Will Pass, DVM

The FDA recently released 5 new draft guidance documents that promote broader patient eligibility for cancer clinical trials.

The policies encourage inclusion of certain individuals who were previously disqualified due to medical conditions or biological factors, including brain metastases, organ dysfunction, prior or concurrent malignancies, chronic infections, and age.

According to Scott Gottlieb, MD, former FDA commissioner, current eligibility criteria have become too restrictive for various reasons, ranging from historical precedence to intentional design. &ldquo;Some eligibility criteria have become commonly accepted over time or used as a template across trials without a clear scientific or clinical rationale or justification,&rdquo; Gottlieb said in a press release. &ldquo;In other cases, eligibility criteria can be deliberately restrictive.&rdquo;

Howard S. Hochster, MD, associate director for clinical research and chief of gastrointestinal medical oncology at Rutgers Cancer Institute and director of cancer clinical research for oncology services at RWJBarnabas Health, both in New Brunswick, New Jersey, described how particular exclusions may lead to uncertainty in routine practice, using checkpoint inhibitors as an example.

&ldquo;With all the antiPD-1 agents, every trial systematically excluded people who had any kind of autoimmune disease,&rdquo; Hochster said in an interview with Targeted Therapies in Oncology(TTO), noting that even minor autoimmune-related historical events, such as a history of suspected Hashimoto&rsquo;s thyroiditis, could lead to exclusion. Without relevant clinical trial data from patient populations that are encountered regularly in clinical practice, Hochster said that clinicians have had to &ldquo;cross their fingers and hold their breath while they are treating people.&rdquo;

Retrospective studies have filled some of the knowledge gaps, at times highlighting the unmerited reality of certain eligibility restrictions. For instance, concerning antiPD-1 agents, a 2018 study by Giulia C. Leonardi, MD, et al showed that patients with autoimmune disease who were treated with checkpoint inhibitors had similar rates of immune-related adverse events (AEs) compared with patients without autoimmune disease. In addition, few patients with autoimmune disease had exacerbations of their preexisting condition.

Although the results from such studies can provide valuable insights, often by drawing data from electronic medical records, retrospective research is not ideal, said Howard &ldquo;Skip&rdquo; Burris, III, MD, president of clinical operations and chief medical officer at Sarah Cannon Research Institute in Nashville, Tennessee, and president-elect of the American Society of Clinical Oncology (ASCO). &ldquo;Frankly, it is a shame we have to do that,&rdquo; Burris said in an interview with TTO. &ldquo;It would be nice to have clinical trials that would do that [research] in a prospective fashion.&rdquo;

Burris suggested that this ambition is shared among several other stakeholders, as demonstrated by the collaborative nature of the FDA&rsquo;s initiative to influence clinical trial reform. &ldquo;In 2017, ASCO and Friends of Cancer Research released a statement recommending strategies to change the exclusionary nature of eligibility criteria,&rdquo; Burris said. &ldquo;These consensus recommendations came from experts in the field, and stakeholders in the cancer community [who] were dealing with [these challenges] every day.&rdquo;

Along with offering more real-world data, the new policies should increase clinical trial enrollment, Burris noted, leading to better outcomes in the near future. &ldquo;It has been shown in a variety of settings that participation in a clinical trial is often the best option for a patient and that participating in a trial leads to better outcomes, more support, more eyes on the patient, and more adherence to the protocol and program,&rdquo; he said.

At the 2019 ASCO Annual Meeting, 1 retrospective analysis conducted in nonsmall cell lung cancer found that these expanded criteria would enable nearly twice as many patients to consider trial participation. Out of a total of 10,346 patients eligible for trial participation under the broadened criteria, 21.2%, 21.5%, and 14.4% would have been deemed ineligible due to brain metastases, prior or concurrent malignancies, and renal function, respectively.

When asked if the new draft guidance documents come with any drawbacks, Burris denied any; in contrast, Hochster suggested that the picture is not entirely positive.

