Liam Davenport

September 09, 2017

MADRID, Spain — Immunotherapy could be the new standard of care in patients with stage III, locally advanced non-small cell lung cancer (NSCLC) who have failed chemoradiotherapy, after a trial showed that the anti-programmed death ligand 1 (PD-L1) inhibitor durvalumab (Imfinzi, AstraZeneca) is effective in this hard-to-treat population.

Up to 35% of patients with NSCLC present with stage III, locally advanced disease that is, in the majority of cases, unresectable.

At present, the standard of care in this group is platinum-based doublet chemotherapy and concurrent radiotherapy, yielding a median progression-free survival (PFS) of 8 to 10 months, with only 15% of patients alive at 5 years.

The new results, from the PACIFIC study, showed that giving durvalumab after chemoradiotherapy doubled PFS over placebo, increasing it by 11 months.

Moreover, just less than half of durvalumab-treated patients were still alive 18 months after starting treatment.

This is the first randomized controlled trial of an immunotherapy in this clinical setting, noted lead author Luis Paz-Ares, MD, PhD, Medical Oncology, Hospital Universitario 12 de Octubre, CiberOnc, Universidad Complutense and CNIO, Madrid, Spain.

The study was presented during a Presidential Symposium at the European Society for Medical Oncology (ESMO) 2017 Congress, and simultaneously published in the New England Journal of Medicine.

In an ESMO press release, Dr Paz-Ares said that the improvement in PFS "was consistent across all patient subgroups that were analysed," and that the toxicity increase seen in the durvalumab group was "slight."

Dr Paz-Ares added: "PD-L1 inhibition after chemoradiation appears to be a new option for patients with locally advanced, unresectable stage III lung cancer. It will be important to see the impact on overall survival after a longer follow-up."

Reacting to the new findings, Pilar Garrido, MD, PhD, head of the Thoracic Tumour Section of the Medical Oncology Department at Ramoón y Cajal University Hospital, Madrid, Spain, who was not involved in the study, described the benefit seen with durvalumab as "clinically relevant" and, in terms of its 18-month PFS benefit, "highly encouraging."

Noting also the "acceptable toxicity profile of durvalumab in this setting," she said: "Overall survival data are awaited, but the magnitude of PFS benefit supports this combination as a new standard of care for unresectable stage III NSCLC patients who had no progression following standard care with platinum-based chemotherapy and concomitant radiotherapy."

Dr Garrido pointed out, however, that further research is needed on the duration and timing of immunotherapy, the best chemoradiotherapy regimen with which to combine it, and the selection of patients based on predictive biomarkers.

At an ESMO press conference where the study was highlighted, Enriqueta Felip, MD, PhD, head of the Lung Cancer Unit at Vall d`Hebron University Hospital in Barcelona, Spain, commented that the study was "very well designed" and that the results are "really promising."

Although again underlining the need to wait for overall survival results, she added: "In my opinion, this is a very relevant trial, in a group of patients [for whom] we need new treatment strategies."

Earlier this year, durvalumab was granted an accelerated approval from the US Food and Drug Administration in patients with locally advanced or metastatic urothelial carcinoma who progress during or after prior platinum-based chemotherapy. The drug is under review in Canada and Australia for similar use.

To coincide with the current results, AstraZeneca announced that, based on the PACIFIC data, it is "in discussions with global health authorities regarding regulatory submissions for durvalumab."

Speaking to Medscape Medical News before the ESMO 2017 Congress, Solange Peters, MD, PhD, ESMO Congress Press Officer, and from the Oncology Department, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland, said results like these are "a kind of a revolution, because these compounds have been developed in order to prolong survival in the palliative setting."

She added: "We are completely changing the paradigm, and the more we move, the more we can say that this will probably take over all the old guidelines and revolutionize all that we have been writing in the last decades."

Study Details

The PACIFIC study involved 713 adult patients with stage III, locally advanced, unresectable NSCLC who have progressed after two or more cycles of platinum-based chemoradiotherapy and a World Health Organization Performance Status of 0 to 1.

The patients were randomly assigned 1 to 42 days after completing chemoradiotherapy in a 2:1 fashion, stratified by age, sex, and smoking history to durvalumab 10 mg/kg once every 2 weeks for up to 12 months (n = 476) or to a matching placebo (n = 237).

The primary endpoints were PFS, determined using the Response Evaluation Criteria in Solid Tumors, version 1.1, and assessed by a blinded independent central review committee, and overall survival.

This latter endpoint was not planned for inclusion in the current interim analysis and will be reported later.

The results presented by Dr Paz-Ares indicated that median PFS was significantly longer with durvalumab, at 16.8 months vs 5.5 months with placebo, yielding a stratified hazard ratio of 0.52 (P < .0001).

Moreover, the 12-month PFS rate was 55.9% with durvalumab and 35.3% with placebo, with the 18-month PFS rates at 44.2% and 27.0%, respectively. The PFS benefits were seen across all subgroups, including by tumor antigen expression, with both patients with PD-L1-positive tumors and those with tumors negative for the marker showing a significant improvement in PFS.

On secondary analyses, the objective response rate was significantly higher with durvalumab than placebo, at 28.4% vs 16.0% and with a relative risk for a treatment effect after durvalumab of 1.78 (P < .001).

The median duration of response was not reached with durvalumab but was 13.8 months with placebo. At 18 months, 72.8% of patients had an ongoing response vs 46.8% of those given placebo.

There were fewer new lesions in the durvalumab group, with 20.4% of patients experiencing a new lesion at any site and 5.5% experiencing a new lesion in the brain. This compared with 32.1% and 11.0%, respectively, among patients given placebo.

As expected, grade 3/4 adverse events were slightly more common with durvalumab than with placebo, seen in 29.9% vs 26.1% of patients, with adverse events leading to discontinuation experienced by 15.4% of durvalumab patients and 9.8% of placebo patients.

Grade 3/4 immune-related adverse events were recorded in 3.4% of durvalumab patients vs 2.6% of patients given placebo. In contrast, any grade immune-related events were seen in 24.2% and 8.1% of patients, respectively, suggesting the majority of the immune-related events with durvalumab were mild in nature.

Study discussant Johan F. Vansteenkiste, MD, PhD, professor and doctor at University Hospitals Leuven in Belgium, said after Dr Paz-Ares presented the data that the trial was "very important."

He nevertheless emphasized that the 15% survival rate seen after chemoradiotherapy in stage III unresectable NSCLC means that traditional treatment was in the territory of being curative, although recent developments in chemotherapy and radiotherapy have not added to that success.

Turning to PACIFIC, Dr Vansteenkiste, said that, given the clinical background, durvalumab is "clearly meeting an unmet clinical need," and that the reported hazard ratio is "very strong."

Furthermore, the current interim response rates may well point to a survival benefit in the future when the full results are available, although he did note that PFS has, in previous trials, "been a poor read-out" for overall survival.

Dr Vansteenkiste said the new results, which are the first set of strong interim findings seen in this setting, suggest radiotherapy and immunotherapy "can be excellent partners," as they have complementary effects.

The study was sponsored by AstraZeneca. Dr. Paz-Ares has received consultancy fees from AstraZeneca, Bristol-Myers Squibb, Merck Sharp and Dohme, Pfizer, Roche, Lilly, Boehringer Ingelheim, Novartis, and Ariad. Several coauthors also reported ties with pharmaceutical companies, and three coauthors are full-time employees of AstraZeneca with stock ownership.

European Society for Medical Oncology (ESMO) 2017 Congress: Abstract LBA1_PR. Presented September 9, 2017.

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