Journal Logo


Immunotherapy Shows Promise Among Lung Cancer Patients

Nalley, Catlin

doi: 10.1097/01.COT.0000534139.15592.7f
  • Free
lung cancer; immunotherapy
lung cancer; immunotherapy:
lung cancer; immunotherapy

CHICAGO—Advances in immunotherapy continue to confirm the power of harnessing the immune system in the treatment of cancer patients.

“This year's AACR conference is incredibly exciting in terms of the basic, clinical, and translation science advances, which are having a huge impact on the lives of cancer patients,” noted Alice Shaw, MD, PhD, Co-Chair of the AACR Annual Meeting 2018 Clinical Trials Committee, and Director of the Center for Thoracic Cancers at Massachusetts General Hospital Cancer Center, at a press conference.

During the AACR Annual Meeting 2018, held April 14-18, research highlighted the impact of immunotherapeutic agents in lung cancer. These studies, according to Shaw, “showcase the enormous benefit of immunotherapies in patients with lung cancer.”


Findings from KEYNOTE-189, a randomized, double-blind, phase III study, showed that overall survival (OS) and progression-free survival (PFS) were significantly longer among patients with newly diagnosed metastatic nonsquamous non-small cell lung cancer (NSCLC) who were treated with pembrolizumab plus chemotherapy compared to those who received chemotherapy alone (Abstract CT075).

The data, which was published simultaneously in the New England Journal of Medicine, are “practice-changing,” according to study author Leena Gandhi, MD, PhD, Associate Professor in the Department of Medicine and Director of Thoracic Medical Oncology Program, Perlmutter Cancer Center at NYU Langone Health (2018; doi:10.1056/NEJMoa1801005).

“This phase III trial demonstrated an improvement in overall response rate (ORR), PFS, and OS across all groups of patients, irrespective of PD-L1 expression, halving the risk of death, which is an unprecedented effect of therapy in the first-line setting for advanced nonsquamous NSCLC without EGFR or ALK alterations,” she noted, in a statement.

The study, which includes patients with metastatic nonsquamous NSCLC, randomized participants (n=616), 2:1, to receive pemetrexed and a platinum-based chemotherapy plus either pembrolizumab (test arm; n=410) or placebo (control arm; n=206).

Key eligibility criteria, according to Gandhi, included untreated stage IV nonsquamous NSCLC, no sensitizing EGFR or ALK alteration, ECOG Performance Status of 0 or 1, provision of a sample for PD-L1 assessment, no symptomatic brain metastases, and no pneumonitis requiring systemic steroids.

Patients were stratified based on PD-L1 tumor proportion score (<1% or ≥ 1%), cisplatin versus carboplatin, and smoking history (never vs. former/current). The primary endpoints were overall survival and progression-free survival; secondary endpoints, included ORR, DOR, and safety.

After a median follow-up of 10.5 months, median OS was not reached in the test arm, versus 11.3 months in the control arm, Gandhi reported. “Compared with patients in the control arm, those in the test arm were 51 percent less likely to die, and those in the high PD-L1 score group were 58 percent less likely to die,” according to investigators. In the pembrolizumab arm, median PFS was 8.8 months (95% CI, 7.6-9.2) compared to 4.9 months (95% CI, 4.7-5.5) for patients in the control group.

If patients progressed on the control arm, they were permitted to cross over to the pembrolizumab group. “Despite a 50 percent crossover rate, there was still a very clear survival benefit, suggesting that combination therapy upfront may be better than if PD-1/PD-L1 inhibitors are given later in the course of illness,” Gandhi noted.

Toxicities were as expected, according to Gandhi, with the exception of an increase in the rate of acute kidney injury among patients treated with pembrolizumab (5.2%) compared to the control arm (0.5%). Treatment discontinuation due to adverse events occurred in 13.8 percent of patients in the test arm compared to 7.9 percent in the control arm. Additionally, immune-related adverse events occurred in 22.7 percent of patients receiving pembrolizumab versus 11.9 percent of patients in the control arm.

“Adding pembrolizumab to pemetrexed and platinum induction therapy and pemetrexed maintenance therapy significantly improves OS, PFS, and ORR in patients with untreated metastatic nonsquamous NSCLC without sensitizing EGFR or ALK alterations,” Gandhi reported during her presentation. She concluded that the treatment “may be a new standard of care for first-line treatment of metastatic nonsquamous NSCLC, irrespective of PD-L1 expression.”


Nivolumab plus ipilimumab significantly improved PFS compared to standard-of-care chemotherapy among newly diagnosed, advanced NSCLC patients with high tumor mutational burden (TMB, >10 mutations/Mb), according to the data presented at AACR (Abstract CT077) and published in the New England Journal of Medicine (2018; doi:10.1056/NEJMoa1801946).

CheckMate-277 is a large, open-label, randomized phase III trial of nivolumab, nivolumab plus ipilimumab, or nivolumab plus platinum-doublet chemotherapy (PT-DC) versus PT-DC in patients with stage IV or recurrent NSCLC who had not received prior treatment.

“The standard of care for patients with newly diagnosed advanced NSCLC has been platinum-based chemotherapy or pembrolizumab for those patients with high PD-L1 expression,” noted Matthew Hellmann, MD, Assistant Attending at Memorial Sloan Kettering Cancer Center, during a press conference. “In a previous phase I study, CheckMate-212, we demonstrated the promising efficacy of the combination of nivolumab plus ipilimumab.

“In this initial study, activity of the combination was particularly enhanced in those patients who had PD-L1 expressing tumors. Since then, emerging data from a variety of studies have highlighted the potential role of TMB as a strong, independent biomarker, particularly in nivolumab plus ipilimumab,” he continued. “In an analysis of CheckMate-568 (Abstract CT078) there was a steady increase in response rate relative to an increase in mutational burden with a plateau around 10 mutations/Mb, which was then applied in CheckMate-227 as a pre-specified population to be examined as a co-primary endpoint of nivolumab plus ipilimumab versus chemotherapy.”