&ldquo;I think that there is a downside to this process,&rdquo; he said. &ldquo;It will make interpreting clinical trials a little bit more difficult.&rdquo; Specifically, intercurrent illness may complicate interpretation of AEs, he said. &ldquo;The more you expand the universe of patients you are treating from the &lsquo;ideal perfect patient,&rsquo; the more you are going to have some noise in the system.&rdquo;

Burris offered a different viewpoint. &ldquo;The hope is that while the data might be different than what we have seen in the past, I think we will know how the trial was written, we will know the patients [who] are accrued, and the data will be the data to support it,&rdquo; he said. &ldquo;It should be more realistic and more consistent with what physicians should be expected to see in their practices.&rdquo;

On this latter topic, Hochster agreed, emphasizing that the new guidance documents should lead to more pragmatic data (FIGURE). &ldquo;I think that by broadening the universe of eligible patients to the clinical trial, we will have a better reflection of the patients we tend to see in our clinics,&rdquo; he said. &ldquo;In the long run, as more drugs are tested in a wider group of patients, or a less select group of patients, we will have a better sense that [the data may be applied] to our everyday patients in the clinic.&rdquo;

Although the new FDA draft guidance documents, if adopted, are not explicitly enforceable, Hochster and Burris anticipate compliance, predicting that future conversations between the FDA and drug developers will be influenced by these new recommendations.

&ldquo;It is going to cause more back and forth between the drug companies and the FDA,&rdquo; Hochster said. &ldquo;If these questions are being raised all the time, I think it will help the drug companies feel more comfortable not excluding those patients. And they will have to actively do something to make sure that they exclude them instead of going along with the flow. Most of the time, if you are [talking about a] drug company and the FDA says, &lsquo;Do this&rsquo;, then 9 out of 10 times, they are going to agree.&rdquo;

&ldquo;It is going to be one study at a time,&rdquo; Burris said. &ldquo;I am optimistic that there is going to be a gradual transition into seeing this become the new standard, and it very well may take a few years, but I think we will get there.&rdquo;

&ldquo;Historically, we have always excluded [patients with brain metastases] from clinical trials because the feeling was that the drugs do not work that well [in this population and their participation] would not have reflected the benefit of the drug,&rdquo; Hochster said. &ldquo;But once people started living longer and longer with immunotherapy, it became important to treat patients with brain metastases as well.&rdquo;

To this end, the FDA recommends including patients with brain metastases in all cancer clinical trials if it is safely possible, preferably throughout the drug development process.

The FDA emphasizes inclusion of patients with brain metastases in trials for cancers that commonly metastasize to the brain, such as lung cancer and melanoma. Baseline central nervous system (CNS) screening should be performed when brain metastases are present or likely to occur, and detection of a brain lesion should not result in automatic exclusion. If a &ldquo;strong rationale&rdquo; exists for exclusion of certain patients, investigators are urged to describe this in the trial protocol.

Multiple justifiable scenarios are described in the guidelines, such as the exclusion of patients who may be at an increased risk of seizures and bleeding or hemorrhage events as a result of the prescribed agent. Furthermore, patients receiving steroids that may compromise agent efficacy should be considered for exclusion. Following these general considerations, the FDA describes trial eligibility in terms of 3 forms of brain metastases: treated/stable, active, or leptomeningeal.

Patients with treated or stable brain metastases should be included regardless of an agent&rsquo;s predicted ability to penetrate the bloodbrain barrier. When included, patients should be neurologically stable to limit confusion of metastatic symptoms with CNS toxicity from a tested agent. Ideally, patients taking corticosteroids should be on a stable or decreasing dose in the week prior to study commencement.

Patients with active brain metastases should be included in clinical trials if CNS treatment is not immediately necessary or likely to be necessary; however, known risks of CNS toxicities may warrant exclusion.

Patients with leptomeningeal metastases should not be automatically excluded from clinical trials. Similar to patients with active brain metastases, those with leptomeningeal metastases who do not require immediate treatment for CNS disease or are unlikely to require treatment in the short term should be included.

