few clinical studies differentiate primary and acquired resistance at study entry and there is lack of uniformity of the definition to standardise enrolment. Future studies may only be successful in defining new standards of care if designed to differentiate distinct patient groups with primary versus acquired resistance.

The authors explained that in the development and testing of tyrosine kinase inhibitors for EGFR-mutated NSCLC, establishing of such definition has been critical for clinical and scientific progress. That definition consisted of several elements and by using the similar approach, the lung cancer experts looked into criteria for acquired resistance to PD-(L)1 blockade in terms of next factors: type of treatment, depth of response, degree of progression, timing of progression, and continuity of treatment.

They also explored the context for applying the definition, and where additional considerations and efforts may be needed. They built on recent efforts by the Society for Immunotherapy of Cancer (SITC) Immunotherapy Resistance Task Force, which have helped highlight specific areas of uncertainty in classification of acquired resistance, such as the classification of stable disease and duration of time required for acquired resistance classification, which require further data and disease-specific applications.

In terms of type of treatment, the experts now propose that prior treatment with PD-(L)1 blockade is required in criteria for acquired resistance in NSCLC. Immunotherapy combinations are allowed.

In terms of depth of response, patients should experience objective response on PD-(L)1 blockade. Stable disease is excluded.

In terms of timing of progression, no duration of response threshold is required. Confirmatory scans of progression after prior response are not required.

In terms of continuity of treatment, they proposed that progression should occur within 6 months of last PD-(L)1 blockade treatment. In patients with progression occurring more than 6 months since last treatment, PD-(L)1 blockade retreatment is required.

The authors wrote that their clinical definition is restricted to advanced NSCLC, and the recommendations differ from SITC in a number of elements including exclusion of stable disease because of its frequency in lung cancer and possibility that indolent disease may confound clinical studies, inclusion of patients with partial or complete responses to PD-(L)1 blockade with disease progression less than 6 months, and no requirement of confirmatory scans after initial disease progression because pseudo-progression is exceptionally uncommon in lung cancer.

Further research is needed to refine criteria of acquired resistance to apply to all treatment scenarios, particularly PD-(L)1 blockade plus chemotherapy combinations. The experts also currently do not have evidence to suggest distinct patterns or phenotypes of acquired resistance among different histologic subtypes of NSCLC and have included all patients with NSCLC within this definition.

The authors highlighted a number of clinical scenarios that require future collaboration for clarification. For example, heterogenous patient population receive chemotherapy and PD-(L)1 blockade; patients could respond to chemotherapy, PD-(L)1 blockade, or the combination, but the active agent(s) are not currently identifiable. Consequently, the treatment associated with acquired resistance is also unknown. In terms of best response of stable disease, it is unknown if this disease state represents naturally indolent disease or minor response. In terms of treatment in the adjuvant setting, initial radiologic response cannot be evaluated since there is no measurable disease to evaluate.

They wrote that their proposed definition takes a conservative approach, but if successful, it may help define evidence-based subsequent therapies. The authors also highlighted specific areas of uncertainty in classification of acquired resistance which if addressed could lead to refinements in the future.


Schoenfeld AJ, Antonia SJ, Awad MM, et al. Clinical definition of acquired resistance to immunotherapy in patients with metastatic non-small cell lung cancer. Annals of Oncology; Published online 3 September 2021. DOI: