Two controversial areas in the management of ductal carcinoma in situ (DCIS) involve appropriate negative margin width for conservative surgery and whether surgery is indicated in all cases with this diagnosis. Pure DCIS is a high-risk breast lesion as it can sometimes be associated with later development of invasive breast cancer in the absence of treatment. Recent national practice guidelines suggest that adequate margins for DCIS should be ≥2 mm after breast-conserving surgery followed by radiotherapy (RT). This guideline is being utilized by many groups as an absolute indication for additional surgery, although clinical judgment was recommended. We evaluated contemporary patient local recurrence outcomes at The University of Texas MD Anderson Cancer Center. The cases had been handled using multidisciplinary DCIS practices, including extensive preoperative, intraoperative pathologic image-guided assessment of margins; offering some patients with small low- or intermediate-grade DCIS the option of no RT; the use/magnitude of radiation boost tailored to margin width; and offering endocrine therapy for estrogen receptor—positive DCIS. Use of these MD Anderson practices has resulted in 10-year local recurrence rates below 5% for patients with margins <2 mm who received RT. Patients with margins <2 mm who do not receive RT experience significantly higher local failure rates, in the 30% range, and are recommended to repeat surgery. Individualized patient care is determined by a multidisciplinary team and there is not an absolute requirement to achieve wider negative surgical margins when margins are found to be <2 mm if the patient will be treated with RT. Globally, there are at least 3 clinical trials ongoing that are testing the hypothesis that biopsy alone with active surveillance is not inferior to immediate breast-conserving surgery with or without radiotherapy for DCIS. In the United States, one study is the COMET trial, run by the Alliance Foundation Trials group. COMET is a randomized trial in which 1200 patients over age 40 years with hormone-positive DCIS, without a mass lesion, will have stereotactic core biopsy; they will then receive guideline-concordant care versus no surgery, with choice of endocrine therapy and close follow-up. The primary endpoints for these trials are invasive breast cancer recurrence.

 The management of ductal carcinoma in situ (DCIS) is one of the most controversial areas in breast cancer management. It is curious that on the one hand we continue to debate whether 1 or 2 mm margins are clinically relevant compared with no tumor on ink for breast conservation, and at the same time, we have begun randomized trials of biopsy alone for DCIS without surgery—just active surveillance. Taken together, this suggests that many therapeutic questions and potential areas for clinical care improvements remain in this field.

For invasive breast cancer, national consensus guidelines state that negative margin width is considered adequate when the tumor is not present on ink when patients are receiving breast-conserving surgery followed by whole breast radiotherapy (RT).

 These guidelines have definitely resulted in fewer repeat surgeries and mastectomies in the United States.

However, there is concern regarding the new margin guideline recently endorsed—an optimal margin width of DCIS of 2 mm&mdash;by the Society of Surgical Oncology, the American Society of Radiation Oncology, and the American Society of Clinical Oncology.

The guideline clearly stated that individualized patient decisions based on clinical judgment should be utilized. The main issue that has been raised is that it is a paradox to have 2 different margin guidelines—one for invasive cancer with DCIS, and another for pure DCIS&mdash;when receiving postoperative RT. These guidelines were based on a meta-analysis of retrospective studies beginning in the 1960s. Theoretically, differences in margin guidelines for negative margin width for pure DCIS have to do with early pathologic studies related to multifocality seen in pure DCIS, but this pathologic finding also applies when DCIS accompanies invasive breast cancer.

Therefore, our group looked at our own recent contemporary experience treating DCIS at The University of Texas MD Anderson Cancer Center, reviewing data involving about 1500 patients from 1996 to 2010. These data were recently presented at the American Society of Clinical Oncology Annual Meeting & Exhibition.

The 10-year rate of local recurrence for patients with negative margins of <2 mm versus >2 mm were not significantly different, both being less than 5%. There was no statistically significant difference in local recurrence between patients with <2 mm and >2 mm negative margins who underwent RT (10-year local recurrence rate, 4.8% vs 3.3%, respectively; hazard ratio, 0.8; 95% CI, 0.2-3.2; 

 = .72) (Figure 1). Being younger than 40 years was also an independent risk factor for local recurrence in patients receiving RT. For patients with close margins and no RT, recurrence rates are about 5 times the risk and in the 30% range. For those patients, we routinely recommend re-excision. MD Anderson utilizes detailed multidisciplinary practices including extensive preoperative/intraoperative pathologic/histologic image-guided assessment of margins; offering some patients with small, low- to intermediate-grade DCIS the option of no RT; the use/magnitude of radiation boost tailored to margin width; and endocrine therapy for estrogen receptor—positive DCIS. These practices can be labor-intensive and require meticulous multidisciplinary collaboration.

