Resistance to Immune Checkpoint Inhibitor Treatment in NSCLC Clinical Trials: A Perspective from Lung-MAP Investigators

The Lung Master Protocol (Lung-MAP) has been focusing on evaluating novel therapeutics for previously treated advanced non-small cell lung cancer (NSCLC) since 2014.¹ Lung-MAP’s initial studies of immune checkpoint inhibitors (ICIs) were for immune-therapy naïve disease.^2,3 As standard of care changed to include ICI alone or in combination with chemotherapy for first-line advanced NSCLC, Lung-MAP changed its focus to evaluating novel therapies for advanced NSCLC previously treated with ICI and chemotherapy.

As discussed by the Society for Immunotherapy of Cancer (SITC) Immunotherapy Resistance Taskforce starting in 2020 and others, Lung-MAP investigators have held that the evaluation of new therapeutic strategies post ICI-containing therapy will often need to consider if a patient experienced any benefit from the prior ICI-containing therapy. Thus, the focus has been to evaluate potential approaches to overcome resistance to prior ICI-containing treatment (i.e. the acquired resistance population) or to address intrinsic (primary) resistance to ICI-containing therapy separately. In order to conduct clinical trials for ICI-pretreated non-small cell lung cancer (NSCLC), the Lung-MAP team needed to define standardized eligibility criteria for resistance to prior ICI-containing therapy. Here, we discuss our approach to defining these populations to be used as eligibility criteria in clinical trials; our purpose is not to guide individualized treatment decisions or to put forth a consensus statement such as provided by the SITC Taskforce.

Interpreting definitions for acquired versus primary resistance is relatively straightforward for treatment with ICI alone and definitions based on measures of clinical benefit are well accepted.⁴ A challenge occurs with ICI combined with chemotherapy as is used as frontline therapy for many with NSCLC. It is reasonable to define primary resistance to both chemotherapy and ICI, but if a patient benefits from ICI and chemotherapy, it is not possible to know if the benefit is from the ICI, the chemotherapy, or both based on a measure of clinical benefit alone. That said, we (Lung-MAP) still need to define eligibility criteria for clinical trials in participants who receive combination chemotherapy and ICI, and until we have a biomarker for response to ICI, we have to accept that there will be heterogenous populations that meet the criteria for acquired resistance.

The major issues that we address are: (1) what degree of prior clinical benefit is needed to define acquired resistance; (2) the minimum exposure to ICI therapy to define any level of resistance; (3) incorporating the first two issues, how we define primary and acquired resistance to ICIs alone or in combination with chemotherapy; and (4) how to define acquired resistance when off ICI either due to a treatment interruption or completion (e.g. for earlier stage disease and adjuvant, neoadjuvant, or consolidation therapy).

We first describe existing definitions of primary and acquired resistance to ICIs alone or with chemotherapy in patients, mentioning when proposed definitions are specific to NSCLC. We then describe the Lung-MAP team’s definitions and the rationale behind them. Where appropriate, we suggest definitions and their application to all stages of NSCLC, where ICI now has an established role, noting that not all prior recommendations have addressed early-stage disease in detail.

Previous Expert Consensus Statements

In 2020, the Society for Immunotherapy of Cancer (SITC) Immunotherapy Resistance Taskforce provided initial guidelines for categorizing primary and acquired resistance to single-agent PD-(L)1 inhibitor across solid tumors in the metastatic setting.⁵ The Taskforce had the following recommendations for advanced disease: (1) primary resistance was defined as progressive disease (PD) within 24 weeks of initiation of therapy, regardless of evidence of clinical benefit (i.e., objective response or stable disease [SD]); acquired resistance was defined as progressive disease (PD) after best response of complete response (CR) or partial response (PR) or SD lasting ≥24 weeks; (2) the minimum required exposure to ICI was to be 6 weeks of treatment prior to declaring resistance to ICI, but to be declared as acquired resistance, ICI must have been given up to the time of PD; and (3) prior clinical benefit includes both response and prolonged SD. In the adjuvant setting, 12 weeks from the last dose of ICI was used to differentiate between primary resistance or “early relapse” (<12 weeks) and “late relapse” (≥12 weeks).

In 2023, the SITC Taskforce addressed these issues for ICI combined with chemotherapy;^6–8 their definitions were modified from the 2020 definitions to address primary versus acquired resistance based on 12 instead of 24 weeks and specified the minimum ICI exposure to be 2 cycles (6–12 weeks, depending on the treatment). (Supplemental Tables 1 and 2).

In the Annals of Oncology in 2021, an international group of thoracic oncologists proposed the following definitions for acquired resistance to ICI alone in NSCLC: (1) to define clinical benefit solely based on objective response; (2) to define the minimum required exposure to ICI to be at least one dose of ICI; (3) to define acquired resistance as PD after best response of complete response (CR) or partial response (PR) of any length; and (4) in the context of interrupted or completed ICI treatment, to define acquired resistance as PD within 24 weeks off treatment.⁴ The definitions differed from the SITC Taskforce by eschewing time-based definitions and focusing on type of therapy, depth of response, time on treatment, and continuity of treatment. By their criteria, patients with early responses followed by progression prior to 24 weeks were categorized as having acquired resistance, whereas the SITC Taskforce characterized such patients as having primary resistance.

