Immunotherapy Poised to Move Forward Into Stage III NSCLC

Everett Vokes, MD

Approximately 30% to 40% of patients with non—small cell lung cancer (NSCLC) have stage III locally advanced disease at diagnosis.^1,2 Stage III NSCLC is a highly heterogeneous disease that encompasses locally advanced primary tumors that have infiltrated mediastinal organs, involve mediastinal lymph nodes, or are larger than 7 cm.^2,3 Patients are categorized as stage IIIA, IIIB, or IIIC, depending on tumor size and localization.³

No consensus exists on the best treatment approach for stage III NSCLC, but a combination of chemotherapy and radiotherapy is typically used.¹ Currently, the 5-year survival rates for stage III NSCLC range from approximately 36% for stage IIIA to 26% for stage IIIB to 13% for stage IIIC.³ Although the past 2 decades saw an abundance of targeted agents and immunotherapies emerge for metastatic NSCLC, progress in locally advanced disease remained stagnant until recently.

The Promise of Immunotherapy for Locally Advanced NSCLC

In September 2017, at the annual European Society for Medical Oncology (ESMO) Congress, researchers presented positive data from a phase III trial of durvalumab (Imfinzi) in patients with stage III NSCLC.^4,5 Durvalumab is an inhibitor of programmed cell death ligand-1 (PD-L1) approved in the United States for urothelial carcinoma. In an OncLive Peer Exchange^®, Everett E. Vokes, MD, moderated a panel of some of the world’s foremost experts on immunotherapy in lung cancer to discuss durvalumab and other emerging approaches for stage III NSCLC.Immunotherapy has changed the paradigm for managing metastatic NSCLC. In took just a few years from the approval of checkpoint inhibitors as a second-line option to their integration into first-line management.

Naiyer A. Rizvi, MD, recalled the first patient with lung cancer he treated with the anti— PD-1 antibody nivolumab (Opdivo) in 2009; the patient had an adrenal mass that was so painful, he went to the emergency department for pain medication right after his first nivolumab infusion. “It’s 8 years later, and he still has no evidence of disease. That’s why I think we’re so excited about incorporating immunotherapy into our treatment,” Rizvi said.

The hope is that the success of immunotherapy in the metastatic setting will be repeated in the locally advanced setting. Although the approach for stage III locally advanced NSCLC has shifted from palliative to curative, Vokes said only one-quarter to one-third of patients survive 3 years. Rizvi said none of the approaches tried after chemoradiation—including consolidation chemotherapy or adjuvant vaccine therapy—has “moved the bar” for stage III patients.

The PACIFIC Trial

Roy S. Herbst, MD, PhD, suggested that immunotherapy is poised to make a real difference for this population. Rizvi agreed, saying that many patients would be affected.For PACIFIC, an ongoing phase III trial, investigators have enrolled approximately 700 patients with untreated, unresectable stage III NSCLC.⁴ Participants underwent standard chemoradiotherapy before being randomly assigned to durvalumab or placebo at a 2:1 ratio.⁴ Interim data presented at the ESMO 2017 Congress and simultaneously published in the New England Journal of Medicine showed an approximately 11-month difference in median progression-free survival (PFS) that favored the durvalumab arm (16.8 vs 5.6 months; stratified HR for disease progression or death, 0.52; 95% CI, 0.42-0.65; P <.0001).^4,5 Compared with placebo, durvalumab was also associated with a higher rate of 1-year PFS (55.9% vs 35.3%, respectively), 18-month PFS (44.2% vs 27.0%), and overall response (28.4% vs 16.0%; P <.0001).⁴

Among patients who responded, significantly more in the durvalumab arm than in the placebo arm were still responding at 18 months (72.8% vs 46.8%). At the time of the interim analysis, data on overall survival (OS) were not yet mature.⁴ “[As far] as PFS goes, this is really a novel and impressive finding,” Vokes said. He added that the PFS data were unmatched by anything published for stage III NSCLC during at least the past 15 years.