1) Kidney function should be measured by glomerular filtration rate, with a consistent equation used throughout the drug development process. When applicable, prospective dose adjustments may be considered for patients with reduced kidney function to facilitate similar exposure as patients with normal kidney function.

2) Patients with &ldquo;significant clinical cardiac abnormalities&rdquo; should be excluded, particularly in early-phase studies. Ejection fraction should be measured by echocardiography or multigated acquisition scan, with the note that no minimum value has been established to predict development of heart failure. Concerning QTc prolongation, baseline clinical evaluation should be developed collaboratively with the FDA.

3) Because drug metabolism through the liver cannot be accurately predicted by liver biochemical testing, the FDA recommends comprehensive patient assessment. Estimations by the Child- Pugh or Model for End-Stage Liver Disease should be considered in light of patient history and epidemiological, environmental, and genetic factors.

&ldquo;Impaired hepatic blood flow, in particular, when portal hypertension is evident, is critical to assessing liver handling of drugs,&rdquo; the FDA guidance noted. &ldquo;Therefore, even in the setting of low Child-Pugh or Model for End-Stage Liver Disease scores, normal international normalized ratio/prothrombin time, and normal total bilirubin, more reliable measures to predict biotrans formation, conjugation, and drug permeability related to hepatic transformation of xenobiotics are needed.&rdquo;

Burris suggested that the new recommendations for prior or concurrent malignancies are becoming increasingly relevant. &ldquo;It is a fact now that patients are living much longer,&rdquo; Burris said, &ldquo;and we are heading toward having 20 million cancer survivors in this country. It is going to be more common, and we see it every week in our clinic.&rdquo;

Now, according to the FDA, patients with &ldquo;prior or concurrent second primary malignancy&rdquo; should be included if &ldquo;natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational drug.&rdquo;

The FDA specifically discusses HIV, hepatitis B virus, and hepatitis C virus in its guidance document for patients with chronic infections.

Inclusion is encouraged when patients infected with these viruses have adequate immune system and organ function. According to Burris, the recommendations are fitting for modern practice. &ldquo;We have great therapies now that are successful in treating HIV and hepatitis, so this is making [clinical trial data] more timely and consistent with the results we are seeing today.&rdquo;

The final 2 draft guidance documents outline eligibility criteria for children (2 to <12 years) and adolescents (&ge;12 to 17 years).

In general, inclusion may be considered if cancer type or molecular target is shared between younger and adult patients, potential benefit could justify risk of participation, and no curative options are available to the patient. Dose modifications may be considered, if necessary, and long-term prospective follow-up is encouraged, particularly if treatment could impact growth and development or result in late effects.

According to Burris, the new FDA recommendations surrounding organ dysfunction represent &ldquo;fairly minor shifts&rdquo; compared with previous guidance. Specifically, the document calls for inclusion of patients with &ldquo;relatively preserved organ function.&rdquo; Further recommendations are broken down into 3 categories by organ system: renal, cardiac, and hepatic.

Some of the key principles are summarized as follows:

FDA in brief: FDA takes new steps to broaden patient participation in cancer clinical trials, advancing policies to promote inclusion of pediatric patients and patients with medical conditions that can occur alongside cancer. FDA website. bit.ly/2UMjclo. Published March 12, 2019. Accessed April 29, 2019.

Leonardi GC, Gainor JF, Altan M, et al. Safety of programmed death-1 pathway inhibitors among patients with non-small cell lung cancer and preexisting autoimmune disorders.

. 2018;36(19):1905-1912. doi: 10.1200/JCO.2017.77.0305.

Harvey RD, Rubinstein WS, Ison G, et al. Impact of broadening clinical trial eligibility criteria for advanced non-small cell lung cancer patients: real-world analysis.

. 2019;37(suppl 18;abstr LBA108). doi: 10.1200/JCO.2019.37.18_suppl.LBA108.

Cancer clinical trial eligibility criteria: brain metastases: guidance for industry. FDA website. https://bit.ly/2vuBJZa. Published March 2019. Accessed April 29, 2019.

