Immunotherapy May Accelerate Some Lung Cancers

Pam Harrison

September 11, 2018

Although immunotherapy for advanced non–small cell lung cancer (NSCLC) is being lauded as game changing, the phenomenon of treatment-associated hyperprogressive disease (HPD) continues to serve as a warning that the new therapy is potentially harmful for some patients, say French researchers.

Their retrospective study of HPD in this setting was published online September 6 in JAMA Oncology.

The analysis was first presented at the 18th World Conference on Lung Cancer in 2017.

The investigators explain that HPD is a pattern of progression in NSCLC in which tumor growth, as measured by CT, is faster after initiation of treatment than it was prior to treatment initiation.

"Colleagues have observed that some patients treated with single-agent immunotherapy have quite a deleterious outcome, which is not something frequently seen with single-agent chemotherapy," lead author Benjamin Besse, MD, PhD, Gustave Roussy Institute, Villejuif, France, said in an online interview.

"What we showed is for those patients who experienced HPD [within the first 6 weeks of initiation of PD-1/PD-L1 inhibitor therapy], overall survival is very poor, at only 3.4 months, compared to patients without HPD who progress under immunotherapy, where overall survival is 6.2 months (P = .003)," he added.

"What this means is that you have to assess patients early for HPD by CT scan at 6 or 8 weeks after the start of immunotherapy, and in the case of rapid acceleration of tumor growth, you need to switch to a new line of chemotherapy," Besse cautioned.

The study involved 406 previously treated patients with stage III or IV NSCLC who received a PD-1/PD-L1 inhibitor at one of eight French institutions. The study included a control cohort of 59 similar patients who received conventional, single-agent chemotherapy at four institutions.

Among the immunotherapy cohort, 13.8% of patients were classified as having HPD. Among the control patients, 5.1% were classified as having HPD.

This is the largest analysis of HPD to date, and it is the first study conducted in a population consisting exclusively of NSCLC patients.

The PD-1/PD-L1 inhibitors included nivolumab (Opdivo, Bristol-Myers Squibb), pembrolizumab (Keytruda, Merck & Co), atezolizumab (Tecentriq, Genentech/Roche) and durvalumab (Imfinzi, AstraZeneca).

Almost all (93%) of the immunotherapy cohort received single-agent PD-1 inhibitor therapy as second-line therapy or later, the investigators report.

For all of the patients in the control cohort, platinum-based therapy had failed, and the patients received any one of a number of single-agent chemotherapy options.

Three CT scans are required to measure HPD, Besse explained. The initial CT scan is taken prior to baseline; another baseline CT scan is taken just before treatment initiation; and a third CT scan is performed at the first assessment point.

"You then measure the tumor growth rate between the pre-baseline CT scan, the baseline CT scan, and then you measure tumor growth rate between the [second] baseline CT scan and the first assessment," Besse elaborated.

For the current study, HPD was defined as a change in tumor growth rate at the first assessment in excess of 50% compared to the baseline CT scan taken just prior to treatment initiation.

The investigators observed that HPD was significantly more likely to occur in patients who had more than two sites of metastasis prior to initiation of PD-1/PD-L1 inhibitor therapy (62.5%) compared with patients who did not have HPD (42.6%; P = .006).

In contrast, no significant differences were observed between patients who experienced HPD and those who did not in terms of baseline tumor burden, the number of previous lines of therapy, or age.

Findings at 1 Year

In the immunotherapy cohort, at a median follow-up of 12.1 months, the objective response rate was 18.9%, the study authors report.

For 41.9% of these patients, progressive disease was the best response to immunotherapy, they add.

The median progression-free survival (PFS) was 2.1 months; the median OS was 13.4 months.

In the single-agent chemotherapy cohort, the median follow-up was 26.3 months.

Among this group of patients, the objective response rate was 10.2%; for 30.5% of the group, progressive disease was the best response.

The median PFS was 3.9 months; the median OS rate was 8.6 months.

Six weeks after initiation of chemotherapy, among patients with HPD, median OS was 4.5 months, compared with 3.9 months among patients without HPD but who were found to have progressive disease at the first assessment (P = .60).

Besse noted that for many phase 3 studies that compared single-agent immunotherapy to single-agent chemotherapy, the results favored immunotherapy.

However, in second-line treatment of advanced NSCLC, Besse suggested that findings from the current study might affect consideration of its use because of the poor OS associated with HPD.

For patients with signs of HPD, "an early switch to salvage chemotherapy should be considered," the investigators conclude.

Dr Besse has received research funding from GlaxoSmithKline, Roche/Genentech,

Clovis Oncology, Pfizer, Boehringer, Eli Lilly, Servier, Onxeo, Bristol-Myers Squibb, Merck Sharp & Dohme, OSE Pharma, Inivata, and AstraZeneca.

Lancet Oncol. Published online September. 6, 2018. Full text

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