Expanding TKI Therapy in Advanced Lung Cancer

Paul A. Bunn Jr, MD

Amid rapid progress in the treatment of advanced lung cancer, several leading organizations have joined in developing new guidelines for the optimal use of molecular testing to help select patients for therapy with tyrosine kinase inhibitors (TKIs).¹

And one of the key messages to emerge from the guidelines is that even patients with stage 4 disease and poor performance status (PS) scores should be considered as candidates for TKI therapy, according to Paul A. Bunn Jr, MD, a professor of Lung Cancer Research at the University of Colorado School of Medicine in Denver (Table 1).

Bunn discussed the role of TKIs as part of his “Current Status of Advanced Lung Cancer” presentation, which he delivered at the 14th International Lung Cancer Congress. Physicians’ Education Resource (PER) hosted the congress, held July 25-27 in Huntington Beach, California.

Bunn, a founding director of the University of Colorado Cancer Center, is also the executive director of the International Association for the Study of Lung Cancer (IASLC), which developed the guidelines in collaboration with the College of American Pathologists and the Association for Molecular Pathology.

Clinical decisions about treating patients with lung cancer formerly were made based on clinical features, particularly PS scores, Bunn noted. Now, molecular advances have resulted in FDA-approved TKIs for patients with epidermal growth factor receptor (EGFR) mutations and anaplastic lymphoma kinase (ALK) gene translocations, and more agents are in development.

Yet, Bunn said that nearly one-third of patients with lung cancer never receive any treatment, according to Surveillance, Epidemiology and End Results data. He noted that 60% of patients with lung cancer, regardless of histology, have metastatic disease.

Table 1. Treatment Algorithm for Advanced Lung Cancer

CR indicates complete response; EGFR, epidermal growth factor receptor; PR, partial response, PS, performance score; SD, stable disease.

Adapted from Bunn PA. Current status of advanced lung cancer. Presented at:14th International Lung Cancer Congress; July 25-27, 2013; Huntington Beach, CA. Reprinted with permission.

“Those patients frequently never even get to medical oncologists,” he said. “Certainly, patients with PS3 and arguably PS4 [scores] are eligible to receive oral tyrosine kinase inhibitors if they have a driver abnormality. It’s important for those of us in thoracic oncology to let our primary care physicians know that lung cancer doesn’t mean hospice."

In an interview, Bunn said that the new joint guidelines recommend that “every patient with stage 4 lung cancer that has any adenocarcinoma component or is too small to characterize—or has clinical features suggesting one of these driver abnormalities—that tumor should be tested.” The guidelines recommend EGFR and ALK testing.

He said many patients “are sent to hospice without any treatment and also without any molecular testing. Now these TKIs are oral, don’t require IV, and they don’t have grade 3 and 4 life-threatening toxicities, so patients who are PS3, some patients who are on ICUs, can benefit from these.

“Even sick patients who have lung cancer should have this molecular testing,” Bunn added. “They may be too sick for chemotherapy, but they’re not too sick for these oral tyrosine kinase inhibitors.”

Importance of Histology

When it comes to histology, researchers are turning away from using the term non-small cell lung cancer (NSCLC) because it is too general to accurately describe a pathologic diagnosis or a clinical category.

The guidelines panel pointed out that a recent update of National Comprehensive Cancer Network recommendations also reflected an “evolution” in thinking about the disease. The distinction between histologic subtypes “has become critical for determining subsequent molecular characterization of tumors and patient management,” the panel said. For example, NSCLC can be classified into three different subtypes (Figure). “Non-small cell lung cancer is not an adequate term anymore,” agreed Bunn.

Bunn said that distinguishing large cell neuroendocrine from squamous and from adenocarcinoma affects whether antiangiogenic therapy or chemotherapy is employed. “Bevacizumab causes too much bleeding in squamous cancer and shouldn’t be used, and pemetrexed doesn’t work well in squamous cancer and shouldn’t be used,” he said.

