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Expert Critique

FROM THE ASCO Reading Room

Brian S. Henick, MD Medical Oncology/Hematology Fellow Yale School of Medicine

At a hazard ratio of 0.52 (p<0.0001), the PACIFIC trial boasts promising 14.5-month median interim progression-free survival (PFS) data for adding 12 months of durvalumab (10 mg/kg Q2w) within 6 weeks of completing concurrent chemoradiotherapy (cCRT) in unresectable stage III non-small cell lung cancer (NSCLC) patients. Those randomized (2:1) to the treatment arm experienced lower incidence of new lesions at all sites including the central nervous system and longer median time to distant metastasis or death (HR 0.52, p<0.0001) compared with placebo in this phase III, international, multi-center study.

Durvalumab-treated patients were more likely to have adverse events (AEs) leading to discontinuation (15.4% versus 9.8%) and severe immune-related AEs as well as pneumonitis (3.4% versus 2.6%), but in general both regimens were comparably well-tolerated. Given that PFS measured by RECIST v1.1 may not be as clinically meaningful as hoped with immune checkpoint inhibitors, and the fact that the mark to beat for this population is a 15% 5-year overall survival (OS) rate, mature OS data will ultimately determine whether PACIFIC鈥檚 tide will turn.

In all, the interim results presented at ESMO are the most encouraging to date for inclusion of an immunotherapy drug in the definitive treatment of unresectable stage III NSCLC patients, and the magnitude of benefit has led to the NCCN鈥檚 inclusion of this regimen as the new standard for this population. As we await final OS data, PACIFIC鈥檚 interim results invite continued investigation into how to optimally leverage the combination of chemotherapy, radiation, and immunotherapy, as well as thoughtful approaches to overcome mechanisms of resistance that may emerge in pan-treatment-experienced progressors.

Full Critique

It's data that is disheartening: The prognosis for many patients with non-small cell lung cancer (NSCLC) who present with stage III, locally advanced, unresectable disease at diagnosis is dismal. The median progression-free survival (PFS) with concurrent chemoradiation therapy is approximately 8 to 10 months, the median overall survival (OS) is 18 months, and only 15% of patients are alive at 5 years.

But results from the have given lung cancer specialists and their patients a reason to take heart. The phase III trial, presented at the 2017 European Society for Medical Oncology (ESMO) congress, is the first to test durvalumab (Imfinzi), an immune checkpoint inhibitor, as sequential treatment in patients with stage III unresectable NSCLC who had not progressed following platinum-based chemotherapy concurrent with radiation therapy.

"This is the first strong interim PFS positive phase III trial on systemic therapy for stage III NSCLC over decades," Johan Vansteenkiste, MD, PhD, of University Hospital KU in Leuven, Belgium, said at the meeting in his remarks as discussant. "And that's good news."

Pilar Garrido, MD, of Ramón y Cajal University Hospital in Madrid, echoed those sentiments in an ESMO press statement: "Giving durvalumab after finishing chemoradiation improved progression-free survival by threefold compared to placebo, which is a clinically relevant benefit. The results for 12- and 18-month progression-free survival were also highly encouraging."

Other lung cancer experts called the trial results "important" and a potential game-changer for similar, ongoing trials. Nonetheless, questions remain as to whether chemoradiation plus durvalumab is a pairing that will last.

PACIFIC Details

For , 713 patients were randomized 2:1 to receive durvalumab at 10 mg/kg every 2 weeks or placebo for up to 12 months post-chemoradiation therapy. The co-primary endpoints were PFS and OS.

"Given preclinical evidence suggesting that chemotherapy and radiotherapy may upregulate [programmed death-ligand 1] PD-L1 expression in tumor cells, which is a predictive factor for a response to durvalumab, we hypothesized that durvalumab would provide clinical benefit after chemoradiotherapy," wrote Scott Antonia, MD, PhD, chair of the department of thoracic oncology at H. Lee Moffitt Cancer Center and Research Institute in Tampa, Florida, and colleagues in the, where the results were published simultaneously with the meeting presentation.

The investigator who presented the results at ESMO, Luis Paz-Ares, MD, PhD, of the Hospital Universitario Doce de Octubre in Madrid, said the PFS data suggests that the triple-combination therapy has the potential to be a game changer for stage III NSCLC treatment.

The median PFS was 16.8 months in the durvalumab arm (476 patients), compared with 5.6 months in the placebo arm (237 patients), Paz-Ares said, also reporting a stratified hazard ratio of 0.52 (95% CI, 0.42-0.65, P<0.0001). The improvement was consistent across subgroup analysis of the study cohort by sex, age at randomization, smoking status, disease stage, histology, best response to concurrent chemoradiation therapy, and epidermal growth factor receptor (EGFR) status.