Figure 1. MD Anderson Contemporary (1996-2010) Local Regional Recurrence Among Patients With DCIS Treated With BreastConserving Surgery, With and Without Radiation Therapy According to Negative Margin Status of ≥ or <2 mm

Based on our results, about 8% to 10% of cases would need additional surgery, potentially without benefit, when receiving RT; therefore, each case needs to be evaluated by a multidisciplinary team that takes into account the patient’s age, the extent of margin involvement, and the patient’s values. The main issue is that many multidisciplinary groups now use the 2 mm margin as an absolute indication for repeat surgery, and not all patients with DCIS and margins <2 mm need repeat surgery when receiving RT.

We treat DCIS to prevent invasive breast cancer.

 DCIS in and of itself is not harmful to patients. In effect, DCIS really may belong in a high-risk breast lesion category. Screening mammography, since its introduction in the mid-1980s, has resulted in about a 500-fold increase in detection of DCIS, and perhaps a significant proportion of these patients, particularly with low-grade and intermediate-grade DCIS, will not go on to develop invasive breast cancers during the patient’s lifetime.

To address this clinical scenario, there are at least 3 currently ongoing clinical trials globally that are testing the hypothesis that biopsy alone with active surveillance is not inferior to immediate breast-conserving surgery with or without RT for DCIS.

 In the United States, 1 such trial is COMET,

 run by the Alliance Foundation Trials group. It is a randomized trial in which 1200 patients over age 40 years with hormone-receptor—positive DCIS without a mass lesion will undergo stereotactic core biopsy (Figure 2). In a randomized manner, patients will receive guideline-concordant care consisting of breast-conserving surgery with or without radiation and endocrine therapy, versus choice of endocrine therapy alone and then followed for multiple endpoints with the primary being the development of invasive breast cancer on follow-up. The second trial, LORIS,

based in the United Kingdom, randomizes patients with low- and intermediate-grade DCIS, and the third trial, LORD,

 based in the Netherlands (now through the European Organisation for the Research and Treatment of Cancer cooperative group), is enrolling patients with low-grade DCIS only.

Figure 2. COMET (Comparison of Operative to Monitoring and Endocrine Therapy) Trial for Low-Risk DCIS

Many of our patients are fearful of the consequences of potential overdiagnosis and overtreatment, and they will welcome the results of these trials. Currently, they are followed closely with 6-month follow-up mammograms in the United States.

DCIS is a common preinvasive breast disease that is detected through screening mammography and often treated similarly to invasive breast cancer. One of the most controversial aspects in the management of breast diseases, and specifically breast cancer, is the appropriate management of DCIS. This brief review highlights important data regarding what constitutes an acceptable negative margin for patients treated with breast-conserving therapy and who receive RT. Not all patients with negative margins less than or equal to 2 mm require repeat surgery when receiving RT, as the local control is extremely high. Outcomes are not significantly different for patients with margins greater than 2 mm, as the results of our large contemporary series indicate. Finally, several key international trials are now addressing the hypothesis that the outcomes of patients with percutaneous biopsy alone for lowrisk DCIS are not inferior to outcomes of surgery with or without RT.

 B Henry M. Kuerer, MD, PhD, FACS, is with The University of Texas MD Anderson Cancer Center, Houston, Texas.

 Henry M. Kuerer, MD, PhD, FACS, PH and Fay Etta Robinson Distinguished Professor in Cancer Research, Division of Surgery, Department of Breast Surgical Oncology, The University of Texas MD Anderson Cancer Center, 1400 Pressler St, Unit 1434, Houston, TX 77030; Tel: (713) 745-5043; E-mail: hkuerer@mdanderson.org.

Henry M. Kuerer, MD, PhD, receives compensation from the NEJM Group, Inc and McGraw-Hill publishing for editorial work. Presented in part at the 16th Annual International Congress on the Future of Breast Cancer, July 15, 2017

Moran MS, Schnitt SJ, Giuliano AE, et al. Society of Surgical Oncology-American Society for Radiation Oncology consensus guideline on margins for breast-conserving surgery with whole-breast irradiation in stages I and II invasive breast cancer.

Morrow M, Abrahamse P, Hofer TP, et al. Trends in reoperation after initial lumpectomy for breast cancer: addressing overtreatment in surgical management. 