Cancer Clinical trial eligibility criteria: patients with organ dysfunction or prior or concurrent malignancies: guidance for industry. FDA website. https://bit.ly/2USmHa0. Published March 2019. Accessed April 29, 2019.

Cancer clinical trial eligibility criteria: patients with HIV, hepatitis B virus, or hepatitis C virus infections: guidance for industry. FDA website. https://bit.ly/2IY5lGi. Published March 2019. Accessed April 29, 2019.

Cancer clinical trial eligibility criteria: minimum age for pediatric patients: guidance for industry. FDA website. bit.ly/2T64nt6. Published March 2019. Accessed April 29, 2019.

Considerations for the inclusion of adolescent patients in adult oncology clinical trials: guidance for industry. FDA website. https://bit.ly/2IMiAdT. Published March 2019. Accessed April 29, 2019.

Articles

The FDA recently released 5 new draft guidance documents that promote broader patient eligibility for cancer clinical trials. The policies encourage inclusion of certain individuals who were previously disqualified due to medical conditions or biological factors, including brain metastases, organ dysfunction, prior or concurrent malignancies, chronic infections, and age.

FDA Issues Draft Guidance to Broaden Clinical Trial Inclusion

Due to an active research landscape, the National Comprehensive Cancer Network (NCCN) Guidelines for nonsmall cell lung cancer (NSCLC) have had 3 recent updates that include numerous clinically relevant recommendations.

&ldquo;These new changes to the NCCN guidelines express the rapidly evolving deluge of new data regarding the targeted and immunologic treatment of lung cancer,&rdquo; said Wallace L. Akerley, MD, senior director of community oncology research at the Huntsman Cancer Institute and professor of internal medicine at The University of Utah in Salt Lake City.

According to Akerley, a guidelines panel expert, the NCCN has kept pace with accelerating research and associated trends. &ldquo;The NCCN lung panel foreshadowed the current treatment paradigm when it made early recommendations for molecular panel testing for NSCLC and completed the transition to true precision medicine in late 2016 when it dropped the recommendation for erlotinib [Tarceva] for lung cancers without an

As the past 3 guideline updates demonstrated, molecular medicine is redefining lung cancer diagnosis and treatment. New mutation categories have been added, such as for

), and existing biomarkers have been revised, as with the new definition of PD-L1 expression positivity. The latest recommendations also make agents available to more patients and affect treatment sequencing.

&ldquo;Recently, brigatinib [Alunbrig], osimertinib [Tagrisso], and lorlatinib [Lorbrena] have been added as recommendations for those with

mutations in various lines of treatment and combined chemoimmunotherapy for those without a targetable mutation,&rdquo; Akerley said. &ldquo;The treatment of NSCLC has been completely overhauled in the last 2-plus years, and the NCCN has been the leader in interpreting these data.&rdquo;

Guideline updates regularly promise better patient outcomes and offer concise therapy recommendations for busy clinicians who need to stay informed. This review provides an outline of the most recent updates, with brief summaries of relevant trials and FDA approvals.

After showing superiority over crizotinib (Xalkori) in the global Ph3 ALEX study, alectinib (Alecensa) was added as a preferred agent for patients with

rearrangements discovered during first-line systemic therapy. It is recommended that patients either complete their prescribed regimen or interrupt and initiate treatment with alectinib. Updated results of the Ph3 ALEX trial showed that participants with stage IIIB or IV

-positive disease treated with alectinib had a median progression-free survival (PFS) of 34.8 months versus 10.9 months for those receiving crizotinib (HR 0.47; 95% CI, 0.34- 0.65;

In another ALK inhibitor superiority trial, brigatinib demonstrated better efficacy than crizotinib in 275 patients with stage IIIB or IV

The confirmed overall response rate (ORR) in patients taking brigatinib was 71% versus 60% in patients taking crizotinib (

= .0678). Of note, brigatinib offered a higher confirmed ORR than crizotinib for patients with measurable intracranial lesions (78% vs 29%;

= .0028). The NCCN now recommends brigatinib as a category 1 option for

-positive disease discovered prior to first-line systemic therapy or as an alternative option if the mutation is discovered during first-line systemic therapy.

