PD-1/PD-L1 Inhibitors May Increase the Risk of Hyperprogressive Disease in NSCLC

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The association between disease progression and PD-1/PD-L1 inhibitors in non-small cell lung cancer is unknown.
The association between disease progression and PD-1/PD-L1 inhibitors in non-small cell lung cancer is unknown.

Hyperprogressive disease (HPD) may occur with greater frequency among pretreated patients with non-small cell lung cancer (NSCLC) who receive programmed cell death 1 (PD-1) or programmed cell death ligand 1 (PD-L1) inhibitors compared with chemotherapy, according to a study published in JAMA Oncology.1

Immunotherapy with PD-1/PD-L1 inhibitors have greatly improved outcomes among patients with cancer, but only a small proportion of patients are eligible for therapy and progression rates are sometimes as high as with conventional therapies. Furthermore, instances of HPD — accelerated tumor growth — have been reported during immunotherapy in nearly a third of patients with head and neck cancer,2 the association between disease progression and PD-1/PD-L1 inhibitors in NSCLC is unknown.

For this retrospective study, researchers evaluated the outcomes of 406 pretreated patients with advanced NSCLC who received PD-1/PD-L1 inhibitors or single-agent chemotherapy. At least 2 computed tomography (CT) scans, 1 at baseline and 1 most recent scan before baseline, and 1 CT during treatment were mandatory for radiological evaluation. HPD was defined as disease progression at the first evaluation with a variable tumor growth rate (ΔTGR) exceeding 50%.

The median follow-up was 12.1 months and the median overall survival (OS) was 13.4 months. Overall, 56 patients (13.8%) met the criteria for HPD, and 19 (4.7%) had pseudo-progressive disease. 

Patients with HPD were significantly associated with having at more than 2 metastatic sites prior to initiating PD-1/PD-l1 inhibitor therapy compared with non-HPD patients (62.5% vs 42.6%; P = .006). Patients with HPD within the first 6 weeks of starting PD-1/PD-L1 inhibitor therapy had a median OS of 3.4 months compared with 6.2 months among patients with progression disease (hazard ratio [HR], 2.18; 95% CI, 1.29-3.69; P = .003).

Of the 59 patients who received chemotherapy, 3 (5.1%) developed HPD.

The authors concluded that there may be “a detrimental association of immunotherapy in a subset of patients with NSCLC. Additional studies are needed to characterize the molecular basis of HPD.”


  1. Ferrara R, Mezquita L, Texier M, et al. Hyperprogressive disease in patients with advanced non-small cell lung cancer treated with PD-1/PD-L1 inhibitors or with single-agent chemotherapy [published online September 6, 2018]. JAMA Oncol. doi: 10.1001/jamaoncol.2018.3676
  2. Saâda-Bouzid E, Defaucheux C, Karabajakian A, et al. Hyperprogression during anti–PD-1/PD-L1 therapy in patients with recurrent and/or metastatic head and neck squamous cell carcinoma. Ann Oncol. 2017;28(7):1605-1611.

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