2017 Jun 5. doi: 10.1001/jamaoncol.2017.0774.

Morrow M, Van Zee KJ, Solin LJ, et al. Society of surgical oncology-American society for radiation oncology-American society of clinical oncology consensus guideline on margins for breast-conserving surgery with whole-breast irradiation in ductal carcinoma in situ. 

Tadros AB, Smith BD, Shen Y, et al. Ductal Carcinoma in Situ and Margins <2 mm: Contemporary Outcomes with Breast Conservation.

 2017; doi: 10.1097/SLA.0000000000002439. [Epub ahead of print].

Tadros AB, Smith BD, Shen Y, et al. Contemporary breast conservation patient outcomes for ductal carcinoma in situ and margins < 2 mm. Proceedings of the American Society of Clinical Oncology. 2017;http:// abstracts.asco.org/.

Kuerer HM, Albarracin CT, Yang WT, et al. Ductal carcinoma in situ: state of the science and roadmap to advance the field. 

Kuerer HM. Ductal carcinoma in situ: treatment or active surveillance? Expert Rev Anticancer Ther. 2015;15(7):777-785.

Comparison of Operative to Monitoring and Endocrine Therapy (COMET) Trial For Low Risk DCIS (COMET). clinicaltrials.gov/ct2/show/NCT02926911. Updated September 14, 2017. Accessed July 17, 2017.

LORIS: A Phase III Trial of Surgery versus Active Monitoring for Low Risk Ductal Carcinoma in Situ (DCIS). http://www.birmingham.ac.uk/research/activity/mds/trials/crctu/trials/loris/index.aspx. Accessed July 17, 2017. 10. Management of Low-risk DCIS (LORD). clinicaltrials.gov/ct2/show/NCT02492607

Articles

The management of ductal carcinoma in situ is one of the most controversial areas in breast cancer management.

Controversies and Clinical Trials for DCIS: Margins and Active Surveillance

Therapeutic options for advanced anaplastic lymphoma kinase (ALK)—positive non–small-cell lung cancer have changed dramatically since the 2011 approval of crizotinib. Since then, 3 additional agents have received FDA approval for use in the second-line setting after progression on crizotinib: ceritinib, alectinib, and brigatinib. Other investigational ALK inhibitors are under evaluation. As these agents represent newer-generation, more potent ALK inhibitors, interest in their use in the frontline setting has quickly grown. Here, we review frontline trials of ceritinib and alectinib, with comparisons drawn with crizotinib, the only FDA-approved frontline choice until the recent approval of ceritinib. With several new promising options, we attempt to better answer the question of which ALK tyrosine kinase inhibitor (TKI) should be favored upfront.

 fusion oncogene in 2007 as a driver of pathogenesis, in the 2% to 7% of patients with non— small-cell lung cancer (NSCLC) who express it, has led to the development over the last decade of several targeted anaplastic lymphoma kinase (ALK) inhibitors.

 The use of ALK inhibitors in advanced disease has transformed the treatment strategy of ALKpositive NSCLC, providing targeted therapeutic options that show significant progression-free survival (PFS) and overall survival (OS) benefit, with an impactful influence on patients and their disease course. There are currently 4 approved agents—crizotinib (Xalkori), ceritinib (Zykadia), alectinib (Alecensa), and brigatinib (Alunbrig)&mdash;with several others in active development.

 Although crizotinib has historically represented the first-line agent of choice, it has quickly been challenged by the newer, more potent, second-generation ALK inhibitors ceritinib and alectinib, with ceritinib recently gaining FDA approval as a first-line option in May 2017. In order to best answer the question of which agent to use upfront, one must consider a variety of factors, including comparative trial data, adverse event (AE) profiles, and response rates, which will be reviewed here.

The use of crizotinib in ALK-positive lung cancer interestingly evolved when the drug, initially developed as a c-MET inhibitor, was in phase I development at the same time the EML4-ALK fusion oncogene was discovered. It was soon found that crizotinib was also a strong inhibitor of ALK phosphorylation and downstream signaling.

 Crizotinib was first tested in a phase I trial evaluating 143 ALK-positive patients treated with escalating doses, reaching a recommended dose of 250 mg twice daily. Results showed an overall response rate (ORR) of 60.8% (95% CI, 52.3%-68.9%), a median duration of response (DOR) of 49.1 weeks (95% CI, 39.3- 75.4 weeks), and a PFS of 9.7 months (95% CI, 7.7-12.8 months), with a well-tolerated profile.

