Checkpoint Combinations Under Investigation to Improve Survival in Lung Cancer

Tetsuya Mitsudomi, MD

Tetsuya Mitsudomi, MD

Immune checkpoint inhibitor pembrolizumab (Keytruda) has demonstrated its ability to improve outcomes in patients with lung cancer, including non—small cell lung cancer (NSCLC), as seen in the KEYNOTE-001 trial. At the 2019 World Congress on Lung Cancer, experts addressed how pembrolizumab and similar agents could improve survival outcomes in these patients.

KEYNOTE-001, the first study to investigate the immune checkpoint inhibitor, demonstrated more favorable rates of response at 5 years with pembrolizumab versus chemotherapy in patients with advanced NSCLC, according to theupdated 5-year findings presented at the 2019 ASCO Annual Meeting.

Overall, 550 patients with locally advanced or metastatic NSCLC were enrolled in this phase Ib trial, in which patients were treated with 2 mg/kg of pembrolizumab every 3 weeks or 10 mg/kg every 2 or 3 weeks. However, the dose was changed to a single dose of 200 mg every 3 weeks for all patients regardless of body weight, which is not the standard clinical use of this agent.

The median follow-up at the data cutoff date was 60.6 months. Out of 550 patients, 449 had been previously treated and 101 were treatment naïve. The updated findings for the KEYNOTE-001 showed a 5-year OS rate of 23.2% in patients who were treatment-naïve and 15.5% in patients who had been previously treated.

Median OS for the treatment-naïve cohort was 23.2 months. For those patients with a PD-L1 tumor proportion score (TPS) of 1% to 49%, their 5-year OS rate was 15.7%, and those patients with a TPS of ≥50% had a 5-year OS rate of 29.6%. Additionally, patients with a lower TPS of 1% to 49% had a 5-year OS rate of 12.6 months, versus 25.0% in those with a TPS of 50% or greater.

For patients in the previously treated cohort, the overall median OS was 10.5 months, but the 5-year OS rate was 3.5% in those with a TPS below 1%, and 12.6% in those with a TPS of 1% to 49%. The 5-year OS rate was 25.0% in those who were previously treated and had a TPS of ≥50%.

Although KEYNOTE-001 has established efficacy in the treatment of pembrolizumab alone in patients with NSCLC, new clinical trials are investigating the role of pembrolizumab further in combination with other agents. For example,the phase III KEYNOTE-189 trial that led to the FDA’s approval of pembrolizumab in combinationwith chemotherapy. Different checkpoint inhibitors and immunotherapy agents are also being evaluated for combination therapy with pembrolizumab in lung cancer.

In an interview withTargeted Oncology, Tetsuya Mitsudomi, MD, of the Department of Surgery, Division of Thoracic Surgery, Kinki University Faculty of Medicine, Osaka-Sayama, Japan, summarized the major areas under investigation for the treatment of patients with lung cancer and highlighted key findings from the updated 5-year data of the KEYNOTE-001 trial.

TARGETED ONCOLOGY: How has the introduction of immune checkpoint inhibitors improved outcomes in patients with NSCLC?

Mitsudomi:The introduction of PD-1/PD-L1 blockade has dramatically changed the treatment paradigm of NSCLC. Initially, it was approved for the second-line treatment, but now it is the standard for first-line treatment. Depending on the PD-L1 expression, patients can be treated with an anti—PD-L1 antibody alone or in combination with chemotherapy. If you combine it with chemotherapy, with respect to the PD-L1 expression, you can treat virtually all patients with lung cancer.

TARGETED ONCOLOGY: Can you discuss the results from the KEYNOTE-001 trial?

Mitsudomi:KEYNOTE-001, as you can imagine, is the oldest study of the PD-L1 antibody, pembrolizumab. This year, Edward Garon, MD, reported the results from the long-term follow-up of the KEYNOTE-001 study. He showed that the 5-year survival is in the order of 30% to 40% for the patients who have high PD-L1 expression without previous treatments. That’s considering that platinum-doublet chemotherapy alone will give you a 1-year median survival time. That means that a 5-year survival rate of pembrolizumab of 30% to 40% is really amazing. It looks like the tail of the survival is now plateaued, meaning that some of the patients may be really, truly cured by immunotherapy.

TARGETED ONCOLOGY: What combinations appear most promising right now for patients with different types of lung cancer?

Mitsudomi:There are actually huge efforts currently going on to find the optimal combination of immunotherapy, but currently, only chemotherapy is approved for [use with immunotherapy for] the treatment of patients with lung cancer. In the future, combinations with other checkpoint inhibitors, antibodies, or both, may change the treatment paradigm. However, currently, we can only recommend the use of an immunotherapy combination with chemotherapy.

TARGETED ONCOLOGY: What biomarkers are currently being investigated to predict response in lung cancer?

Mitsudomi:Currently, immunohistochemistry for PD-L1 testing is standard procedure to determine the indication for the PD-1/PD-L1 blockade. If PD-L1 expression is high, then the likelihood of the efficacy should be high. This is routine testing.

The next biomarker may be tumor mutational burden (TMB). The study of nivolumab (Opdivo)showed that TMB may predict treatment efficacy, but [at this meeting], the new data from the pembrolizumab study, KEYNOTE-189, was presented. Curiously, in that study, TMB was not predictive of any treatment benefit, so there is a lot of difficult things. TMB, currently, has no standardization of [cutoffs for] measuring the TMB. That may be 1 of the reasons, but no one knows an exact reason why TMB is not predictive of the efficacy for pembrolizumab. However, maybe [it could be predictive] for nivolumab.

TARGETED ONCOLOGY: What new strategies could be employed that would affect outcomes in NSCLC treated with immunotherapy?

Mitsudomi:There are many combination therapies, but the most innovative approach to improve the survival outcome for patients with NSCLC includes engineered T-cell therapy, vaccine therapy, or viral therapy. Several clinical trials are currently ongoing, but none of the studies have matured yet, so we don’t know if this kind of new technology really improves the survival outcome for patients. However, this is the way to go.

TARGETED ONCOLOGY: What are the key takeaways from your talk at the meeting?

Mitsudomi: