 has accelerated exponentially since 1985, when Masahide Takahashi, MD, PhD, and colleagues first reported a fusion rearrangement in lymphoma DNA.

 Early progress was slow. Other investigators noted 

 abnormalities—both fusions and mutations&mdash;in papillary thyroid cancer (PTC), in multiple endocrine neoplasia type 2 (MEN2), and after radiation exposure, but targeted interventions were still on the distant horizon.

In 2005, the structure of the RET kinase domain was described, and in subsequent years, as small-molecule inhibition gained traction and 

 fusions were discovered in patients with lung cancer, research on RET targeting built momentum.

 Initial multikinase inhibitor trials suggested that RET could be a viable target, but “off-target” toxicity limited effective drug design.

In light of these findings, the focus has shifted to the development of RET-specific inhibitors. In September 2018, the leading prospect in the field, LOXO-292, was granted a breakthrough designation by the FDA for 

 fusion—positive metastatic non–small cell lung cancer (NSCLC) and 

 Five weeks later, the designation was expanded to 

RET-specific inhibition appears well tolerated and effective regardless of gatekeeper mutations or 

 fusion partners, and researchers are optimistic about the value of RET inhibition across tumor types. How this inhibition will be accomplished—by selective agents, custom-tailored multikinase inhibitors, or in combination with other therapies&mdash;has yet to be determined.

RET is a transmembrane glycoprotein receptor tyrosine kinase (RTK) encoded by 

 During embryogenesis, RET aids in development of the enteric nervous system and kidneys; throughout life, in the homeostasis of multiple tissues.

Receptor activation is achieved through indirect ligand binding; glial cell line—derived neurotrophic factor (GDNF) family ligands (GFLs) bind to GDNF family receptor-α coreceptors, resulting in a GFL–GFRα complex that homodimerizes RET.

With homodimerization, intracellular tyrosine residues are trans-autophosphorylated, signaling adaptors are recruited, and several signaling cascades are activated. RET-associated pathways include RAS/MAPK/ERK, PI3K/AKT, JAK/STAT, and C-gamma, all of which regulate cell proliferation (

With knowledge of associations between RET and downstream cell proliferation pathways, it follows logically that cancer might result from RET dysfunction. Such dysfunction can be retraced to various 

 aberrations, which are divided into 2 types: chromosomal rearrangements (fusions) or mutations.

Chromosomal rearrangements, such as the gene fusion originally described by Takahashi, most commonly lead to overexpression of RET or uncontrolled activation of the 

 intracellular domain. Either mechanism can increase downstream activity, thereby contributing to malignancy via angiogenesis, cell survival, or invasion.

Figure. RET Pathway Signaling Associated With Cancer

Other rearrangements have also been documented, resulting in gain-of-function of 

 or inhibition of tumor suppressor gene partners, but such instances are rare.

, and rearrangements occur via inversion.

 aberrations have been identified in less than 2% of diverse cancers, according to a molecular analysis of malignancies present in nearly 5000 patients. These include mutations (38.6%), fusions (30.7%), and amplifications (25%).

 rearrangements occur in 1% to 2% of patients with NSCLC (usually adenocarcinomas).

 These cases often share characteristics with patients who have 

 rearrangements; namely, that they tend to be nonsmokers less than 60 years of age.

 rearrangements are more common in PTC compared with NSCLC, and they are still even more prevalent in patients who develop PTC secondary to radiation exposure, such as those involved in the Chernobyl disaster. In this population, approximately three-quarters exhibited 

In contrast with the rearrangements found in NSCLC and PTC, proto-oncogene activation in MTC is most commonly due to an 

 These can be somatic or germline and are often substitution mutations of the intracellular or extracellular domains; in the latter case, cysteine residues may be replaced with other amino acids, ultimately resulting in ligand-independent dimerization and activation.

 germline mutations are responsible for MEN2, a syndrome that leads to about 25% of MTC cases.

Specifically, certain mutations can be associated with subsets of this disease, such as substitutions at the V804 codon, which lead to familial MTC.

 In the other 75% of MTC cases, which are sporadic, 43% to 71% have a 

 M918T mutations are most common, followed by Cys634 point mutations, deletions, or small insertions.

 mutations also occur in about 20% of patients with sporadic pheochromocytoma.

 Recently, both similar and novel mutations have been found in a variety of other cancer types, including hepatoma, gastrointestinal stromal tumor, meningioma, atypical lung carcinoid, paraganglioma, and Merkel cell, endometrial, colorectal, and breast carcinoma.

 This list may continue to expand with increasing usage of next-generation sequencing.

 aberrations in NSCLC and thyroid cancer, the ever-expanding list of other 

-mutated cancers, and the upstream location of RET itself, RET targeting has potential for pan-cancer application. However, the orientation of 

 and its roles in organ development and homeostasis have given rise to safety concerns for inhibition.

-knockout models and diseases with inactivating 

mutations have provided some hints at safety issues, as documented by a plethora of studies, but the relevance of their findings is diminished by recent clinical trials with RET-specific inhibitors. In short, despite the potentially catastrophic consequences of RET inhibition in early development, resulting in tissue agenesis and fatal physiologic derangements, inhibition from late childhood onward appears relatively safe.

A variety of RET inhibitors have been approved as multikinase agents, in which RET is not the primary target.

 These include sunitinib (Sutent), cabozantinib (Cabometyx), and lenvatinib (Lenvima), with various indications. Although some are labeled for thyroid cancer, none are specifically approved for 

Efficacy is comparable across agents, but mechanisms of action vary.

 For example, sunitinib is a type I inhibitor that attaches to the adenosine triphosphate binding pocket of activated RET, cabozantinib is a type II inhibitor, binding the inactive form; others have unknown mechanisms.

 Several of these agents have shown activity against 

-rearranged models, resulting in suppression of downstream pathways and decreased cell proliferation.

 Similarly, treatment of mutant models results in decremental tumor growth, both through RET wild-type targeting and activity against specific mutant isoforms.

Clinical trials have echoed these findings. For example, in the phase III EXAM trial evaluating cabozantinib, patients with 

 M918T—mutated MTC had longer progression-free survival with the drug compared placebo than did those whose 

 Cabozantinib has also shown activity in 

 fusion-positive NSCLC, with response rates ranging from 20% to 50% in patients who have received 2 or more lines of therapy.

 These are, however, essentially proof-of-concept trials, because results do not match the efficacy of multikinase inhibitors against other major oncogenic drivers such as 

 In part, this is because off-target activity results in dose-limiting toxicities before substantial RET inhibition can occur.

Other agents are required to achieve significant RET inhibition without toxicity. Combination therapies may be needed, since some studies suggest that RET inhibition is most effective with additional downstream targeting. Similarly, custom multikinase agents that are more selective for RET but still maintain some downstream inhibition could potentially accomplish the same goal. Although the possibilities of multitarget agents remain open, the research spotlight is currently on RET-selective inhibitors. Of these, three leading agents warrant a closer look:

-selective inhibitor, LOX-292, was recently granted a breakthrough designation by the FDA for 

 These designations were given following the notable responses among patients treated with LOXO-292 during the phase I/II LIBRETTO-001 trial (NCT03157128). Patients were heavily pretreated, with a median 3 lines of prior therapy.

At the 2018 American Society of Clinical Oncology Annual Meeting, investigtors reported an objective response rate (ORR) of 77% (95% CI, 58%-90%) with LOXO-292 for patients with 

 fusion—positive (NSCLC and 45% for patients with 

-mutated MTC. By the April 2018 data cutoff, 82 patients had been treated with LOXO-292 across 7 cohorts.

In the most recently reported data, treatment with LOXO-292 resulted in the following ORRs: 

Additionally, all patients (n = 4) with intracranial lesions responded to therapy. LOXO-292 appeared safe and well tolerated, with very few patients discontinuing therapy; most adverse events (AEs) were limited to grade 1 and unrelated to treatment. About 5% of patients had grade 3 treatment-related AEs, including elevated liver enzymes, diarrhea, thrombocytopenia, and tumor lysis syndrome, but all resolved with dose interruption.

, lead investigator Alexander E. Drilon, MD, a medical oncologist and clinical director of the Early Drug Development Service at Memorial Sloan Kettering Cancer Center in New York, New York, reflected on the LIBRETTO-001 findings. “Just to put the [results] in perspective: With the older and ‘dirtier’ multikinase inhibitors for 

 fusion—positive cancers, we see a 30% response rate with much more toxicity. Here, we are seeing a drug that is achieving outcomes that are similar to what we would expect for targeted therapy in  

Results from the phase I ARROW trial (NCT03037385) demonstrated slightly lower response rates than LOXO292.

 During the dose-escalation study, 51 patients were treated. Those with 

-mutated MTC had a best ORR of 40%, and the 

 fusion-positive NSCLC group had a best ORR of 50%. Treatment with BLU-667 resulted in 3 dose-limiting toxicities. Grade 3 AEs included hypertension and neutropenia.

Reporting these findings at the American Association for Cancer Research Annual Meeting in April 2018, lead author Vivek Subbiah, MD, of The University of Texas MD Anderson Cancer Center in Houston, said, “ARROW dose escalation data validate BLU-667 as a promising precision therapy for 

-altered cancers.” He added that the responses were noteworthy considering the low doses given to most patients.

In 2017, at the European Society for Medical Oncology Annual Congress, investigators reported results from a phase I/IB clinical trial (NCT01877811) in which the RET inhibitor RXDX-105 was given to 152 patients.

 The presenters highlighted a subgroup of 22 patients with 

fusion—positive NSCLC. Six out of 8 patients (75%) with non–

fusions had partial responses. Of the 14 NSCLC patients with 

 fusions, 3 achieved stable disease. Early data also pointed to some potential issues with toxicity. Grade 3 or higher rash occurred in 12% of patients, and nephrotoxicity was documented. Additionally, 1 patient had a serious AE that did not resolve upon dose interruption.

Presenting the findings, coauthor Lyudmila A. Bazhenova, MD, of the University of California, San Diego, Health Moores Cancer Center in La Jolla, said, “RXDX-105 has demonstrated a manageable safety profile in patients with advanced or metastatic solid tumors.”

Over the past 30 years, from the discovery of a fusion rearrangement to the recent promise of LOXO-292, RET targeting has gone from distant concept toward clinical reality. 

 rearrangements and mutations are represented across multiple tumor types, so emerging agents may serve as pan-cancer therapies. Whether RET-selective inhibitors are used alone or in combination with other agents remains to be seen, as does first-line efficacy. Regardless, the results from LIBRETTO-001 prompt optimism for the future of RET inhibition.

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Loxo Oncology announces LOXO-292 durability update in patients with RET-mutant medullary thyroid cancer and RET fusion-positive thyroid cancer from LIBRETTO-001 at the 88th annual meeting of the American Thyroid Association [press release]. Stamford, CT: Loxo Oncology, Inc; October 6, 2018. ir.loxooncology.com/press-releases/2370515-Loxo-oncology-announces-loxo-292-durability-update-in-patients-with-ret-mutant-medullary-thyroid-cancer-and-ret-fusion-positive-thyroid-cancer-from-libretto-001-at-the-88th-annual-meeting-of-the-american-thyroid-association. Accessed October 25, 2018.

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Articles

Over the past 30 years, from the discovery of a fusion rearrangement to the recent promise of LOXO-292, RET targeting has gone from distant concept toward clinical reality.

Direct Targeting of RET Aberrations Moves Closer to the Clinic

 is among the most commonly mutated genes in human breast cancer, developing drugs that effectively target this aberration has proved challenging. This year’s American Society of Clinical Oncology (ASCO 2018) Annual Meeting featured disappointing results from a phase III study into taselisib, one of the most advanced agents aimed at the mutation.

Nevertheless, researchers remain keenly interested in exploring 

 is in the PI3K/AKT/mTOR network, which controls a variety of essential cellular processes such as proliferation, growth, metabolism, and motility.

 This pathway is activated via receptor tyrosine kinase or G protein—coupled receptors to undergo complex intracellular and extracellular interactions, involving other pathways to form a larger network that is not yet fully understood (

The pathway is dysregulated in a variety of cancer types, where aberrations promote uncontrolled cell survival and propagation of abnormal cells and downregulate autophagy. The process implicates a number of oncogenes, including 

 mutations in breast cancer are associated with both disease progression and endocrine therapy resistance.

 mutations have been observed across the spectrum of subtypes—notably, in hormone receptor—positive disease, which, in turn, makes up 75% of breast cancer cases.

 These mutations have been found in 30% to 40% of estrogen receptor (ER)—positive/HER2-negative, 20% to 25% of HER2-positive, and 10% to 15% of triple-negative tumors.

 mutations appear to hold prognostic and predictive value in hormone receptor—positive, HER2-negative advanced or metastatic breast cancer. In an analysis of results from 12 studies, investigators found that patients who received non-PI3K inhibitor therapy had a lower median progression-free survival (PFS) if their tumors harbored 

 mutations than those without the aberration. Among patients who received anti-PI3K therapy, those with 

 mutations achieved a higher median PFS than those without the mutation.

 alterations result in activation of PI3K-α, 1 of 4 PI3K isoforms. Of the isoforms, PI3K-α and PI3K-β are widely expressed, in contrast with PI3K-δ and PI3K-γ, which are mainly found in immune and hematopoietic cells.

 Although early trials suggested that an isoform-selective inhibitor of PI3K-α could be more effective and tolerable than a pan-PI3K inhibitor,

 the realities thus far have been disappointing. Still, existing research has at least shown proof of concept.

At ASCO 2018, Jose Baselga, MD, PhD, physician-in-chief at Memorial Sloan Kettering Cancer Center in New York, New York, presented results from the phase III SANDPIPER trial for taselisib. Baselga has pioneered the development of dual pathway inhibitors in breast cancer.

“Our findings are proof that targeting this pathway [PI3K] in breast cancer is effective,” Baselga said. “However, the benefit to patients was more modest than we had hoped for, and there is a risk of considerable side effects.”

Figure. The PI3K Pathway and its Cascade of Activity

RTKs indicates receptor tyrosine kinases.

 mutations in breast cancer: reconciling ndings from preclinical and clinical data. 

ASCO expert Harold J. Burstein, MD, PhD, of Dana-Farber Cancer Institute in Boston, Massachusetts, said the SANDPIPER trial is “a modest step forward but an important step forward, because it does suggest we can effectively target the pathway, and, hopefully, this is something we can build on.

 research can be divided into 2 broad categories. The first is tolerability: Inhibition of PI3K-α causes on-target hyperglycemia and other adverse events (AEs), particularly if selectivity is incomplete. The second is efficacy: PI3K inhibition may be insufcient to control 

-mutated breast cancer. This could be due to interactions downstream or with other mutated pathways. For example, 

 mutations seem to nullify PI3K-α inhibitors, and mutated 

—of the KRAS/RAF/MEK/ERK pathway&mdash;appears to overcome a variety of PI3K/ AKT/mTOR inhibitors.

 Future research aims to investigate such interactions, possibly leading to new combination therapies or dual inhibitors.

More than 20 PI3K inhibitors have entered clinical trials, but many were abandoned before reaching phase III. So far, 2 have been approved: Copanlisib (Aliqopa), which is predominantly active against PI3K-α and PI3K-δ isoforms expressed in malignant B cells, is approved for patients with relapsed follicular lymphoma; idelalisib (Zydelig), a PI3K-δ inhibitor, is indicated in relapsed follicular lymphoma, chronic lymphocytic leukemia, and small lymphocytic lymphoma.

Current breast cancer research concerning the 

 mutation revolves around developing an effective PI3K-α inhibitor. The leading agent in this field has been taselisib. Unfortunately, recent results from the phase III SANDPIPER trial demonstrated limited benefit and poor tolerability, likely due to a lack of complete specificity for the alpha isoform.

The double-blind, placebo-controlled SANDPIPER trial involved 516 postmenopausal women with ER-positive, HER2-negative locally advanced or metastatic breast cancer. In all, 340 patients had 

-mutant tumors. Each cohort received either taselisib 4 mg daily in combination with 500 mg of fulvestrant (Faslodex) or placebo plus fulvestrant.

Patients receiving taselisib plus fulvestrant achieved a median PFS of 7.4 months (95% CI, 7.26-9.07), compared with 5.4 months (95% CI, 3.68- 7.29) for placebo plus fulvestrant (HR, 0.70; 95% CI, 0.56-0.89; 

 = .0037). Although this improvement was statistically significant, almost half (49.5%) of the participants receiving taselisib plus fulvestrant experienced grade 3 or greater AEs, compared with just 16.4% of patients receiving placebo plus fulvestrant. Diarrhea (60.1%) and hyperglycemia (40.4%) were most common for patients receiving taselisib plus fulvestrant.

In response to these results, Baselga said, “Although [taselisib] is powerful against alpha [isoform], it also hits delta and gamma. The [adverse] effects we see that are limiting our patients staying on are mostly delta and gamma. I do think that in the case of breast cancer, what we need to do is to work on more specific alpha inhibitors that will be safer, because I think the negative factor here is actually the [adverse] effect profile that is based on the nonspecificity against the other isotopes.”

The results prompted Genentech to halt plans to pursue a breast cancer indication for taselisib. “The magnitude of benefit observed in SANDPIPER isn’t as strong as we had hoped for, and, given the challenging safety profile of this combination and the current clinical landscape, we will not be pursuing an FDA submission for taselisib based on the data presented at ASCO,” the company said in a statement.