 In August 2011, crizotinib was granted accelerated approval by the FDA for treatment in patients with ALK-positive advanced NSCLC.

Crizotinib was later tested in 2 landmark phase III trials. In the PROFILE 1007 trial, 347 previously treated 

-positive patients were randomized to either crizotinib or single-agent pemetrexed or docetaxel. At a follow-up of 1 year, crizotinib showed a statistically significant PFS benefit of 7.7 versus 3 months for single-agent chemotherapy (HR, 0.49; 95% CI, 0.37-0.64; 

 <.001) as well as improved ORR and DOR. Patients reported improved lung cancer symptoms and also greater global quality of life with crizotinib rather than chemotherapy. No significant difference in OS was found (20.3 vs 22.8 months; hazard ratio [HR], 1.02; 95% CI, 0.68-1.54; 

 = .54), likely a result of 64% crossover.

 With evident success in the second-line setting, crizotinib was then tested in the first-line setting in the PROFILE 1014 trial, in which 343 patients who were 

-positive with no prior systemic treatment were randomized to crizotinib 250 mg twice daily or standard platinum doublet with cisplatin or carboplatin plus pemetrexed. The primary endpoint was PFS, which was met with a statistically significant benefit with crizotinib of 10.9 versus 7 months with chemotherapy (HR, 0.45; 95% CI, 0.35-0.60; 

 <.001). The ORR was 74% for crizotinib versus 45% for chemotherapy (

<.001), though the difference in OS was not significant (HR, 0.82; 95% CI, 0.54-1.26; 

 = .36), again likely due to a high crossover rate of 70% of patients. The most frequently occurring AEs in the crizotinib arm compared with chemotherapy were visual disturbances (71%), diarrhea (61%), and edema (49%). Overall, there was less permanent discontinuation of the drug compared with chemotherapy and a greater improvement in quality-of-life measures.

This trial solidified crizotinib as the standard of care in the frontline setting of metastatic 

-positive NSCLC, for which it was approved in November 2013 as the first-line agent of choice. The success of crizotinib unfortunately is ultimately tempered by the development of drug-resistance mechanisms and disease progression, which on average occur toward the end of the first year of therapy, with central nervous system (CNS) metastasis being a common site of relapsed disease. These resistance mechanisms include secondary mutations within the ALK kinase domain, most notably the “gatekeeper” substitution L1196M, followed by a G1269A mutation, amplification of the ALK fusion gene, and activation of other receptor tyrosine kinase sites such as EGFR, cKIT, and IGF-1R.

 In contrast to EGFR tyrosine kinase inhibitor (TKI) resistance, in which approximately 50% of the time a specific mutation (T790M) develops, in ALK patients, there is significant tumor heterogeneity as well as the presence of varying point mutations that can occur at nonactive sites, with only one-third of crizotinib resistant cases being an on-target mutation.

Given that crizotinib targets not only ALK, but MET and ROS1, several newer-generation ALK inhibitors have subsequently been developed, with higher affinity for inhibiting ALK, auto phosphorylation, resultant downstream signaling, and improved CNS penetration. These include ceritinib, alectinib, and brigatinib, all of which are FDA-approved for treatment after progression on or intolerance to crizotinib, with ceritinib also approved in the upfront setting. Other investigational agents include lorlatinib and ensartinib, with lorlatinib having achieved a breakthrough FDA designation as a second-line agent.

 To further add to the complexity of ALK resistance, there are also differing activities of ALK inhibitors across ALK mutations, with varying selectivity profiles, making the understanding of the mechanism of resistance important to choosing an effective therapy.

The potency of ceritinib, alectinib, and brigatinib, and their demonstrated efficacy as second-line ALK inhibitors after progression on crizotinib, were shown in early phase I/II clinical trials, which led to approvals and also to interest in their use as first-line agents.

 In the ASCEND-4 trial, 376 treatment-naïve stage IIIB/IV ALK-positive NSCLC patients were randomized to 750 mg daily of ceritinib or 4 cycles of platinum-based chemotherapy with cisplatin or carboplatin plus pemetrexed followed by pemetrexed maintenance. Crossover to the ceritinib arm was allowed if patients progressed on chemotherapy. 

 rearrangement was determined by immunohistochemistry. The primary endpoint was PFS, with secondary endpoints of ORR, DOR, OS, and intracranial response.