Similarly, molecular mutations and subsequent TKI therapies are associated with histology. Most tumors with EGFR mutations are adenocarcinomas or mixed carcinomas with an adenocarcinoma component, including adenosquamous carcinomas, the guideline panel said. All grades of adenocarcinomas should be tested because the mutations have been found throughout subtypes.

Figure. Lung Cancer Classification

^aHistorically categorized as non-small cell lung cancer Adapted from Baas P. How can the chest physician help in optimal lung cancer care. Presented at:14th International Lung Cancer Congress; July 25-27, 2013; Huntington Beach, CA.

Likewise, ALK rearrangements are found in adenocarcinomas, with no single subtype more likely to exhibit the abnormality, the panel said.

Although these are the broad outlines of testing recommendations, the panel described further complexities, such as differences in testing based on whether a resection specimen or more limited sample is available.

The guidelines also discuss best practices for obtaining and analyzing specimens. Bunn noted that tumor samples should be tested in a Clinical Laboratory Improvement Amendments (CLIA)- approved environment and that the results should be available within 10 days.

“Histology, performance status, and molecular features need to be determined before embarking on treatment,” said Bunn.

Timing of Testing and TKI Therapy

Since patients with advanced lung cancer have life expectancies of 4 months to 5 months without treatment, those with stage IV disease should undergo EGFR and ALK testing at the time of diagnosis or, if previously treated, at recurrence or progression, the guidelines panel said.

Moreover, institutions are encouraged to develop plans for testing patients at earlier stages of disease, said Bunn. He noted that all patients with stage II and stage III disease undergo molecular testing at the University of Colorado, when the most tissue is available, even though TKI therapy would not begin at that point. However, the mutation status would be known, in the event of relapse.

For patients with advanced disease who test positive for either aberration, the evidence supports first-line treatment with a correlating TKI instead of chemotherapy.

During his presentation, Bunn noted that the results of seven clinical trials have demonstrated progression-free survival (PFS) ranging from 9.2 months to 13.1 months for patients who took EGFR TKIs versus PFS values ranging from 4.6 months to 6.9 months for those who received chemotherapy. The studies included pivotal findings reported during the past three years for erlotinib (Tarceva), gefitinib (Iressa), and afatinib (Gilotrif).

“All these differences were statistically significant,” Bunn said. “Not only did these improve response rate and progression-free survival, but they also improved patients’ symptoms and time to deterioration of the patients’ symptoms. They also had far less toxicity.”

However, if the mutation status is not confirmed, the treatment options change, Bunn said. He said the TORCH study demonstrated that patients who received cisplatin plus gemcitabine and then erlotinib achieved a median overall survival (OS) of 11.6 months, while participants who had taken erlotinib then cisplatin plus gemcitabine experienced an 8.7-month median OS.²

“You should not start patients on these TKIs as first-line therapy in the absence of a driver abnormality,” he said.

For patients who test positive for the ALK translocation, the FDA approved crizotinib (Xalkori) in 2011 based on two single-arm trials that demonstrated objective response rates of 50% and 61% with median duration of response of 42 weeks and 48 weeks, respectively. Research into the drug has continued.

Bunn cited the results of the PROFILE 1007 trial,³ which Shaw et al reported earlier this year. That study indicated a median PFS of 7.7 months for patients treated with crizotinib compared with 3.0 months for those who received chemotherapy.

Emerging Agents

Although TKIs are superior to chemotherapy in patients with corresponding mutations, they do not cure patients, observed Bunn. Resistance inevitably develops, and research is under way to identify agents that may improve efficacy with fewer adverse events.

Bunn said there are three generations of EGFR TKI inhibitors (Table 2). Erlotinib and gefitinib are first-generation TKIs with reversible binding to activating EGFR mutations and to wild-type EGFR, which in turn causes diarrhea and skin rash. Second- generation agents are irreversible and bind to other members of the HER family and to the T790M gatekeeper mutation; the group includes the recently approved afatinib as well as several other agents in later-stage clinical investigation. The third-generation agents in development also are irreversible and do not bind to the wild-type receptor.

