There is a lot of enthusiasm about the role of immune checkpoint inhibitors in oncology treatment. The recent approval of nivolumab in non-small cell lung cancer (NSCLC) marks a change in the treatment landscape for malignancies, meaning that patients’ own immune systems can be harnessed to attack tumors.
Mark Socinski, MD
According to experts, the challenge in using these drugs is finding ways to clarify which patients can benefit most from them.
A panel of clinical and research experts moderated by Mark A. Socinski, MD, discusses the rapid development and evolution of immunotherapy and individualized medicine for the application of precision medicine in NSCLC.
Thomas E. Stinchcombe, MD
Immunotherapy: An Intuitive Approach
Immunobiologists have successfully identified the underlying mechanisms associated with tumor-induced immunosuppression of infiltrating lymphocytes and immune cells in the tumor microenvironment. Understanding of these mechanisms has led to insights into several therapies, including programmed death receptor-1 (PD-1).
PD-1 is a type 1 transmembrane protein expressed in immune cells, and tumors can express PD-1 ligands, PD-L1 and PD-L2. In general, tumor cells expressing PD-L1 can bind PD-1 so that T cells do not attack the tumor. Inhibitors of PD-1/ PD-L1 block this interaction, thereby eliciting an immune response. Therefore, this mechanism for inhibiting the development of PD-1 or PD-L1 makes intuitive sense.
Many checkpoint inhibitors of PD-1 / PD-L1 in clinical trials, along with nivolumab, were also approved for NSCLC in March. these antibodies include pembrolizumab, which, much like nivolumab, targets PD-1, and MPDL3280A and MEDI4736, which target PD-L1.
These drugs work by blocking the interaction between PD-1 and PD-L1, and Socinski noted that these drugs can produce sustained remission rates from 15 to 25 percent. He added that a remarkable feature about this remission is the durability of these responses.
Thomas E. Stinchcombe, MD, reviewed and analyzed the results of the Phase II trial CheckMate-063 and the Phase III trial CheckMate-017, which led to the approval of single-agent nivolumab for the treatment of patients with treated advanced squamous cell NSCLC. In the CheckMate-063 clinical trial, patients were treated with nivolumab and an objective remission rate of 15 percent was found at 11-month follow-up. The assessed 1-year survival rate was 41% and median overall survival (OS) was 8.2 months.1 In addition, the CheckMate-017 trial demonstrated that nivolumab prolongs OS in patients with treated squamous cell NSCLC compared to docetaxel (Table).2 Stinchcombe said, “I think most of us are I think most of us are eagerly awaiting the full presentation of this data because it really has the potential to be a clinical practice changing trial,” Stinchcombe said.
Table. Survival Statistics in Pivotal Nivolumab NSCLC Trial
Response Patterns of Immunotherapy
While a subset of patients are benefiting from immunotherapy, one issue that oncologists must recognize is pseudoprogression.
Roy S. Herbst, MD, PhD, and Heather A. Wakelee, MD, discuss the phenomenon of pseudoprogression, during which 10 to 20 percent of tumors grow before they begin to shrink. They discuss strategies for assessing the difference between pseudoprogression and true progression, including scanning.
Roy S. Herbst, MD, PhD
Also, Herbst describes how different patient and tumor characteristics (including smoking status, histology, and genetic mutations) may exhibit different responses to immunotherapy.
In contrast to many other current treatments that lack success, studies have found that patients with squamous cell lung cancer who smoke and patients with tumors containing KRAS mutations respond to immunotherapy.
Toxic Effects of Immunotherapy
Anne S. Tsao, MD
As oncologists learn more about the efficacy of immunotherapy, another goal is to better understand the toxic effects associated with these drugs, which are distinct from those of standard cytotoxic chemotherapy or tyrosine kinase inhibitor (TKI)-based drugs. Although diarrhea is a common toxic effect of many treatments, this toxicity will be more severe when immunotherapy is administered, as it often occurs in conjunction with colitis, she explained. She emphasized that oncologists must recognize that “patients are actually vulnerable to autoimmune disease.”