The results showed a median PFS of 16.6 months in the ceritinib group versus 8.1 months in the chemotherapy arm (HR, 0.55; 95% CI, 0.42-0.73; 

 = .00001). This PFS benefit was observed in both patients with and without brain metastasis, with those without brain metastasis sustaining an impressive median PFS of 26.3 months versus 8.3 months in the chemotherapy group (HR, 0.48; 95% CI, 0.33-0.69). The ORR was also significantly improved for ceritinib (72.5% vs 26.7%) as well as the DOR (66.4 weeks vs 26.9 weeks). The OS data at the time of analysis were immature and did not cross the efficacy-stopping boundary, though it was not reached in the ceritinib group and was 26.2 months in the chemotherapy group (HR, 0.73; 95% CI, 0.50-1.08; 

 = .056). With regard to toxicity, notable AEs that were higher in the ceritinib arm compared with chemotherapy were diarrhea, nausea, and vomiting, as well as elevation in aminotransferases. Eighty percent of patients in the ceritinib group versus 45% in the chemotherapy group required dose adjustments or interruption of therapy, primarily as a result of gastrointestinal (GI) toxicity or liver function abnormalities. Five percent of patients discontinued therapy in the ceritinib group. Lung cancer—specific symptoms as evaluated by questionnaire were significantly improved for those randomized to the ceritinib arm versus chemotherapy arm.

The study design of ASCEND-4 closely mirrored that of the PROFILE 1014 study in terms of the comparator chemotherapy arm, with similar results of witnessed control-arm PFS between the trials. No new AEs using a more potent ALK inhibitor were observed, although GI toxicity with ceritinib was an issue for a significant number of patients, requiring dose reductions. Data have been reported that decreasing the dose of ceritinib to 450 mg daily and taking with food may mitigate many of the GI toxicities seen with 750 mg daily.

The convincingly positive results of the ASCEND-4 trial across all subgroups led to the recent frontline FDA approval of ceritinib. The updated National Comprehensive Cancer Network NSCLC guidelines now include ceritinib alongside crizotinib as a category 1 option in the frontline setting in ALK-positive metastatic disease.

The phase III J-ALEX trial was the first trial with data comparing 2 ALK inhibitors in the first-line setting. Conducted exclusively in Japan, this trial randomized 207 Japanese patients with stage IIIB/IV 

-positive NSCLC, previously given 0 to 1 lines of chemotherapy, but ALK TKI naïve, to alectinib 300 mg twice daily or crizotinib 250 mg twice daily. The primary endpoint was PFS with secondary endpoints of OS, ORR, DOR, time to onset of CNS lesions in patients without any at baseline, time to progression of CNS lesions in those with lesions present at baseline, and quality of life. At the time of analysis, median PFS was not reached in the alectinib arm (20.3 months at the low end of the confidence interval) and was 10.2 months in the crizotinib arm (HR, 0.34; 99.7% CI, 0.17-0.70; 

 <.0001). The ORR of alectinib was 85.4% (95% CI, 78.6%-92.3%) versus 70.2% (95% CI, 61.4%-79%) in the crizotinib arm. There was also an improved response to alectinib in the subgroup of patients with brain metastasis (HR, 0.08; 95% CI, 0.01- 0.61). AEs of any grade favored alectinib, with the most common being constipation in the alectinib arm. In patients randomized to crizotinib, diarrhea, nausea, vomiting, visual disturbances, and transaminase elevations were significantly witnessed. No AEs resulting in a fatal outcome occurred. Survival data remain immature at present with only 9 events reported between the 2 groups.

With the J-ALEX trial conducted exclusively in Japan, the international ALEX trial was launched to assess whether these findings could be replicated on a global scale. Spanning 31 countries, the ALEX trial enrolled 303 treatment-naïve 

-positive metastatic patients with NSCLC who were randomized to alectinib 600 mg twice daily or crizotinib 250 mg twice daily, with PFS as the primary endpoint. Secondary endpoints included OS, ORR, DOR, time to CNS progression, quality of life, and safety.20 In addition to being an international study, the ALEX trial design differed from J-ALEX in that the dose of alectinib used was 600 mg twice daily compared with 300 mg twice daily, and the patients were treatment-naïve, whereas about one-third of patients in the J-ALEX trial had previously received 1 line of chemotherapy.