Lorlatinib is a third-generation oral TKI active against

-positive NSCLC. In a phase II trial, a subgroup of 215 patients with

-positive disease who had received 1 or more previous ALK kinase inhibitors had an ORR of 48%.

Of these patients, 44% were partial responders and 4% had a complete response. Estimated median response duration was 12.5 months, and 60% of patients with measurable intracranial lesions responded to therapy. Based on these findings, lorlatinib received an FDA approval, which prompted new NCCN recommendations. For patients with

-positive metastatic NSCLC, lorlatinib is now recommended after disease progression on crizotinib, ceritinib (Zykadia), brigatinib, or alectinib; it may also be used after subsequent therapy and progression on the 3 latter agents.

-positive disease for which lorlatinib is now recommended as subsequent therapy for patients with

-positive metastatic NSCLC who have progressed after treatment with crizotinib or ceritinib. This indication, however, has yet to receive FDA approval.

The updated guidelines include a new category for patients that test positive for

mutations and recommend a combination of dabrafenib (Tafinlar) plus trametinib (Mekinist), which inhibit some mutated forms of BRAF and MEK 1/2 kinases, respectively. This recommendation is supported by an FDA approval granted in May 2018 based on results of the phase III COMBI-AD trial.

Patients receiving the combination experienced relapses at a rate of 38% compared with 57% in the placebo arm (HR 0.47; 95% CI, 0.39-0.58;

Oral tyrosine kinase inhibitor (TKI) dacomitinib (Vizimpro) was added as a category 1 option for first-line therapy in patients with

-mutationpositive, metastatic NSCLC and is also an option for asymptomatic patients and those with brain or isolated lesions. Dacomitinib received first-line FDA approval on September 27, 2018, following the phase III ARCHER 1050 trial, in which the agent showed better efficacy data than gefitinib (Iressa).

Median PFS for patients with metastatic NSCLC with

exon 19 deletions or exon 21 L858R substitution mutations treated with dacomitinib was 14.7 months compared with 9.2 months for those treated with gefitinib (

Durvalumab (Imfinzi), a checkpoint inhibitor that prevents PD-L1 from binding with PD-1 and CD80, showed promise in new data from the phase III PACIFIC trial in 2017 and 2018. In total, 713 patients with NSCLC and no disease progression following chemoradiotherapy were randomized 2:1 to receive either durvalumab or placebo.

Recent results showed that durvalumab extended PFS by a considerable margin, with a median duration of 17.2 versus 5.6 months (

<.001). The 2-year OS rate was 66.3% with durvalumab compared with 55.6% in the placebo group (

= .005). Median time to distant metastasis or death was also improved (28.3 vs 16.2 months). Durvalumab received FDA approval on February 16, 2018, following release of initial PFS results in 2017.

Based on the results from PACIFIC, the NCCN changed the recommendation level for durvalumab from category 2A to category 1. Specifically, durvalumab is now recommended for consolidation therapy in patients with unresectable stage III NSCLC who have not had disease progression after 2 or more cycles of concurrent platinum-based chemotherapy.

On November 26, 2018, larotrectinib (Vitrakvi) received FDA approval for patients with solid tumors and

gene fusions without a known acquired resistance mutation or metastatic or unresectable disease and who have no satisfactory alternative therapy. Because larotrectinib is effective across ages and tumor types, it is considered an age- and tumor-agnostic therapy.

Three multicenter clinical trialsSCOUT, NAVIGATE, and LOXO-TRK-14001&mdash;evaluated larotrectinib for a variety of cancer types, prompting FDA approval and NCCN recommendation. Out of 55 patients in the trials with unresectable or metastatic tumors, ORR was 75%, divided between partial and complete responders at rates of 53% and 22%, respectively. A recent data update showed that 1-year OS was 90%, with 69% still responding and slightly more than half of the patients (58%) remaining progression free.