“Another point that came out from the trial was that programmed death ligand 1 [PD-L1] expression didn’t seem to matter— patients with low and high PD-L1 expression benefited from getting the durvalumab maintenance or consolidation therapy,” Suresh S. Ramalingam, MD, said. PACIFIC investigators measured PD-L1 expression level prior to chemoradiotherapy. The HR for PFS in durvalumab-treated patients with a baseline PD-L1 expression level <25% was 0.59 (95% CI, 0.43-0.82) compared with 0.41 (95% CI, 0.26-0.65) for patients with a PD-L1 expression level ≥25%.⁴ “I think that these results come as a very refreshing step forward in a disease where we have been stuck with stagnation, and I think it will be incorporated into clinical practice,” Ramalingam said.

Rizvi agreed that the results were impressive. “To see a trial with 11-month difference in PFS—that’s massive. I think it’s going to be a new standard of care,” he said.

Fred R. Hirsch, MD, PhD, said although he concurred with the panel members that the PACIFIC findings were encouraging, he was unsure about prescribing it to patients based on the data presented. “I would like to see the OS data...and the quality of life [QOL] data. Does the improvement in PFS also lead to a better performance for the patients? We don’t know that yet,” he said.

“Although the data are not mature enough to have OS data, it is almost impossible in my mind to think that there isn’t going to be an OS benefit,” Rizvi countered. “If you hit PFS with an immunotherapy agent, you’re going to hit OS,” he said.

Nothing in the safety data suggested durvalumab would negatively affect QOL, according to Vokes. “I think the cough rate was a little bit higher, and maybe [there was] a higher pneumonitis rate [in the durvalumab arm],” he said. Approximately 35% of patients in the durvalumab arm developed cough compared with 25% of patients in the placebo arm.⁴ Just 0.4% of patients in each arm developed a grade 3 or 4 cough. In the durvalumab arm, 34% of patients developed pneumonitis compared with 25% of patients in the placebo arm.⁴ Rates of grade 3 or 4 pneumonitis were 3.4% with durvalumab therapy versus 2.6% with placebo.⁴ The study investigators described the treatment-related adverse effects as manageable.⁴

Herbst said that although patients in PACIFIC were a select, relatively fit group, which might affect toxicity outcomes, the study was randomized and the groups were balanced. He called the results historic and said he would recommended the drug to patients “as soon as there’s an approval and reimbursement available.” Herbst added that he does want to see OS data to “make sure that it’s trending in the right direction.”

Based on results of the PACIFIC trial, the FDA a granted priority review to a supplemental biologics license application for durvalumab to treat patients with stage III unresectable NSCLC that remains stable after at least 2 cycles of chemoradiation; a decision is pending.⁶ The decision deadline is April 17, 2018. The National Comprehensive Cancer Network updated its guidelines for NSCLC to recommend durvalumab in the same setting.⁷

UPDATE 2/16/2018: FDA Approves Durvalumab for Locally Advanced NSCLC

Other Immunotherapy Studies for Stage III NSCLC

According to Rizvi, data from PACIFIC suggest that immunotherapy acts synergistically with chemotherapy, radiation, or both. “Those patients who were randomized within 2 weeks of finishing radiation therapy had a slightly better HR than patients who were randomized more than 2 weeks after finishing radiation therapy,” he said. The panel agreed that the limited data available support the premise of starting treatment with immunotherapy early, in the adjuvant or neoadjuvant setting.

Data from a small study of neoadjuvant nivolumab were presented at the 2017 American Society of Clinical Oncology meeting.⁸ The 22 participants had resectable stage IB-IIIA NSCLC and received 2 doses of nivolumab in the month prior to surgery.⁸ Rizvi said he was surprised at the strength of the pathological response, which included tumor necrosis and T-cell infiltration. “The potential advantage of giving [immunotherapy] neoadjuvantly versus adjuvantly is you have the tumor onboard, so as you destroy the tumor, you release antigens [and] can magnify your T-cell response,” he said. Rizvi and colleagues are conducting a phase II trial of neoadjuvant atezolizumab (Tecentriq) plus chemotherapy (NCT02716038).