The results, like those of J-ALEX, were again compelling. Median PFS was not reached in the alectinib arm (17.7 months at the low end of the confidence interval) versus 11.1 months in the crizotinib arm (HR, 0.47; 95% CI, 0.34-0.67; P <.001). Nearly all subgroups benefited, with the exception of smokers and patients with an Eastern Cooperative Oncology Group score of 2, although these patients were represented in small numbers. ORR was 82.9% (95% CI, 76%-88.5%) in the alectinib arm versus 75.5% (95% CI, 67.8%-82.1%) in the crizotinib arm. Of those patients without brain metastasis at baseline, time to CNS progression was significantly longer with alectinib, with a 12-month incidence rate of 9.4% (95% CI, 5.4%-14.7%) versus 41.4% (95% CI, 33.2%-49.4%) in the crizotinib cohort. Of those patients with measurable CNS metastasis at baseline, results showed an 81% (95% CI, 58%-95%) response rate in the alectinib arm versus 50% (95% CI, 28%-72%) in the crizotinib arm. An impressive 38% of patients in the alectinib arm achieved a complete response. In terms of grade 3 to 5 AEs, 41% of patients in the alectinib arm experienced such an event versus 50% in the crizotinib arm, with fewer rates of AEs leading to dose reduction, interruption, or discontinuation in those treated with alectinib. The median OS data are immature at present.

So how can a clinician integrate the results of the PROFILE 1014, ASCEND-4, J-ALEX, and ALEX trials into deciding which ALK agent should be favored upfront? Crizotinib, ceritinib, and alectinib all show remarkable frontline overall response rates of 74%, 73%, and 80% to 85%, respectively.7,16,19,20 Refer to the Table for trial comparisons. When taking into account comparative toxicities, the above trials demonstrate that although the spectrum of AEs is similar, alectinib seems to be better tolerated overall than are crizotinib or ceritinib, with less GI toxicity, nearly no visual disturbances, and less transaminase elevation. Increased peripheral edema and skin rash can be seen, however, as well as some generally mild myositis.

With regard to CNS penetration, even with good control of systemic disease, about 40% to 50% of patients on crizotinib will develop brain metastases. Nonetheless, crizotinib still has modest penetration in the CNS. As evidenced by the PROFILE 1014 trial, of the 23% of patients with brain metastases, there was a nonsignificant trend toward improved time for intracranial progression in the crizotinib versus chemotherapy arm (HR, 0.60). At 24 weeks of follow-up in the patients with previously treated brain metastases, 56% were controlled in those receiving crizotinib versus 25% in those receiving chemotherapy.7 The second-generation ALK inhibitors, however, have more robust CNS activity. In the ASCEND-4 trial, in patients with at least 1 brain metastasis, ceritinib had a 72.7% intracranial ORR versus 27.3% for chemotherapy.16 In both the J-ALEX and ALEX studies, alectinib was significantly favored over crizotinib in the subset of patients with brain metastases.19,20 It would thus seem reasonable that in patients who present with significant brain metastasis, an upfront secondgeneration agent should be considered over crizotinib. The survival data, when mature, will provide a more definitive answer.

Certainly based on the head-to-head comparison posed in both J-ALEX and ALEX, alectinib demonstrated an improved PFS, ORR, and CNS response over crizotinib in the front line, and its toxicity profile was preferable. Even without mature OS data, it would be hard to picture alectinib not being granted FDA approval as a first-line option in the near future. It now represents a “preferred” frontline agent compared with crizotinib and ceritinib in the most recently updated NCCN guidelines.18 Both the 300 mg twice-daily dose as used in J-ALEX and the 600 mg twice-daily dose used in ALEX appear highly effective, with a response rate of more than 80% and median PFS that is yet to be reached. Like most drugs, higher dosages can come with higher toxicity, and alectinib at 300 mg twice daily appeared to be better tolerated than 600 mg twice daily. Twenty six percent of patients in J-ALEX experienced at least 1 grade 3 or 4 AE on alectinib 300 mg twice daily compared with 41% with at least a grade 3 AE on alectinib 600 mg twice daily in the ALEX trial. Despite encouraging CNS responses in both J-ALEX and ALEX, it is difficult to compare the 2 trials in this regard, because J-ALEX had significantly fewer patients with measurable brain lesions in comparison with ALEX (13.6% vs 42%). At present, alectinib 600 mg twice daily remains the recommended dose in the United States when used as a second-line agent.