A second generation of ALK inhibitors also is in the works, notably LDK378, which the FDA has granted Breakthrough Therapy status, putting it on a faster review track.

Table 2. Checkpoint-Targeting Agents in Development

Development Status

Industry Sponsor(s)

First Generation

Erlotinib (Tarceva)

FDA-approved, 2004

Genentech/ Astellas

Gefitinib (Iressa)

FDA-approved, 2003

AstraZeneca

Second Generation

Afatinib (Gilotrif)

FDA-approved, 2013

Boehringer Ingelheim

Dacomitinib

Phase II/III

Pfizer

Icotinib

Phase II-IV

Zhejiang Beta Pharma

Neratinib

Phase II

Puma Biotechnology

Third Generation

CO-1686

Phase I/II

Clovis Oncology

AP26113

Phase I/II

Ariad Pharmaceuticals

AZD9291

Phase I

AstraZeneca

Adapted from Bunn PA. Current status of advanced lung cancer. Presented at:14th International Lung Cancer Congress; July 25-27, 2013; Huntington Beach, CA.

More Mutations Explored

While EGFR mutations and ALK translocation are the two best-defined molecular drivers in advanced lung cancer today, ongoing research is rapidly identifying new targets. Notably, ROS1 fusions have been identified in approximately 2% of NSCLC tumors,⁴ and there is evidence suggesting crizotinib effectively targets the rearrangement.

The Lung Cancer Mutation Consortium is investigating 14 biomarkers and is developing clinical trials for each driver, said Bunn, who plays a leading role in the research cooperative. Novel targets include MEK1, BRAF, HER2, PI3KCA, KRAS, MET, and RET.

“Sixty-four percent of the patients with an adenocarcinoma had one or more driver oncogenes for which there was a drug,” Bunn noted, adding that consortium research has shown higher median survival rates for patients treated with a therapy targeted to a driver mutation.

Moving Forward

There are many unanswered questions about the optimal use of TKI therapies in lung cancer, including how the targeted agents can be combined with immunotherapies. Data presented at the 2013 American Society of Clinical Oncology Annual Meeting indicate that checkpoint blockade immunotherapies aimed at programmed death 1 (PD-1) and its ligand (PD-L1) hold promise in advanced lung cancer.

Bunn said one strategy might be to treat patients with a TKI and then follow with an immunotherapy. “Combinations of these immune therapies with TKIs is obviously another logical approach,” he said. “We know that people with these abnormalities should receive the TKI first, but there’s a number of questions that we need to ask to have better outcomes still.”

References

1. Lindeman NI, Cagle PT, Beasley MB, et al. Molecular testing guideline for selection of lung cancer patients for EGFR and ALK tyrosine kinase inhibitors [published online ahead of print April 3, 2013]. Arch Pathol Lab Med. 2013;137(6):828-860.
2. Gridelli C, Ciardiello F, Gallo C, et al. First-line erlotinib followed by second-line cisplatin-gemcitabine chemotherapy in advanced nonsmall- cell lung cancer: the TORCH randomized trial [published online ahead of print July 9, 2012]. J Clin Oncol. 2012;30(24):3002-3011.
3. Shaw AT, Kim DW, NakagawanK, et al. Crizotinib versus chemotherapy in advanced ALK-positive lung cancer [published online ahead of print June 1, 2013]. N Engl J Med. 2013;368(25):2385-2394.
4. Lovly C, Horn L, Pao W. ROS1 in non-small cell lung cancer (NSCLC). My Cancer Genome website. http://www.mycancergenome.org/ content/disease/lung-cancer/ros1. Updated September 13, 2012. Accessed September 9, 2013.