Neoadjuvant therapy has been recognized as an important approach in NSCLC for years, Hirsch said, adding that he and others have long advocated for more studies into the biologic response to neoadjuvant treatment. He said the FDA recently approached the International Association for the Study of Lung Cancer, which he heads, about organizing a workshop to help identify response criteria for neoadjuvant therapy, as well as a standardized approach to clinical trials of neoadjuvant therapy.

Ramalingam said he is involved in the Adjuvant Lung Cancer Enrichment Marker Identification and Sequencing Trials (ALCHEMIST), which are evaluating the effect of adjuvant treatment with a targeted agent or an immunotherapy drug in patients with resected stage IB-IIIA NSCLC. Investigators are looking at how gene alterations affect outcomes.

Clinical Trials and Progress

“It’s really remarkable— quite a large effort—and we should encourage people to support it and to participate,” Vokes said.Immunotherapy really has taken over as the other alternative for patients without drivers,” Herbst said, crediting immunotherapy for the survival of many patients in the metastatic setting. Questions remain, however, about how best to integrate immunotherapy in the treatment paradigm for patients with actionable targets and how to help the bulk of patients who do not appear to benefit from immunotherapy.

Answering these and other questions will require more and larger clinical trials, Hirsch said. “Scientific achievements and progress in treatment results come through clinical trials.” He expressed concern that clinical trials in the United States tend to take place in a handful of states, which leaves out many patients who might benefit. The panel predicted that combinations of immunotherapy agents or of immunotherapy and targeted agents will provide the key for improving outcomes for patients with stage III NSCLC.

References

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2. Rizvi NA, Peters S. Immunotherapy for unresectable stage III non-small-cell lung cancer. N Engl J Med. 2017;377(20):1986-1988. doi: 10.1056/NEJMe1711430.
3. Detterbeck FC, Boffa DJ, Kim AW, Tanoue LT. The eighth edition lung cancer stage classification. Chest. 2017;151(1):193-203. doi: 10.1016/j.chest.2016.10.010.
4. Antonia SJ, Villegas A, Daniel D, et al. Durvalumab after chemoradiotherapy in stage III non-small-cell lung cancer. N Engl J Med. 2017;377(20):1919-1929. doi: 10.1056/NEJMoa1709937.
5. Paz-Ares L, Villegas A, Daniel D, et al. PACIFIC: a double-blind, placebo-controlled phase III study of durvalumab after chemoradiation therapy (CRT) in patients with stage III, locally advanced, unresectable NSCLC. Abstract presented at: 2017 ESMO Congress; September 9-12, 2017; Madrid, Spain. Abstract LBA1_PR. oncologypro.esmo.org/Meeting-Resources/ESMO-2017-Congress/PACIFIC-A-double-blind-placebo-controlled-Phase-III-study-of-durvalumab-after-chemoradiation-therapy-CRT-in-patients-with-Stage-III-locally-advanced-unresectable-NSCLC.
6. US FDA accepts supplemental biologics license application for Imfinzi in locally advanced unresectable non-small cell lung cancer [press release]. Wilmington, DE: AstraZeneca; October 17, 2017. astrazeneca.com/media-centre/press-releases/2017/us-fda-accepts-supplemental-biologics-license-application-for-imfinzi-in-locally-advanced-unresectable-non-small-cell-lung-cancer-171017.html. Accessed January 25, 2018.
7. NCCN clinical practice guidelines in oncology (NCCN Guidelines): non-small cell lung cancer, version 2.2018. National Comprehensive Cancer Network website. nccn.org/professionals/physician_gls/pdf/nscl.pdf. Updated December 19, 2017. Accessed January 25, 2018.
8. Chaft JE, Forde PM, Smith KN, et al. Neoadjuvant nivolumab in early-stage, resectable non-small cell lung cancers. J Clin Oncol. 2017;35(suppl; abstr 8508). meetinglibrary.asco.org/record/145331/abstract.