With alectinib showing overall superiority to crizotinib, and being on pace to replace crizotinib as a new standard of care in the frontline setting, an important question arises: Is frontline alectinib better than sequential therapy with crizotinib followed by alectinib or another second-generation ALK TKI? One can conjecture that when assessing PFS, the answer depends on which drugs are used. Although PFS comparisons between trials should always be taken with caution, given that the low end of the confidence interval in ALEX with regard to PFS was 17.7 months with alectinib, this already is trending toward exceeding the median PFS of upfront crizotinib followed by alectinib or ceritinib in the second line, which is around 10 to 11 months for crizotinib7 plus 7 to 8 months with alectinib or ceritinib.

 However, this calculation changes if the recently approved brigatinib is used as a sequential therapy to crizotinib, as it was the first ALK TKI to show more than a 12-month PFS benefit in the second-line setting.15 Therefore, it can be said that the verdict is still out on sequential therapy, regarding first-in-class crizotinib versus upfront use of the newer-generation ALK TKIs. Time and more mature survival data will likely settle this.

In sum, the current landscape of first-line treatment for ALKpositive stage IIIB/IV disease is quickly, excitingly evolving. Several ALK TKIs are emerging as effective options, with crizotinib and ceritinib already FDA-approved in the frontline setting, and alectinib undoubtedly soon to follow. In addition, phase III trials of brigatinib versus crizotinib as well as ensartinib versus crizotinib in ALK treatment-naïve patients are underway, and their results are likely to eventually add to the pot of upfront therapies.

 The decision of which ALK inhibitor to use first has become complex, and without yet firm survival data to support 1 agent over another, it is fair to say that clinician decisions will vary, and drug tolerance, resistance patterns, quality-of-life measures, patient preference, accessibility, and cost should be carefully assessed and evaluated for each individual patient. Based on available data, alectinib appears to be the most promising agent of the group, and time will tell if it eventually wins out. One thing is for sure: There is indeed much hope for patients with advanced ALK-positive NSCLC who, before August 2011, were left with chemotherapy as their sole treatment choice. Now, just about 6 years later, they can take advantage of a list of effective ALK inhibitors that, as time progresses, only appears to be growing.

 Both Jeffrey Zweig, MD, and Heather Wakelee, MD, are with Department of Medicine, Division of Oncology, Stanford University, Stanford, California.

 Heather Wakelee, MD, Department of Medicine, Division of Oncology, Stanford University, 875 Blake Wilbur Dr, Stanford, CA 94305-5826. Tel: (650) 736-7221; Fax: (650) 498-5800; E-mail: hwakelee@stanford.edu.

Soda M, Choi YL, Enomoto M, et al. Identification of the transforming EML4-ALK fusion gene in nonsmall-cell lung cancer. Nature. 2007;448(7153):561-566.

Wu J, Savooji J, Liu D. Second- and third-generation ALK inhibitors for non-small cell lung cancer. J Hematol Oncol. 2016;9:19. doi: 10.1186/s13045-016-0251-8

Christensen JG, Zou HY, Arango ME, et al. Cytoreductive antitumor activity of PF-2341066, a novel inhibitor of anaplastic lymphoma kinase and c-Met, in experimental models of anaplastic large-cell lymphoma. Mol Cancer Ther. 2007;6(12 Pt 1):3314-3322

Bang Y, Kwak EL, Shaw AT, et al. Clinical activity of the oral ALK inhibitor PF-02341066 in ALKpositive patients with non—small cell lung cancer (NSCLC). J Clin Oncol. 2010;28(suppl 18); abstract 3

Camidge DR, Bang YJ, Kwak EL, et al. Activity and safety of crizotinib in patients with ALK-positive non-small-cell lung cancer: updated results from a phase 1 study. Lancet Oncol. 2012;13(10):1011-1019. doi: 10.1016/S1470-2045(12)70344-3.

Shaw AT, Kim DW, Nakagawa K, et al. Crizotinib versus chemotherapy in advanced ALKpositive lung cancer [published correction appears in N Engl J Med. 2015;373(16):1582]. N Engl J Med. 2013;368(25):2385-2394. doi: 10.1056/NEJMoa1214886

Solomon BJ, Mok T, Kim DW, et al; PROFILE 1014 Investigators. First-line crizotinib versus chemotherapy in ALK-positive lung cancer. N Engl J Med. 2014;371(23):2167-2177. doi: 10.1056/NEJMoa1408440.

Doebele RC, Pilling AB, Aisner DL, et al. Mechanisms of resistance to crizotinib in patients with ALK gene rearranged non-small cell lung cancer. Clin Cancer Res. 2012;18(5):1472-1482. doi: 10.1158/1078- 0432.CCR-11-2906.

