First-line Immune Checkpoint Inhibitors May Have Lower Risk of Hyperprogression

Hyperprogression—paradoxically accelerated tumor growth—has been reported in a subset of patients with non-small cell lung cancer being (NSCLC) treated with second- or later-line monotherapy immune checkpoint inhibitors (ICIs) such as Keytruda (pembrolizumab), Opdivo (nivolumab) and Tecentriq (atezolizumab). But the risk is “markedly lower” with first-line ICIs, particularly chemoimmunotherapy, according to a study pubished in The Oncologist by Lee Li of Flinders University in Australia, and an international team of investigators.

Their study, to their knowledge, is the largest to evaluate risk factors of ICI hyperprogression and one of the most thorough evaluations of contemporary biomarkers. Earlier studies that investigated hyperprogression in single-agent, second/later-line ICI settings provided “limited insights” into the phenomenon’s occurrence with first-line and/or chemoimmunotherapy treatment, the researchers say. Moreover, prior studies examining clinicopathological features had small sample sizes and did minimal investigation of key biomarkers, such as tumor mutation burden or immunophenotypes, said Li and colleagues.

In contrast, these researchers reviewed data on 4,644 patients from seven clinical trials who were treated with Tecentriq as a first-, second-, and later-line therapy of locally advanced or metastatic NSCLC, either as monotherapy or chemoimmunotherapy. Secondarily, they wanted to identify biomarkers that could predict hyperprogression. Tecentriq is a PD-L1 inhibitor, a group that also includes Bavencio (avelumab) and Imfinzi (durvalumab).

The study involved 3,129 patients who received therapy containing Tecentriq and 1,515 who did not. Of the patients who received Tecentriq as first-line therapy, 92% were treated with chemoimmunotherapy and 8% with Tecentriq monotherapy. Median follow-up was 17.3 months.

Among those who were treated with Tecentriq, 119 experienced hyperprogression; 106 were receiving second- or later-line treatment. The risk was 0.7% for first-line treatment compared with 8.8% for later-line monotherapies. There was no statistically significant difference in risk between first-line atezolizumab-chemotherapy and chemotherapy alone.

Younger age, liver metastases, and higher metastatic site count increased the risk of hyperprogression. Median survival with hyperprogression was similar in both groups: 4.3 months in the first-line patients, 6.1 months in the second- or later-line patients.

Biomarkers associated with a higher risk of hyperprogression included higher neutrophil-to-lymphocyte ratio (the single strongest predictor), platelet count, and C-reactive protein levels. Notably, Li and colleagues said, tumor mutation burden and PD-L1 expression were not meaningfully associated with risk of hyperprogression.