Taking Lung Cancer Care into the Precision Medicine Era

Mark Socinski, MD

There is great enthusiasm about the role of immune checkpoint inhibitors in cancer treatment. The recent approval of nivolumab in the non—small cell lung cancer (NSCLC) setting marks a unique shift in the treatment landscape of this malignancy, one that harnesses the patient’s own immune system to target the tumors.

The challenge in using these agents, according to experts who participated in a recent OncLive Peer Exchange program, is pinpointing ways of identifying which patients will reap the greatest benefit.

Led by moderator Mark A. Socinski, MD, the panel of clinical and research experts discussed the burgeoning and evolving field of immunotherapy and personalized medicine during a Peer Exchange session entitled “Aiming for Precision Medicine in NSCLC.”

Thomas E. Stinchcombe, MD

Immunotherapy: An Intuitive Approach

Immunobiologists have successfully identified the underlying mechanisms related to tumor induced immune suppression on the infiltrating lymphocytes and immune cells in the tumor microenvironment. The understanding of these mechanisms has led to several therapeutic insights, including the programmed death receptor-1 (PD-1).

PD-1 is a type 1 transmembrane protein expressed on immune cells, and tumors can express the PD-1 ligands, PD-L1 and PD-L2. In general, tumor cells express PD-L1, which binds to PD-1, causing T cells not to attack the tumor. PD-1/PD-L1 inhibitors block this interaction, allowing for an immune response. Thus, the development of mechanisms to combat either PD-1 or PD-L1 intuitively makes sense.

Along with nivolumab, which was approved for NSCLC in March, a number of PD-1/PD-L1 checkpoint inhibitors are in clinical trials. These antibodies include pembrolizumab which, like nivolumab, targets PD-1, and MPDL3280A and MEDI4736, which are aimed at PD-L1.

These agents work by blocking the interaction between PD-1 and PD-L1. The data for these agents produce a consistent response rate ranging from 15% to 25%, Socinski noted. One of the remarkable things about the response, he added, is the durability of many of these responses.

Thomas E. Stinchcombe, MD, reviewed the findings from the phase II CheckMate-063 and the phase III CheckMate-017 trials, which led to the approval of singleagent nivolumab in heavily pretreated patients with advanced squamous cell NSCLC. In the CheckMate-063 trial, the objective response rate with nivolumab, at an 11-month follow-up, was 15%. The estimated 1-year survival rate was 41% and the median overall survival (OS) was 8.2 months.¹ Additionally, CheckMate-017 demonstrated that nivolumab extended OS compared with docetaxel in patients with pretreated squamous cell NSCLC (Table).² “I think most of us are eagerly awaiting to see the full presentation of this data because it does have the potential to be a practice-changing trial,” said Stinchcombe.

Table. Survival Statistics in Pivotal Nivolumab NSCLC Trial²

NSCLC indicates non—small cell lung cancer.

Patterns of Response With Immunotherapy

While a subgroup of patients are reaping benefits from immunotherapy, one issue that oncologists must be cognizant of is pseudoprogression.

Roy S. Herbst, MD, PhD, and Heather A. Wakelee, MD, discussed the phenomenon of pseudoprogression, during which 10% to 20% of tumors will grow before they start to shrink. They discussed strategies for assessing the difference between pseudoprogression and actual progression, including scans.

Roy S. Herbst, MD, PhD

Herbst also described how different patient and tumor characteristics, including smoking status, histologies, and mutations, might exhibit different responses to immunotherapy.

In contrast to the lack of success with many other current therapies, studies are finding activity with immunotherapy in patients with squamous lung cancer, who are smokers, and in tumors that harbor KRAS mutations.

Toxicities With Immunotherapy

As oncologists learn more about the effectiveness of immunotherapy, another goal is to gain a better understanding of these agents’ associated toxicities, which are very different from standard cytotoxic chemotherapies or the tyrosine kinase inhibitor(TKI) class of drugs. Anne S. Tsao, MD, described the more common side effects, such as colitis, fatigue, and pneumonitis, and explained that while diarrhea is a common toxicity of many treatments, it is more serious with the immunotherapies, as it is often coupled with colitis. She stressed that oncologists must also become “very cognizant that [patients] may actually be more likely to develop an autoimmunity.”

Search for Predictive Biomarkers

Treatment with PD-1 inhibitors results in a tremendous response in a minority of patients, noted Stinchcombe. Research is still needed to find a biomarker that is predictive for response in order to guarantee that only patients who will respond actually receive treatment.

Heather A. Wakelee, MD

In April, investigators reported that pembrolizumab demonstrated an overall response rate of 45.2% among a cohort of patients with high PD-L1-expressing NSCLC in the KEYNOTE-001 trial.³ The choice of biomarker, however, is not straightforward.

