Model Emerges for Targeting Oncogenes in NSCLC

Alice T. Shaw, MD, PhD

Between 2007 and 2011, a collaboration among clinical oncologists, pathologists, and industry scientists led to the identification of a new molecularly defined subset of non-small cell lung cancer (NSCLC), followed by the finding that crizotinib, then under development as a MET inhibitor, was an inhibitor of anaplastic lymphoma kinase (ALK). Clinical testing rapidly established the efficacy of crizotinib in patients withALK-rearranged NSCLC, and FDA approval of crizotinib followed for this indication in August 2011.¹

That less than 5 years had elapsed between discovery of a newly defined subtype of NSCLC and the development, testing, and FDA approval of an effective targeted therapy (along with a diagnostic test) may serve as a model for successful next-generation development of targeted therapies, according to Alice T. Shaw, MD, PhD, from Harvard Medical School and Massachusetts General Hospital, in Boston. Shaw traced events that mark this example of contemporary bench-tobedside science at the 11th International Congress on Targeted Therapies in Cancer, held mid-August in Washington, DC by Physicians’ Education Resource (PER).

ALKrearrangements were first discovered in anaplastic large cell lymphoma about 20 years ago, and “rediscovered” in 2007 by Hiroyuki Mano, MD, PhD, and colleagues from Japan. Mano led a research team that found a fusion gene with portions of the echinoderm microtubule-associated protein-like 4 (EML4) gene and ALK in a small subset of Japanese patients with NSCLC.²TheEML4-ALKfusion activates ALK, which is normally not expressed in the lung.

Mano’s research also found that, not only was theEML4-ALKfusion gene a potent oncogenic driver in nude mice models, but blocking the kinase activity ofEML4-ALK“completely abrogated” the oncogenic activity.²Gene translocations that activate tyrosine kinases may represent excellent drug targets for many cancers, especially with NSCLC, according to Shaw.

ALKrearrangements occur in 3% to 7% of patients with NSCLC who share a few key characteristics. Specifically,ALKrearrangements are enriched in patients who are never- or light smokers and tend to be found in patients who are 10 to 15 years younger than the average patient with NSCLC. They occur primarily in the adenocarcinoma type of NSCLC.^3,4

When the expansion phase of the phase I clinical study of crizotinib commenced— at approximately the same time as theALK-rearranged NSCLC subtype was identified—early results showed that the majority of patients had responded.^5,6In the phase II follow- up, single-arm study in patients with advancedALK-positive lung cancer, the drug produced a similarly high response rate of about 60%. In both studies, median progression-free survival (PFS) was about 8 to 10 months. Crizotinib approval was based on the response rate seen in these trials.¹

The role of crizotinib in the treatment ofALK-positive lung cancer was confirmed by a head-to-head comparison of crizotinib to standard chemotherapy in patients with advancedALK-positive lung cancer.⁷In this phase III trial, all patients wereALK-positive by the standard fluorescence in situ hybridization (FISH) assay, and all had failed first-line platinum-based chemotherapy. The primary endpoint was PFS. Secondary endpoints were response rate, overall survival, safety, and patient-reported outcomes.⁷

Patients were randomized 1:1 to receive either crizotinib or a standard second-line agent, such as pemetrexed or docetaxel. No crossover was designed. However, once patients progressed on the chemotherapy arm, they came off study and received crizotinib in a separate ongoing phase II study, according to Shaw.⁷

The study met its primary endpoint of PFS. Median PFS with crizotinib was nearly 8 months (7.7 months) versus 3 months with standard chemotherapy with a hazard ratio [HR] of 0.49 and a highly statistically significant^Pvalue.⁷At over 60%, the response rate with crizotinib was consistent with data that had previously been seen in the phase I and II studies. Reponses with chemotherapy were low, at about 20%.⁷

Especially encouraging in this phase III trial were responses to a patient-reported outcomes instrument.⁷“Patients who received crizotinib experienced significantly improved disease-related symptoms and also reported improved quality of life relative to baseline, compared to those patients who had received chemotherapy,” Shaw said.

That study is currently being followed by another randomized study of crizotinib versus first-line platinum plus pemetrexed.⁸Additional data on crizotinib in the first-line setting may be available within the next year.

These highly positive data with crizotinib inALK-positive NSCLC have led to a surge of interest in targeting ALK in other forms of cancer in which ALK is rearranged. (ALKrearrangements have been reported in such cancer types as inflammatory myofibroblastic tumors, anaplastic large cell lymphoma, and sporadically in breast cancer and colorectal cancer.)