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Katayama R, Shaw AT, Khan TM, et al. Mechanisms of acquired crizotinib resistance to ALK-rearranged lung cancers. Sci Transl Med. 2012;4(120):120ra17. doi: 10.1126/scitranslmed.3003316

Huang WS, Liu S, Zou D. Discovery of brigatinib (AP26113), a phosphine oxide-containing, potent, orally active inhibitor of anaplastic lymphoma kinase. J Med Chem. 2016;59(10):4948-4964. doi: 10.1021/acs. jmedchem.6b00306.

Awad MM, Shaw AT. ALK inhibitors in non-small cell lung cancer: crizotinib and beyond. Clin Adv Hematol Oncol. 2014;12(7):429-439.

Shaw AT, Kim DW, Mehra R, et al. Ceritinib in ALK-rearranged non-small-cell lung cancer. N Engl J Med. 2014;370(13):1189-1197. doi: 10.1056/NEJMoa1311107.

Ou SH, Ahn JS, De Petris L, et al. Alectinib in crizotinib-refractory ALK-rearranged non-small-cell lung cancer: a phase II global study. J Clin Oncol. 2016;34(7):661-668. doi: 10.1200/JCO.2015.63.9443.

Camidge DR, Bazhenova L, Salgia R, et al. Safety and efficacy of brigatinib (AP26113) in advanced malignancies, including ALK+ non—small cell lung cancer(NSCLC). J Clin Oncol. 2015;33(15_ suppl):abstract 8062

Soria JC, Tan DS, Chiari R, et al. First-line ceritinib versus platinum-based chemotherapy in advanced ALK-rearranged non-small-cell lung cancer (ASCEND-4): a randomised, open-label, phase 3 study. Lancet. 2017;389(10072):917-929. doi: 10.1016/S0140-6736(17)30123-X.

Dziadziuszka R, Kim D-W, Bearz A, et al. Phase I study of ceritinib 450 mg or 600 mg taken with a lowfat meal versus 750 mg in fasted state in ALK+ metastatic NSCLC. J Thorac Onc. 2017;12(1 Suppl):S1184. doi: 10.1016/j.jtho.2016.11.1666.

National Comprehensive Cancer Network (NCCN). Non—small cell lung cancer (version 8.2017). NCCN website. https://www.nccn.org/professionals/physician_gls/pdf/nscl.pdf. Published July 14, 2017. Accessed July 24, 2017.

Hida T, Nokihara H, Kondo M, et al. Alectinib versus crizotinib in patients with ALK-positive non-smallcell lung cancer (J-ALEX): an open-label, randomised phase 3 trial. Lancet. 2017;390(10089):29-39. doi: 10.1016/S0140-6736(17)30565-2.

Peters S, Camidge DR, Shaw AT, et al; ALEX Trial Investigators. Alectinib versus crizotinib in untreated ALK-positive non-small-cell lung cancer [published online June 6, 2017]. N Engl J Med. doi: 10.1056/ NEJMoa1704795.

Ou SH, Ahn JS, De Petris L, et al. Alectinib in crizotinib-refractory ALK-rearranged non-small-cell lung cancer: a phase II global study. J Clin Oncol. 2016;34(7):661-668. doi: 10.1200/JCO.2015.63.9443. 22. Shaw AT, Kim DW, Mehra R, et al. Ceritinib in ALK-rearranged non-small-cell lung cancer. N Engl J Med. 2014;370(13):1189-1197. doi: 10.1056/NEJMoa1311107.

A phase 3 multicenter open-label study of brigatinib (AP26113) versus crizotinib in patients with ALKpositive advanced lung cancer. clinicaltrials.gov/ct2/show/NCT02737501?term=NCT02737501&rank=1Mar ch 2016. Updated June 29, 2017. Accessed July 24, 2017.

Phase 3 randomized study comparing x-396 (ensartinib) to crizotinib in anaplastic lymphoma kinase (ALK) positive non-small cell lung cancer (NSCLC) patients. clinicaltrials.gov/ct2/show/NCT02767804?term =NCT02767804&rank=1. Updated May 19, 2017. Accessed July 24, 2017.

With several new promising options, Jeffrey Zweig, MD, and Heather Wakelee, MD attempt to better answer the question of which ALK tyrosine kinase inhibitor (TKI) should be favored upfront.

January 2018 | Special Issues

Controversies and Clinical Trials for DCIS: Margins and Active Surveillance

The Evolution of Frontline Therapy in ALK-Positive Advanced NSCLC: Which ALK TKI to Use Upfront?