“Each company that’s developing a PD-1 or PD-L1 drug has also developed their own test for how we select these patients,” said Wakelee. “They’re based on PD-L1 expression, but just as each of the therapeutic drugs is a different antibody, the antibodies to look for PD-L1 are different, as well as the threshold and which cells we are looking at.” Wakelee described the complexity of PD-L1 expression and, thus, the variation of thresholds for positivity and test interpretations. In addition, patient selection for trials of these agents may affect rates of response and, given the trials’ goals of demonstrating high response rates, many studies may not be inclusive of all patients who could benefit from these types of agents.

Tsao added that PD-L1 is a very dynamic marker—it fluctuates during the course of the disease.

She also said that there is a wealth of data coming out about strategies to induce PD-L1 expression.

Herbst mentioned that gamma interferon is the single best inducer of PD-L1. He added that, “In the postbiopsy, you’re going to see upregulation of PD-L1 in a patient who is responding with more T cells, so when you measure is going to make a big difference.”

Anne S. Tsao, MD

Until more is learned, Tsao stated, it remains problematic to use PD-L1 as a biomarker. Herbst suggested that if PD-L1 is not the best marker, there might be another T-regulatory cell that can be measured. He explained that due to the toxicities of these checkpoint inhibitors, there has to be a strategy for weeding out patients who will not benefit from these agents.

Digging Deeper Into Genetic Mutation

In an effort to individualize treatment, genetic testing is being implemented not solely at the time of diagnosis. Herbst stated that obtaining tissue samples from individuals with lung cancer at initial diagnosis and relapse helps guide care. Molecular testing can identify mutations in EGFR and BRAF and fusions in ALK and ROS1, subsequently determining which therapies may be effective. He noted that currently approximately 20% of patients have so-called actionable mutations, and that researchers are looking at ways to personalize care for the other 80%.

Tsao discussed the ALCHEMIST lung cancer trial, which she described as “…basically a surgical trial where patients get surgical resection and then, based on their profiling, they get [targeted therapy].

For instance, if they’re EGFR mutant, they’ll get an EGFR TKI as adjuvant therapy.”⁴ She listed other similar precision medicine studies including the NCI-MATCH trial and the Lung-MAP trial.^{5, 6}

Third-Generation Tyrosine Kinase Inhibitors

First- and second-generation EGFR TKIs target both mutant and wild-type receptors, accounting for the typical EGFR inhibitor toxicities of rash and diarrhea. Third-generation EGFR inhibitors are designed to be more specific for mutant EGFR versus wild-type EGFR, said Socinski, and thus are associated with less skin and gastrointestinal toxicity.

The third-generation TKIs were developed with the goal of targeting the T790M mutation, the major secondary mutation for resistance. This mutation occurs in about 50% to 60% of patients with known EGFR mutations after exposure to first- and second-generation EGFR inhibitors, stated Socinski.

Two third-generation agents currently in development are rociletinib and AZD9291. In T790M-positive tumors, response rates are over 50% with these investigational agents. Socinski noted that patients with T790M-negative disease also receive some benefit, and thus these two agents should not be ruled out as a treatment in that population. Rociletinib may cause hyperglycemia that is typically manageable, and both agents may cause minor cardiac abnormalities.

Socinski discussed the possibility of using these third-generation agents in earlier treatment settings, and noted that with growing options, the most effective sequencing of treatments will also need to be determined. Wakelee and Herbst added that combining ALK and EGFR-targeted therapies with immunotherapy might be another approach in the future.

References

1. Ramalingam SS, Mazieres J, Planchard D, et al. Phase II study of nivolumab (anti-PD-1, BMS-936558, ONO-4538) in patients with advanced, refractory squamous non-small cell lung cancer. Presented at: 2014 Multidisciplinary Symposium in Thoracic Oncology; October 30-November 1, 2014; Chicago, IL. Abstract Number: LB2.
2. Opdivo [package insert]. Princeton, NJ: Bristol-Myers Squibb; 2015.
3. Garon EB, Rizvi N, Hui R, et al. Efficacy of pembrolizumab (pembro; MK-3475) and validation of PD-L1 expression as a biomarker in patients (pts) with non-small cell lung cancer (NSCLC): findings from KEYNOTE-001. Presented at: 2015 AACR Annual Meeting; April 18-22, 2015; Philadelphia, PA. Abstract 9109.
4. The ALCHEMIST lung cancer trials. National Cancer Institute website. http://www.cancer.gov/researchandfunding/areas/clinical-trials/ alchemist. Published August 18, 2014. Accessed April 24, 2015.
5. NCI molecular analysis for therapy choice program (MATCH) & pediatric MATCH. National Cancer Institute website. http://www.cancer. gov/researchandfunding/areas/clinical-trials/match. Updated March 2, 2015. Accessed April 24, 2015.
6. Lung-MAP. http://www.lung-map.org. Accessed April 24, 2015.