In the Journals

Anti-PD-1 drugs may cause hyperprogressive disease in lung cancer

Show Citation

September 6, 2018

Patients with advanced non-small cell lung cancer who underwent treatment with PD-1 and PD-L1 inhibitors had higher rates of hyperprogressive disease than those who received chemotherapy, according a multicenter retrospective study conducted in France.

Patients treated with immunotherapy who experienced hyperprogressive disease also demonstrated worse survival.

In previous trials, PD-1 and PD-L1 inhibitors — including nivolumab (Opdivo, Bristol-Myers Squibb), pembrolizumab (Keytruda, Merck), atezolizumab (Tecentriq, Genentech) and durvalumab (Imfinzi, AstraZeneca) — conferred a survival benefit among patients with advanced NSCLC.

“However, progression rates reported with single-agent PD-1/PD-L1 inhibitors are in some cases equal to or higher than with conventional treatment, ranging from 33% to 44% in pretreated patients with NSCLC,” Roberto Ferrara, MD, medical oncologist at the Institut de Cancérologie Gustave Roussy in France, and colleagues wrote. “Recently, an acceleration of tumor growth during immunotherapy, defined as hyperprogressive disease, was reported in 9% of advanced cancers and in 29% of patients with head and neck cancer treated with PD-1/PD-L1 inhibitors.”

To explore whether hyperprogressive disease occurs among patients with advanced NSCLC treated with immunotherapy, Ferrara and colleagues compared 406 patients (63.8% men; 46.3% aged 65 years or older; 72.4% nonsquamous histology) who received PD-1/PD-L1 therapy with 59 patients who received single-agent chemotherapy.

Inclusion criteria included measurable disease defined by RECIST v1.1 on at least two CT scans before treatment and one CT scan during treatment.

Researchers defined hyperprogressive disease as disease progression at the first evaluation based on an absolute increase in the tumor growth rate of more than 50% per month.

For 92.9% of patients in the immunotherapy group, PD-1 inhibitor monotherapy was their second-line or later therapy.

Median follow-up was 12.1 months (95% CI, 10.1-13.8) for the immunotherapy cohort and 26.3 months (95% CI, 22.6-33.5) for the chemotherapy cohort.

Researchers observed a median OS of 13.4 months (95% CI, 10.2-17) and a median PFS of 2.1 months (95% CI, 1.8-3.1) among patients treated with immunotherapy. In the chemotherapy group, median OS was 8.6 months (95% CI, 6.2-13.4) and median PFS was 3.9 months (95% CI, 3.1-4.8).

During immunotherapy, the tumor growth rate appeared stable or decreased in 266 patients (65.5%) and increased in 140 patients (34.5%). Sixty-two patients (15.3%) with increased tumor growth rate were classified as having hyperprogressive disease.

Nineteen patients (4.7%), who researchers classified as pseudoprogressors, had progressive disease followed by complete response, partial response or stable disease for longer than 6 months.


After excluding six pseudoprogressors who had hyperprogressive disease on the first CT scan from the hyperprogressive disease group, researchers calculated the definitive rate of hyperprogressive disease as 13.8% (n = 56).

Conversely, three patients (5.1%) treated with chemotherapy experienced hyperprogressive disease.

A greater proportion of patients with hyperprogressive disease in the immunotherapy group had more than two metastatic sites before treatment compared with those with non-hyperprogressive disease (62.5% vs. 42.6%; P = .006).

Patients undergoing treatment with PD-1/PD-L1 inhibitors who experienced hyperprogressive disease in the first 6 weeks had significantly lower median OS compared with patients with progressive disease (3.4 months vs. 6.2 months; HR = 2.18; 95% CI, 1.29-3.69). However, this association did not persist in the chemotherapy group (4.5 months vs. 3.9 months).

“In our study, hyperprogressive disease was associated with poor survival in patients with NSCLC treated with PD-1/PD-L1 inhibitors,” the researchers wrote. “Hyperprogressive disease could potentially explain the initial excess of death in some phase 3 trials.”

More studies are needed to characterize the molecular basis for hyperprogressive disease, according to the investigators. – by Cassie Homer

Disclosures: Ferrara reports no relevant financial diclosures. Please see the study for all other authors’ relevant financial disclosures.

itj+ Infographic

itj+ Perspective