Rationale and Methods

A multidisciplinary panel of thoracic medical oncologists, radiation oncologists, surgical oncologists, and biostatisticians participating in Lung-MAP was convened. This commentary draws upon the perspectives through the lens of the Lung-MAP experience. A group of 22 Lung-MAP investigators met three times virtually and shared written comments between meetings. Dr. Deborah Doroshow maintained the meeting minutes, compiled the recommendations and drafted the manuscript, along with Drs. Ticiana Leal, Mary Redman, Saiama Waqar, and Karen Reckamp. All authors reviewed and approved the final manuscript. The majority agreed on the recommendations included unless stated otherwise.

The panel agreed on the following tenets. First, 6 weeks is the minimum exposure to ICI inhibition required to declare resistance (primary or acquired); fewer than 6 weeks of exposure was deemed insufficient exposure to ICI therapy to determine resistance. This benchmark is used as it accounts for at least 2–3 doses of therapy, depending on the treatment schedule. Next, definitions for resistance type would not differ between ICI alone versus chemoimmunotherapy, mostly for practical considerations. That response of any duration along with prolonged stable disease (SD) should be included in a measure of clinical benefit to ICI. Next, PD >24 weeks after the last dose of PD-(L)1 inhibitor for nonmetastatic disease would be considered acceptable for enrollment of the patient on a first-line clinical trial based on the expected pharmacokinetics and pharmacodynamics of ICIs and the aggressive nature of NSCLC.⁹

In the context of clinical trial eligibility, our group recommends that baseline imaging (CT or PET/CT) be performed within 4 weeks of starting standard treatment to ensure an accurate baseline and does not recommend a confirmatory scan in the case of either response or progression based on practicality, ensuring an inclusive study population, and because delayed responses and pseudoprogression are uncommon in NSCLC.¹⁰ Furthermore, this could delay start of the next line of treatment which could be detrimental. Finally, while clinical trials primarily use the RECIST 1.1 criteria for radiographic evaluation,¹¹ this may not be accessible or feasible for many practitioners in standard practice. Thus, our recommendations rely on oncologists’ and radiologists’ clinical assessments for study entry.

Metastatic NSCLC

Table 1 describes our proposed eligibility criteria for studies of second line acquired resistance and primary resistance populations. Among patients who have received the minimal amount of therapy, we define acquired resistance in the metastatic setting as: 1) radiographic response to therapy (i.e. CR/PR) followed by PD – regardless of timing; 2) best response of SD followed by PD after at least 12 weeks from start of therapy; or 3) Completion of 2 years of ICI therapy with disease control followed by PD within 24 weeks after discontinuation of ICI therapy. Patients meeting any of these criteria would be eligible for a second-line trial focused on acquired resistance. It follows that for patients receiving the minimal therapy could be eligible for a second line study if they had a best response of PD or SD followed by PD within 6–12 weeks of start of therapy, although many trials exclude this population as they have poor clinical outcomes.¹² Finally, referencing the last scenario, if PD was greater than 24 weeks after discontinuation of ICI therapy, re-start of ICI may be appropriate.

Table 1.

ICI Resistance Categorization and Trial Eligibility

Category	Clinical Outcome	Progression (PD) Timing: Window to Define Resistance Category	Surgical Timeline	Trial Eligibility
Metastatic disease
Insufficient exposure	Immediate PD or insufficient ICI	<6 weeks of ICI therapy regardless of clinical outcome	Not applicable	Depends on protocol
Sufficient exposure, primary resistance	PD as best response	≥6 weeks to <12 weeks from start of ICI	Not applicable	Second line
Sufficient exposure, acquired resistance	PD after CR or PR	≥6 weeks from start of ICI	Not applicable	Second line
	PD after SD	≥12 weeks from start of ICI
	PD after completing 2 years of ICI	≥104 weeks from start of ICI to ≤24 weeks from last dose of ICI
		>24 weeks from last dose of ICI		Favor first line
Locally advanced unresectable disease
Insufficient exposure	Immediate PD or insufficient ICI	<6 weeks of ICI therapy regardless of clinical outcome	Not applicable	Depends on protocol
Sufficient exposure, primary resistance	PD compared with post-chemoRT scans	≥6 weeks from start of ICI to <12 weeks from last dose of ICI	Not applicable	Second line
Sufficient exposure, acquired resistance	PD compared with post-chemoRT scans	≥12 weeks from start of ICI to ≤24 weeks from last dose of ICI
		>24 weeks from last dose of ICI		First line
Resectable disease
Insufficient exposure	Immediate PD or insufficient ICI	<6 weeks of ICI therapy regardless of clinical outcome	Not applicable	Depends on protocol
Sufficient exposure, primary resistance	PD while on neoadjuvant ICI or at preoperative scan after neoadjuvant ICI	≥6 weeks from start of ICI to ≤ time of preoperative scan (during neoadjuvant)	Preoperative	Second line
	PD while receiving adjuvant ICI; no neoadjuvant ICI	≥6 weeks from start of adjuvant ICI to ≤12 weeks from last dose of ICI	Postoperative
Sufficient exposure, acquired resistance	PD after neoadjuvant ICI only; no adjuvant given	> Preoperative scan to ≤24 weeks from last dose of ICI
		>24 weeks from last dose of ICI		First line
	PD while receiving adjuvant ICI; no neoadjuvant given	≥12 weeks from start of adjuvant ICI to ≤24 weeks from last dose of ICI		Second line
		>24 weeks from last dose of ICI		First line
	PD while receiving adjuvant ICI; neoadjuvant given	≤24 weeks from last dose of ICI		Second line
		>24 weeks from last dose of ICI		First line