Paz-Ares highlighted hazard ratios of PD-L1 expression in a subgroup analysis of the cohort: "Tumors with more than 25% expression of PD-L1 of the cells had a hazard ratio of 0.41, as compared to 0.59 for those patients whose tumor expressed PD-L1 less than 25% of the cells."

Also of note, he said: patients in the durvalumab arm showed fewer new lesions, 20.4%, than those in the placebo arm, 32.1%, with significantly fewer brain metastases (5.5%) than in the placebo patients (11.4%).

Treatment-related adverse events occurred in 67.8% of patients in the durvalumab group compared with 53.4% in the placebo group. The rate of immune-mediated adverse events was 24.2% with durvalumab and 8.1% with placebo.

"The safety profile of durvalumab in this population was consistent with that of other immunotherapies and with its known safety profile as a monotherapy in patients with more advanced disease (stage IIB or IV NSCLC)," Antonia's group wrote.

Severe pneumonitis or radiation pneumonitis (grade 3/4) was found in 3.4% and 2.6% of patients on durvalumab and placebo, respectively. Treatment was discontinued for this reason in 6.3% of patients on durvalumab and 4.3% on placebo.

"Durvalumab demonstrated a clinically meaningful benefit in overall response rate (28.4% versus 16%; P<0.001), with durable responses versus placebo (median duration of response not reached versus 13.8 months)," said Paz-Ares, adding that the study remains blinded to OS.

The PACIFIC investigators concluded: "These positive findings in an unselected patient population, irrespective of baseline expression of PD-L1 on tumor cells, suggest that durvalumab may be an effective adjuvant therapy in patients with stage III disease after standard treatment."

Praise for RT

Vansteenkiste observed that the trial demonstrated the synergy of radiotherapy with immunotherapy: "The main thing here is that radiotherapy and checkpoint immunotherapy are probably excellent partners for different reasons. Radiotherapy has a priming effect by immunogenic cell death; it promotes release of danger signals and chemokines that inflame the tumor microenvironment; radiotherapy promotes the release of neo-antigens -- the principle that irradiated cancer acts as an in-situ vaccine; it upregulates PD-1 and PD-L1; and finally, with radiotherapy alone, there are rare instances of abscopal effects."

Maria Werner-Wasik, MD, director of Clinical Research and co-director of the Thoracic Oncology Program at Sidney Kimmel Cancer Center at Thomas Jefferson University in Philadelphia, offered the radiation oncology take on the PACIFIC trial, which was also presented as a late-breaking abstract at the 2017 American Society for Radiation Oncology (ASTRO) annual meeting: "What's interesting is that benefits were derived for virtually all patient subgroups, with the particularly interesting finding that independent of PD-L1 status, all groups derived benefit," she noted in an .

But Werner-Wasik also pointed out that with any immunotherapy, "there is the fear that adverse events may occur in the form of inflammatory immune reactions in pretty much any organ of the body ... with pneumonitis being of most concern in patients treated with thoracic radiotherapy, who are at risk for [radiation-induced] pneumonitis already."

On the other hand, she called the data "reassuring -- specifically, pneumonitis or radiation pneumonitis was not significantly different for any grade ... between the two arms."

She said the trial results may have implications for other studies, such as the currently recruiting randomized phase III trial that will assess patients with stage III unresectable NSCLC who receive thoracic radiation, cisplatin, and etoposide followed by nivolumab (Opdivo) or placebo every 2 weeks for a year.

Popping the OS Question

Not surprisingly, the experts said they are waiting on OS results to see if the PACIFIC results will stay true in the long-term. Three future OS analyses are planned, Vansteenkiste noted. "Overall survival results will have more weight. For sure, we need to follow these data for survival in the curative setting. Still, I think this [trial] is a tsunami of benefit."

Bishal Gyawali, MD, PhD, most recently of Nagoya University in Japan, agreed, stating in an eCancer video that this "is one of the , but whether it will be a game changer, whether it will be ground-breaking, will depend on the OS details."

While, "we have to accept that there is substantial improvement in PFS with very excellent hazard ratio, all of us assume that this will translate to an OS benefit, and that's why we're excited about it," he added.

While Garrido conceded that OS data is important, she pointed out that "the magnitude of progression-free survival 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."

More research is necessary on the "duration and timing of immunotherapy, the best regimen of chemoradiation to combine it with, and the selection of patients most likely to benefit based on predictive biomarkers."

Durvalumab received a Breakthrough Therapy designation from the for the treatment of patients with locally advanced, unresectable NSCLC whose disease has not progressed following platinum-based chemoradiation therapy.