Clinical pattern of failure after a durable response to immune checkpoint inhibitors in non-small cell lung cancer patients

Abstract

Although immune checkpoint inhibitors (ICIs) can induce durable responses in non-small-cell lung cancer (NSCLC) patients, a significant proportion of responders still experience progressive disease after a period of response. Limited data are available on the clinical patterns of acquired resistance (AR) to ICIs. Clinical and radiologic data from 125 NSCLC patients treated with anti-PD-1 or PD-L1 antibodies between 2011 and 2018 at two tertiary academic institutions were retrospectively reviewed. Overall, 63 (50.4%) patients experienced AR after ICI treatment in a median of 10.7 months. Among the 13 patients with a partial response with ICI, 12 (32.4%) had only lymph node progression. Most patients (n = 52, 82.5%) had one or two sites with progression (oligo-progression). The median overall survival (OS) after progression was significantly longer in the extrathoracic group than in the thoracic and liver progression groups (30.2 months [95% confidence interval (CI), 13.4 to not reached (NR)], 11.7 months [95% CI, 9.5–21.1], and 5.4 months [95% CI, 2.6-NR], respectively, P < 0.001). Patients with oligo-progression had significantly longer OS after AR than did the multi-progression patients (18.9 months [95% CI, 10.6-NR] vs. 8.8 months [95% CI, 5.7-NR], P = 0.04). No significant difference in progression-free survival was observed between the subsequent chemotherapy and the ICI after AR groups (P = 0.723). Patients with AR after ICI treatment had a unique progression pattern with oligo-progression and high rates of progression only in the lymph nodes. Local treatment and/or continuation of ICIs beyond AR might be an effective option.

Atypical Response in Metastatic Non-Small Cell Lung Cancer Treated with PD-1/PD-L1 Inhibitors: Radiographic Patterns and Clinical Value of Local Therapy

“…In addition, all lesions during the initial radiological examination were evaluated, and patients with more than three metastatic organs or sites were found to be more likely to develop AR. The spatial distribution of progressive lesions in patients with AR, in terms of sites and number, was quite similar to that reported in those with acquired resistance to PD1/PD-L1 inhibitor [5,[21][22][23][24][25]. In both clinical scenarios, the common sites of progressive disease often occurred in the lymph nodes and lung, and the most common progressive lesion mainly occurred in the originally existing sites; meanwhile, the majority of patients had no more than three progressive lesions, indicating potential shared mechanisms regarding intra-tumoral heterogeneity and reductant immune evasion pathways in metastatic NSCLC [22,[26][27][28].…”

Characteristics and Prognosis of Acquired Resistance to Immune Checkpoint Inhibitors in Gastrointestinal Cancer

“…In our cohort, the time to AR was approximately 7 to 8 months for either mono or combination ICIs or different primary sites, and most patients developed AR within 24.0 months. 11 , 13 , 15 Accumulating evidence suggests that dynamic cross-talk between cancer cells and the immune microenvironment is associated with the occurrence of AR. 7 Although the current mechanisms of AR are summarized as defects in tumor antigen presentation, neoantigen depletion, tumor-mediated immunosuppression or exclusion, and additional inhibitory checkpoints, the exploration of the mechanism is still far from sufficient.…”

“…The progression patterns of AR have been previously reported in melanoma and NSCLC but, to our knowledge, have not been explored in GI cancer. 12 , 15 , 21 In the present study, we classified the progression patterns of AR into oligoprogression and polymetastatic progression on the basis of findings from previous studies. Consistent with studies on other solid tumors, we found that the pattern of AR was predominantly oligoprogression and was associated with a good prognosis.…”

International consensus on radiotherapy in metastatic non-small cell lung cancer

“…Oligo-progression is a common phenomenon in TKItreated oncogene-addicted NSCLC (95)(96)(97), and is increasingly encountered in patients treated with ICIs (98)(99)(100). Once acquired resistance (AR) is identified, systemic treatment options include next generation TKIs or other ICIs, introduction of other biological agents targeting bypass signaling pathways leading to AR, and chemotherapy.…”