The study was designed prior to the emerging data about TMB as a biomarker and was focused solely on PD-L1, Hellmann explained. “Patients with treatment-naïve advanced NSCLC were screened for PD-L1 expression and randomized based on [this],” he reported during his presentation. “Based on that initial data demonstrating that there was an improved response based on PD-L1, the original co-primary endpoint of this study was to examine nivolumab plus ipilimumab versus chemotherapy in PD-L1-selected patients. This endpoint remains a part of the study and is ongoing.”

Of the 299 patients with high TMB, 139 received nivolumab plus ipilimumab and 160 received chemotherapy, investigators reported. “PFS at 1 year was nearly tripled, 43 percent versus 13 percent, as was the duration of response at 1 year, 68 percent and 25 percent,” noted Hellmann. The objective response rate was 45.3 percent in patients who received nivolumab plus ipilimumab, versus 26.9 percent in those who received chemotherapy.

“Of particular importance is that nivolumab plus ipilimumab significantly improved PFS in both PD-L1 positive and PD-L1 negative patients with a striking degree of similarity in both settings,” Hellmann noted. “This result highlights that TMB and PD-L1 are independent biomarkers; that TMB is predictive of benefit of nivolumab plus ipilimumab irrespective of PD-L1; and that TMB high represents a distinct new subgroup of NSCLC.”

The combination therapy was well-tolerated and the safety profile was similar to previous research regarding this treatment regimen, according to Hellmann. The rate of treatment-related grade 3/4 toxicities was 31 percent, versus 36 percent with chemotherapy. Treatment-related adverse events leading to discontinuation was 17 percent among patients receiving nivolumab plus ipilimumab compared to 5 percent in the chemotherapy cohort.

“Overall, this study has the opportunity to introduce two new options for patients with NSCLC,” Hellmann said. “This first is that the study demonstrates the clinical value of nivolumab plus ipilimumab as a treatment option for patients with TMB high NSCLC.

“The combination provides a durable benefit, builds upon our progress in precision medicine thus far in lung cancer, spares the use of chemotherapy in the first-line setting, and allows the second-line an effective option to be used if needed,” he continued.

Secondly, according to Hellmann, the research validates TMB as an important and independent biomarker. “This establishes TMB as a distinct and definable new subgroup of lung cancer and broadens the clinical actionability of data we can derive from routine next-generation sequencing.”

Neoadjuvant PD-1 Blockade

Researchers found that nivolumab was safe and resulted in major pathological responses in 45 percent of patients when administered prior to surgical resection of stage I-III NSCLC (Abstract CT079; N Engl J Med 2018; doi:10.1056/NEJMoa1716078).

“The rationale for neoadjuvant anti-PD1 treatment of resectable NSCLC was essentially to use the primary tumor as a ‘vaccine’ to induce T cells against the tumor antigens that would then circulate through the body systemically and seek out any distant sites of micrometastases,” said senior study author Drew Pardoll, MD, PhD, Director of Bloomberg~Kimmel Institute for Cancer Immunotherapy and Director of Cancer Immunology at Johns Hopkins School of Medicine, in a statement. “Micrometastases are the primary source of relapse after surgery.”

Twenty-one patients with stage I-IIIA NSCLC were enrolled in the trial between August 2015 and October 2016; 62 percent had adenocarcinoma, according to researchers. All patients received at least one dose of nivolumab. The median time from second dose of nivolumab to surgery was 18 days. “One patient was non-resectable due to tracheal invasion, and so 20 patients were fully resected followed by standard of care postoperative treatment,” noted Pardoll. “The anti-PD1 treatment was tolerated well and there were no surgical delays related to neoadjuvant treatment.”

The study objectives were safety and feasibility and the exploratory endpoints were pathologic and immune responses and correlations to total number of mutations in the tumor.

“Nine of 20 patients (45%) achieved a major pathological response defined as less than 10 percent of the viable cells in the tumor were actually cancer cells, and in fact, three of those patients were pathologic complete responses in their primary tumor, which means that there was no evidence of the viable cancer in the tumor just 4 weeks after they were given one of two doses of nivolumab,” Pardoll reported.

Researchers observed major pathologic responses in patients' tumors irrespective of PD-L1 expression by tumor cells. Additionally, TMB closely predicted the degree of pathologic response, according to Pardoll.

After a median follow-up of 12 months, 16 of 20 (80%) patients who underwent surgical resection were alive and recurrence-free. Median recurrence-free survival had not been reached at the time of data analysis. At 18 months, the rate of recurrence-free survival at was 73 percent.

“To date, among the resectable patients, there have only been two deaths, one of those was a traumatic fall unrelated to cancer or therapy, so there has only been one death from recurrent cancer in this trial,” Pardoll noted during his presentation.

“While it is still too early to tell whether our findings will translate into lower relapse rate and improved survival, pending confirmation in a larger study, we are very optimistic that this approach will eventually be practice-changing and may augment or even replace chemotherapy prior to surgical resection,” he concluded.

“This is very exciting and interesting study that shows, for the first time, that in lung cancer the benefit of immunotherapy may extend beyond advanced or metastatic disease to early stage disease,” commented Shaw. “This was a small pilot, but the findings are very compelling, particularly the major pathologic response rate of 45 percent.”

Catlin Nalley is associate editor.

Wolters Kluwer Health, Inc. All rights reserved.
    Home  Clinical Resource Center
    Current Issue       Search OT
    Archives Get OT Enews
    Blogs Email us!