Abbreviations: CR, complete response; ICI, immune checkpoint inhibitor; PD, progressive disease; PR, partial response; SD, stable disease.

Locally Advanced Unresectable NSCLC

The treatment of patients with locally advanced unresectable disease who experience recurrence after consolidation ICI therapy represents a clinical challenge. Clinical investigators designing second-line studies must clarify the extent of previous ICI therapy required to define acquired resistance; while in first-line studies, they must decide which patients exposed to consolidation therapy should be excluded to define an “ICI naïve” population.

As we do for the metastatic setting, we define sufficient exposure as 6 weeks of ICI therapy. Not only is this enough ICI therapy exposure to determine resistance, this timeline also affords sufficient distance from concurrent chemoradiation to determine that clinical progression cannot be entirely attributed to failure of chemoradiation to control disease. We propose that PD between 6 weeks from the start of ICI up to 24 weeks after the last dose of PD-(L)1 inhibitor to define eligibility for a second-line study for advanced NSCLC with acquired resistance to ICI. We propose PD after 24 weeks from the last dose of ICI as potential eligibility for a first-line trial.

Resectable NSCLC

Regimens utilizing ICI(s) with chemotherapy have become the standard of care for resectable NSCLC. While ICI is given as neoadjuvant with alone, adjuvant alone or in both settings, we apply our definitions to ICI therapy during all components of the perioperative period.

As in metastatic and locally advanced unresectable settings, we define sufficient exposure as 6 weeks of ICI inhibitor therapy. The best measure to assess clinical benefit in this setting is less clear and evolving. We chose to base eligibility definitions for second line trials following resistance to perioperative (chemo)immunotherapy on imaging alone (presence of absence of PD). While pathological responses (pathologic complete response – pCR – or major pathologic response – MPR) are associated with improved disease-free and overall survival,¹³ defining resistance based on pathologic response for those receiving neoadjuvant ICI may exclude patients who may benefit from continued ICI therapy; i.e., the eligibility definition for a second line trial would be too restrictive.

For neoadjuvant ICI-containing therapy, we propose that primary resistance be defined as PD while receiving neoadjuvant ICI or on a preoperative scan after ICI. Then, eligibility for a second line trial of acquired resistance would be based on PD after completion of neoadjuvant ICI and the preoperative scan and up to 24 weeks after the last dose of PD-(L)1 inhibitor. Some patients may have preoperative imaging suggesting tumor progression but may have a pCR or MPR at the time of surgery; such a scenario would not be considered primary resistance.

For adjuvant only therapies, we propose that PD between 6 weeks from the start of ICI up to 24 weeks after the last dose of PD-(L)1 inhibitor to define eligibility for a second-line study for advanced NSCLC with acquired resistance to ICI. As in previous scenarios, if recurrence occurs >24 weeks after the cessation of ICI, such patients would be eligible for a first-line trial.

Use of Biomarkers to Define Resistance

As research into mechanisms of resistance to ICIs continues to evolve, future first-line ICI combination studies should assess the relationship of these processes to radiologic or clinical disease progression.

A complementary approach could incorporate a potential biomarker or surrogate of ICI sensitivity in the design or as a pre-specified subset analysis. Multiple studies have demonstrated that circulating tumor DNA (ctDNA) dynamics are a sensitive and early marker of response to ICIs^14–16 and may be used to predict the development of acquired resistance.^17,18 Additionally, detection of molecular alterations associated with the emergence of resistance may guide therapeutic decision-making.

We have yet to develop a standardized method for assessing ctDNA dynamics, e.g., what extent of increase or decrease that might be required to determine whether a patient has progression or response. Limitations to such an approach include low shedding of ctDNA in patients with early-stage disease due to limited tumor burden or indolent tumors with low proliferation rates, though newer platforms are in development that have higher sensitivity while maintaining the high specificity needed for such studies. In addition, pathologic response and machine learning tools are potential surrogate biomarkers under development to define resistance to ICI.¹⁹

In summary, this proposed structure distinguishes primary and acquired resistance to ICIs in all disease stages of NSCLC with the goal of identifying patients who should be considered for first-line or second-line trials for the treatment of advanced NSCLC. The aim in doing so is to harmonize clinical trial eligibility definitions within LUNG-MAP so that study data are more uniform and generalizable. Ultimately, we look forward to the development of biological data which will render such definitions more accurate and beneficial for clinical research.