Finding predictive biomarkers
Stinchcombe noted that treatment with PD-1 inhibitors only elicits a strong response in a small number of patients. Research is still needed to find a biomarker that can predict treatment response to ensure that only patients who will respond receive treatment.
This past April, researchers reported that the KEYNOTE-001 trial confirmed that pembrolizumab had an overall remission rate of 45.2% in patients with NSCLC with high PD-L1 expression.3 However, biomarker selection is not straightforward.
Heather-Wakelee, MD
Every company that is developing a PD-1 or PD-L1 drug is also already developing their own assays to determine how we should select the right patients,” Wakelee said. They’re based on PD-L1 expression, but just as each therapeutic is a different antibody, the way those antibodies look for PD-L1 is different, and the thresholds and the cells we’re considering are all different as well.” Wakelee described the complexity of PD-L1 expression, explaining the resulting different positive thresholds and assays. In addition, patient selection for these drug trials may affect remission rates, and given that the goal of these trials is to demonstrate high response rates, many studies may not include all patients who may benefit from this type of drug.
Tsao added that PD-L1 is a dynamic marker – it fluctuates throughout the pathogenesis process.
She also said there is a wealth of data suggesting that there are strategies to induce PD-L1 expression.
Herbst mentioned gamma interferon as the best inducer of PD-L1 alone. He added, “After the biopsy, you’re going to see PD-L1 upregulation among patients who are generating more T cells, so measuring at this time will make a big difference in the results.”
Tsao said until more is known, it remains questionable to consider PD-L1 as a biomarker, and Herbst suggested that if PD-L1 is not the best marker, it is possible that there is another T regulatory cell that can be detected. Because of the toxic side effects of these checkpoint inhibitors, there must be a strategy to exclude patients who would not benefit from these drugs, he explained.
Digging deeper into gene mutations
In efforts to shape individualized treatment, genetic testing is being implemented, not just used at the time of diagnosis. Herbst says obtaining tissue samples from individuals at the time of initial diagnosis and recurrence in lung cancer patients can help guide treatment. Molecular testing can identify EGFR and BRAF mutations as well as fusions of ALK and ROS1, which can then determine which treatment is likely to be effective. He noted that about 20 percent of patients currently have so-called actionable mutations, and researchers are looking for ways to individualize treatment for the other 80 percent.
Tsao discussed the ALCHEMIST lung cancer clinical trial, which she described as “…… basically a surgical trial in which patients get surgical resection and then receive targeted therapy based on their genetic profile. For example, if the patient has an EGFR mutation, then they will have adjuvant EGFR TKI therapy.” 4 She lists other similar precision medicine studies including the NCI-MATCH and Lung-MAP trials.5, 6
Third-generation tyrosine kinase inhibitors (TKI)
First- and second-generation EGFR tyrosine kinase inhibitors target both mutant and wild-type receptors and have the rash and diarrheal toxicity of typical EGFR inhibitors. third-generation EGFR inhibitors specifically target EGFR mutations, rather than wild-type EGFR, and thus have less skin and gastrointestinal toxicity, Socinski said.
The development of third-generation TKIs targets the T790M mutation, a major secondary mutation in drug resistance, which Socinski said occurs in 50-60 percent of patients with known EGFR mutations treated with first- and second-generation EGFR inhibitors.
The two third-generation drugs currently in development are rociletinib and AZD9291. in T790M-positive tumors, the response rate for these investigational drugs exceeds 50%. socinski notes that some benefit can be achieved in T790M-negative patients, so both drugs should not be ruled out in this group. rociletinib may cause controlled hyperglycemia, and both drugs may cause mild cardiac abnormalities.
Socinski discussed the possibility of applying third-generation agents in early treatment and noted that as more options become available, the ranking of the most effective treatment modalities should be determined. wakelee and Herbst added that ALK and EGFR-targeted therapy in combination with immunotherapy may be another treatment approach for the future.