This outcome is particularly frustrating because it mirrors that of buparlisib, a pan-PI3K inhibitor previously pursued by Baselga and colleagues.

 The phase III BELLE-2 trial compared fulvestrant, an ER agonist, with and without buparlisib in postmenopausal women with hormone receptor—positive, HER2-negative advanced breast cancer. The findings demonstrated that adding PI3K inhibition could extend PFS and was most effective for patients with 

However, the buparlisib combination also came with more serious AEs than fulvestrant alone (23% vs 16%, respectively) and a higher incidence of all-grade AEs, particularly hyperglycemia, and elevated alanine aminotransferase and aspartate aminotransferase levels. This prompted a redirection of efforts from pan-PI3K inhibition to alpha isoform selectivity.

Finding strategies to inhibit the PI3K pathway in Obreast cancer remains an active area of research. Several trials for buparlisib are continuing and other novel agents also are being studied (

A selective PI3K-α inhibitor, alpelisib is under study in the phase III SOLAR-1 trial in combination with fulvestrant in patients with advanced breast cancer that has progressed during or after aromatase inhibitor therapy (NCT02437318). It also is being evaluated in phase II trials for a variety of solid tumor types, including breast cancer.

Table. Selected Ongoing PI3K Inhibitor Trials in Breast Cancer

BC indicates breast cancer; ER, estrogen receptor; MBC, metastatic breast cancer; TNBC, triple-negative breast cancer.

Study is active but not recruiting participants.

LSZ102 is a selective estrogen receptor degrader.

In an ongoing phase II trial, 17 patients with advanced ER-positive, HER2-negative breast cancer who had received at least 1 previous systemic therapy in the advanced setting were given 350 mg of alpelisib daily in 28-day cycles. The objective response rate (ORR) was 41%, and 59% of patients achieved clinical benefit. Researchers also reported that coexisting 

 mutations were associated with a more favorable outcome, whereas 

 mutations predicted unfavorable responses.

Another phase I/II trial showed encouraging results when alpelisib was combined with nab-paclitaxel (Abraxane) for patients with advanced or metastatic HER2-negative breast cancer. Forty-three patients were given 250, 300, or 350 mg of alpelisib daily plus 100 mg/m

 nab-paclitaxel on days 1, 8, and 15 every 28 days. The ORR for this group was 60%, and the clinical benefit rate was 79%. Of patients with PI3K pathway—activated breast cancer, which consisted of those with either a 

 mutation, 100% (n = 19) showed clinical benefit. Additionally, the longest duration of response of 26 months was observed in a patient with 

Hyperglycemia was among the most frequently observed AEs in the study. Overall, 75% of patients experienced hyperglycemia of any grade, including 27% with grade 3 severity, and 32% required metformin to manage the AE. Other common all-grade AEs included diarrhea (88%), fatigue (68%), peripheral neuropathy (63%), and rash (63%).

GDC-0077 has demonstrated greater than 300-fold selectivity for the alpha isoform over the beta, delta, and gamma isoforms in preclinical models. This effort may fulfill the call for more selective agents to improve tolerability. In 

-mutant breast cancer xenograft models, GDC-0077 induced tumor regressions as monotherapy and enhanced the combination of palbociclib (Ibrance) and fulvestrant.

 A phase I study under way involves patients with hormone receptor—positive, HER2-negative breast cancer (NCT03006172) as a single agent and in combination with hormone-targeting therapies.

Janku F, Yap TA, Meric-Bernstam F. Targeting the PI3K pathway in cancer: are we making headway? 

. 2018;15(5):273-291. doi: 10.1038/nrclinonc.2018.28.

 mutations in breast cancer: reconciling findings from preclinical and clinical data. 

-mutant advanced breast cancer in the clinical setting. 

. 2017;18(7):842-843. doi: 10.1016/S1470-2045(17)30430-8.

Di Leo A, Johnston S, Lee KS, et al. Buparlisib plus fulvestrant in postmenopausal women with hormone-receptor-positive, HER2-negative, advanced breast cancer progressing on or after mTOR inhibition (BELLE-3): a randomised, double-blind, placebo-controlled, phase 3 trial. 

. 2018;19(1):87-100. doi: 10.1016/S1470-2045(17)30688-5.

Kratz J, Burkard M, O’Meara T, Pusztai L, Veitch Z, Bedard PL. Incorporating Genomics Into the Care of Patients With Advanced Breast Cancer. 

Researchers remain keenly interested in exploring PIK3CA as an anticancer target in breast cancer.

William Pass, DVM

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