Meanwhile, several next-generation ALK inhibitors are currently in clinical trials:

• AF802 (CH5424802). This potent and highly selective ALK inhibitor is currently under investigation for first-line treatment of crizotinib-naïve patients in Japan. AF802 does not inhibit cMET or ROS. As reported by Nakagawa et al9 at the 2013 American Society of Clinical Oncology (ASCO) Annual Meeting, the response rate of AF802 exceeded 93%. The median duration of responses among AF802- treated patients has already exceeded 14 months, according to Shaw.
• LDK378. Research with this ALK inhibitor, more potent and selective than crizotinib, is very advanced. It does not inhibitcMET, although it does haveROS1activity. This compound has now gone through phase I trials and is currently in phase II and III studies. Data on LDK378 were presented at ASCO 2013 in crizotinib-naïve as well as crizotinib-resistant patients.¹⁰Durable responses are being seen in the majority ofALK-positive patients who are treated, including those who had become resistant to crizotinib. In about one-third of cases, crizotinib resistance can be mediated by specific secondary resistance mutations within the ALK tyrosine kinase domain. Amplification of the targetALKitself is another mechanism of resistance. A minority of patients have target gene alterations. In about twothirds of resistant cases, Shaw noted, an alteration of ALK cannot be found. This leads investigators to believe that “a number of different bypass tracks, like EGFR, may mediate resistance.” The durations of response to LDK378 have been quite impressive. “Median PFS to date in crizotinib-resistant patients is over 8 months,” Shaw said.
• AP26113. Results from a phase I/ II dose-finding study of this next-generation ALK/EGFR inhibitor were reported at ASCO 2013 in patients with advanced malignancies who were refractory to available therapies or for whom no standard treatment exists. The longest response was 40 weeks (ongoing). The agent appears to have activity in the central nervous system (CNS): patients with untreated or progressing CNS lesions at baseline had evidence of radiographic improvement with follow-up scans.¹¹A phase II study is being planned.

ROS1 and RET: New Targetable Oncogenes

In addition toALK, chromosomal rearrangements involvingROS1andREThave been identified as targetable oncogenes in NSCLC.

ROS1was first discovered in the context of glioblastoma multiforme, the most common and most aggressive malignant primary brain tumor in humans.¹²ROS1is also a target of crizotinib, with a proportion of kinase domains that are similar to ALK at the amino acid level.¹³

Although less common than ALK rearrangements (they occur in about 1% of patients with NSCLC who are treated within Shaw and colleagues’ practices),^ROS1rearrangements share the demographic profile with patients with^ALK-positive NSCLC: most commonly younger than average, never- or light smokers, with adenocarcinoma histology.¹³

The efficacy of crizotinib against NSCLC withROS1genetic alterations has been demonstrated. In the same phase I trial in whichALK-positive patients were tested, an expansion cohort for patients withROS1was included. The overall response rate was in the 50% to 60% range.⁵

RETrearrangements, which represent the third and most recent fusion kinase target to be identified in NSCLC, cause constitutive activation of the RET tyrosine kinase. Although these rearrangements are a familiar finding in the context of thyroid cancers, as Shaw said, they are reported to occur in only about 1% to 2% of patients with NSCLC.¹⁴In vitro data have determined thatRETfusions were oncogenic drivers, and that cancer cells harboringRETfusions would be sensitive to RET inhibition.¹⁵

In a first clinical validation ofRETrearrangement as another target in NSCLC, a group in New York examined whether the multitargeted kinase inhibitor cabozantinib would have activity in patients withRETfusions.¹⁶Of three patients, two had “very nice” responses, Shaw said. The third patient had stable disease. Importantly, she said, the responses had endured for longer than six months (at the time of publication of the data).¹⁶

Ponatinib is a potent RET inhibitor. This targeted agent is currently under investigation in patients withRET-positive lung cancer who have relapsed on cabozantinib, and patients who are tyrosine kinase inhibitor-naïve.¹⁷

Today, it is evident, Shaw said, that chromosomal rearrangements leading to oncogenic kinase activation are clearly are an emerging and important paradigm in epithelial cancers. Cancers harboring tyrosine kinase fusions drive the initiation and progression of malignancy, and this leads to a state of oncogene addiction, which is the basis for patient responses to kinase inhibitors.

“To date, several tyrosine kinase inhibitors have been shown to be very active in these patients, and, in the case ofALK-positive lung cancer, have become the standard of care.”

Going forward, Shaw said, multiplex analyses that are becoming available should include screening for fusion kinases such as ALK, ROS1, and RET. In addition to informing treatment decision making, this strategy, according to Shaw, will “…facilitate the discovery of new targets for our patients.”

References

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