Based on the FDA approval and these results, the NCCN now recommends larotrectinib as first-line therapy for patients with

gene fusion positive metastatic NSCLC. In addition, the guidelines now include an entire page diagramming the treatment of patients with

sensitizing mutations and the T790M resistance mutation which occurs in about 60% of patients after first-line TKI therapy. Based on results from the phase III FLAURA trial, the NCCN now considers osimertinib the preferred first-line agent in

mutation positive NSCLC (category 1 recommendation).

The trial involving 556 patients with treatment-na&iuml;ve,

mutation-positive advanced NSCLC showed that osimertinib produced a median PFS of 18.9 months versus 10.2 months with standard gefitinib or erlotinib (HR, 0.46; 95% CI, 0.37-0.57;

<.001). ORR was comparable between osimertinib and standard EGFR TKIs, at 80% and 76%, respectively (odds ratio, 1.27; 95% CI, 0.85 to 1.90;

= .24). At 18 months, 83% of the patients in the osimertinib group were still alive compared with 71% of patients receiving standard therapy. Fewer patients receiving osimertinib had grade &ge;3 adverse events than those receiving standard EGFR TKIs (35% vs 45%), which further supports the superiority of osimertinib.

To go along with updates in immunotherapy and chemotherapy combinations in 2018, the NCCN changed PD-L1 testing from a category 2A recommendation to category 1 for both squamous and nonsquamous disease. Eligibility for checkpoint inhibitor therapy was clarified to include patients with PD-L1 expression &ge;50% rather than &ldquo;PD-L1 positivity,&rdquo; per the old guidelines. For patients within these criteria who do not harbor

abnormalities, 3 chemotherapy and immunotherapy agent combinations joined the checkpoint inhibitor pembrolizumab (Keytruda) on the list of recommended frontline therapies:

For patients with nonsquamous NSCLC, a combination of carboplatin or cisplatin plus pemetrexed and pembrolizumab received an FDA approval on August 20, 2018.

This approval was based on results from the phase III KEYNOTE-189 trial in which 616 treatment-na&iuml;ve patients with metastatic disease were randomized to chemotherapy plus pembrolizumab or placebo. Patients in the pembrolizumab arm had a significantly higher ORR (48% vs 19%;

= .0001), overall survival (OS; HR 0.49; 95% CI, 0.38-0.64;

<.00001), longer median PFS (8.8 vs 4.9 months), and longer median response duration (11.2 vs 7.8 months).

Also for patients with nonsquamous NSCLC, the combination of carboplatin, paclitaxel, bevacizumab (Avastin), and atezolizumab (Tecentriq) received FDA approval on December 6, 2018, following results of the phase III IMpower150 trial, in which 1202 patients with metastatic nonsquamous NSCLC were randomized to 3 study arms, all including a duo of carboplatin and paclitaxel.

The checkpoint inhibitor atezolizumab and VEGF inhibitor bevacizumab were added individually and then together to the chemotherapy duo, with the full 4-drug regimen ultimately demonstrating superiority. Results showed a median OS of 19.2 months for patients on the 4-drug regimen compared with those in the control group, who had an OS of 14.7 months when receiving carboplatin, paclitaxel, and bevacizumab (P = .016). Similar gains were seen in median PFS (8.5 vs 7.0 months;

= .0002) and ORR (55% vs 42%). Of note, 36% of trial participants developed antidrug antibodies to atezolizumab. Although survival was similar regardless of antidrug status, future atezolizumab studies will monitor for any impact on efficacy, safety, and pharmacokinetics.

On October 30, 2018, a combination of carboplatin or cisplatin and either paclitaxel or nab-paclitaxel (Abraxane) with pembrolizumab received FDA approval for patients with squamous NSCLC. This approval was supported by the KEYNOTE-407 trial, in which 559 patients were randomized to receive pembrolizumab or placebo with chemotherapy.

Like the 2 previously mentioned studies, adding the checkpoint inhibitor demonstrated significant advantages. Along with a better median OS (15.9 vs 11.3 months;

= .0017), patients receiving pembrolizumab had an improved median PFS (6.4 vs 4.8 months;

= .0008), and estimated median response duration (7.2 vs 4.9 months).

NCCN Clinical Practice Guidelines in Oncology. Non-Small Cell Lung Cancer, version 3.2019. National Comprehensive Cancer Network website. nccn.org/professionals/physician_gls/pdf/nscl.pdf. Published January 18, 2019. Accessed February 13, 2019.

Peter S, Camidge DR, Shaw AT, et al. Alectinib versus Crizotinib in Untreated ALK-Positive NonSmall Cell Lung Cancer. N Engl J Med. 2017;377(9):829&ndash;838. doi: 10.1056/NEJMoa1704795.

FDA approves lorlatinib for second- or third-line treatment of ALK-positive metastatic NSCLC. FDA website. www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm625027.htm. Published December 17, 2018. Accessed February 20, 2019.

Camidge R, Kim HR, Ahn M, et al. Brigatinib vs crizotinib in patients with ALK inhibitor-na&iuml;ve advanced ALK+ NSCLC: first report of a phase 3 trial (ALTA-1L). Presented at: International Association for the Study of Lung Cancer 19th World Conference on Lung Cancer; September 23-26, 2018; Toronto, Ontario, Canada. Abstract PL02.03. jto.org/article/S1556-0864(18)30969-9/abstract.

FDA approves dabrafenib plus tremetinib for adjuvant treatment of melanoma with BRAF V600E or V600K mutations. FDA website. www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm606165.htm. Updated May 1, 2018. Accessed February 20, 2019.

FDA approves dacomitinib for metastatic nonsmall cell lung cancer. FDA website. www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm621967.htm. Updated December 17, 2018. Accessed February 20, 2019.

Antonia SJ, Villegas A, Daniel D, et al. PACIFIC Investigators. Overall survival with durvalumab after chemoradiotherapy in stage III NSCLC.

2018;379(24):2342-2350. doi: 10.1056/NEJMoa1809697.

FDA approves durvalumab after chemoradition for unresectable stage III NSCLC. FDA website. www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm597248.htm. Updated February 20, 2018. Accessed February 20, 2019.

FDA approves larotrectinib for solid tumors with NTRK gene fusions. FDA website. www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm626720.htm. Updated December 17, 2018. Accessed February 20, 2019.

Lassen UN, Albert CM, Kummar S, et al. Larotrectinib efficacy and safety in TRK fusion cancer: an expanded clinical dataset showing consistency in an age and tumor agnostic approach. Presented at: ESMO 2018 Congress; October 19-23, 2018; Munich, Germany. Abstract 4090. doi.org/10.1093/annonc/mdy279.397.

Soria JC, Yuichiro O, Vansteenkiste J, et al; FLAURA investigators. Osimertinib in untreated EGFR-mutated advanced non-small-cell lung cancer.

2018;378(2):113-125. doi: 10.1056/NEJMoa1713137.

FDA grants regular approval for pembrolizumab in combination with chemotherapy for first-line treatment of metastatic nonsquamous NSCLC. FDA website. www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm617471.htm. Updated August 20, 2018. Accessed February 20, 2019.

Socinski MA, Jotte RM, Cappuzzo F, et al; IMpower150 Study Group. Atezolizumab for First-Line Treatment of Metastatic Nonsquamous NSCLC.

2018;378(24):2288-2301. doi: 10.1056/NEJMoa1716948.

FDA approves pembrolizumab in combination with chemothreapy for first-line treatment of metatstatic squamous NSCLC. FDA website. www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm624659.htm. Updated December 17, 2018. Accessed February 20, 2019.

Due to an active research landscape, the National Comprehensive Cancer Network Guidelines for non&ndash;small cell lung cancer have had 3 recent updates that include numerous clinically relevant recommendations.

Will Pass, DVM | Authors

Articles

FDA Issues Draft Guidance to Broaden Clinical Trial Inclusion

Treatment Advancements in NSCLC Change Therapy Recommendations in 2019 NCCN Guidelines