Immunotherapy agents have been rapidly absorbed into the treatment paradigm for various cancer types. Nowhere is this more obvious than in the treatment for patients with bladder cancer. In May alone, 3 checkpoint inhibitors were approved for use in bladder cancer, bringing the total of checkpoint inhibitors approved in this field to 5 agents.

Following such a surge in such a short time, it can be difficult to keep track of the new drugs, what sets them apart, and where we stand in treating patients with bladder cancer with immunotherapy.

HISTORY OF IMMUNOTHERAPY IN BLADDER CANCER

Prior to 2016, Bacillus Calmette-Guérin (BCG) was the only immunotherapy agent to show activity in patients with urothelial carcinoma, the most common type of bladder cancer. Originally created as a tuberculosis vaccine in the 1920s,1 BCG is a unique strain of mycobacterium bovis that activates the immune system and induces an in ammatory response. The drug was FDA-approved for use in bladder cancer in 1990, and it was the first signal that urothelial carcinoma is an immune-responsive tumor.

BCG remains a standard of care in patients with high-risk nonmuscle invasive bladder cancer.

Following BCG, studies investigated the use of interferons as a potential therapy for patients with bladder cancer, particularly those with nonmuscle invasive disease.

Yet, they were unable to provide a benefit in these patients.

&ldquo;Bladder cancer has, in fact, been one of the first diseases for which immunotherapy was active, and we need to go back [more than] 15 years ago [to] when BCG was shown to be effective,&rdquo; Joaquim Bellmunt, MD, PhD, said in a presentation on immunotherapy options in bladder cancer. &ldquo;Since then, nothing has happeneduntil quite recently when the checkpoint inhibitors came.&rdquo;

BEGINNING OF THE CHECKPOINTS IN BLADDER CANCER

Atezolizumab (Tecentriq) was the first checkpoint inhibitor to be approved for use in bladder cancer (F I G U R E ). The PD-L1 inhibitor was approved by the FDA on May 18, 2016, for the treatment of patients with locally advanced or metastatic urothelial carcinoma (mUC) whose disease has progressed during or after platinum-based chemotherapy or within 12 months of having received platinum-containing chemotherapy, either before or after surgery. The accelerated approval was based on data from the phase II IMvigor 210 study, which investigated atezolizumab in patients with locally advanced or mUC. It had previously received a breakthrough therapy designation for patients with PD-L1positive metastatic bladder cancer in March 2016.

In the IMvigor 210 study, atezolizumab demonstrated an overall response rate (ORR) of 14.8% (95% CI, 11.1%-19.3%) among 310 patients.

By PD-L1 expression, atezolizumab showed an ORR of 26% (95% CI, 17.7%-35.7%) in patients with expression &ge;5% on tumor-in ltrating immune cells and 9.5% (95% CI, 5.9%- 14.3%) in patients with expression below 5% (n = 210). The median duration of response (DOR) was not reached.

Ten patients discontinued treatment due to adverse events (AEs) and 3 patients died due to sepsis, pneumonitis, or intestinal obstruction. Grade 3/4 AEs included urinary tract infection (9%), anemia (8%), fatigue (6%), dyspnea (4%), and hematuria (3%).

Although the drug was approved regardless of PD-L1 expression, the PD-L1 assay Ventana PD-L1 (SP142) was approved at the same time as a complementary diagnostic.

On February 2, 2017, nivolumab (Opdivo) was granted an accelerated approval in the second line as well. The treatment was approved for use in patients with locally advanced unresectable or mUC following progression on a platinum-containing regimen based on ndings from the phase II CheckMate-275 trial; the PD-1 inhibitor had received a breakthrough therapy designation for this indication in June 2016. Nivolumab was also approved for patients who have disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy.

The ORR in the CheckMate-275 trial was 19.6% of 270 patients with platinum-refractory metastatic urothelial carcinoma with complete responses (CRs) in 3%.6 The median progression-free survival (PFS) was 2.0 months, and the median overall survival (OS) was 8.7 months. The median DOR was not reached in this trial either.

Among patients with PD-L1 expression on &ge;1% of cells, the median PFS was 3.55 months and the OS was 11.3 months compared with 1.87 months and 5.95 months in those with no PD-L1 expression, respectively.

The most common AEs during the trial were fatigue (16.7%), pruritus (9.3%), diarrhea (8.9%), decreased appetite (8.1%), hypothyroidism (7.8%), nausea (7.0%), asthenia (5.9%), rash (5.9%), and pyrexia (5.6%). Treatment-related AEs were experienced by 64.4% of patients; 17.8% were grade 3/4. Quality of life was also improved from baseline, according to Global Health Status Scale measurements.

The FDA recommended a at dose of 240-mg nivolumab intra- venously in urothelial carcinoma every 2 weeks.

Atezolizumab was granted an additional indication by the FDA on April 17, 2017, for the frontline treatment of cisplatin-ineligible patients with locally advanced or mUC based on a cohort of cisplatin-ineligible, treatment-naïve patients from the same IMvigor 210 trial. This was the rst checkpoint inhibitor to be granted an approval in the rst-line setting in bladder cancer.

The ORR was 23.5% (95% CI, 16.2%-32.2%) from the 119 eligible patients in the cohort, with a CR rate of 6.7%.7 The median PFS was 2.7 months (95% CI, 2.1-4.2), and the median OS was 15.9 months (95% CI, 10.4 to not estimable).

Patients with PD-L1 expression &ge;5% (n = 32) had an ORR of 28.1% (95% CI, 13.8%-46.8%), with a CR rate of 6.3%. In those with PD-L1 expression below 5%, the ORR was 21.8% (95% CI, 13.7%-32.0%) and the CR rate was 6.9%. Additionally, an association between tumor mutation load and response was noted.

In this cohort, 5 patients discontinued atezolizumab therapy and 5 patients died, due to sepsis, cardiac arrest, myocardial infarction, respiratory failure, and respiratory distress. An additional patient had in ammation of the brain due to the herpes simplex virus and disease progression. Similar common grade 3/4 AEs were experienced in this cohort, including fatigue (8%), urinary tract infection (5%), anemia (7%). Additional grade 3/4 AEs included diarrhea (5%), increase in the level of creatinine in the blood (5%), increase of the liver enzyme alanine transaminase (4%), hyponatre- mia (15%), decreased appetite (3%), and back/neck pain (3%).

Both approvals for atezolizumab were contingent upon results from the phase III con rmatory study, IMvigor 211.

On May 1, 2017, durvalumab (Imfinzi), another PD-L1 inhibitor, was granted an accelerated approval by the FDA in the second-line setting for the treatment of patients with locally advanced or mUC who have disease progression during or following platinum-containing chemotherapy or who have disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy. The approval is contingent upon results from a confirmatory trial.

A breakthrough therapy designation had been granted to the agent in February 2016 for patients with PD-L1positive inoperable or mUC following progression on prior treatment with a platinum-based regimen.

The FDA granted the approval based on the results of a single-arm trial of 182 patients with locally advanced or mUC who experienced disease progression following platinum-containing chemotherapy. The ORR among the patients was 17% (95% CI, 11.9%-23.3%) by blinded independent central review.

In patients with high PD-L1 expression (n = 95), as assessed by the Ventana PD-L1 (SP263) assaythe complementary diagnostic approved for use with durvalumab&mdash;the ORR was 26.3% (95% CI, 17.8%-36.4%) compared with 4.1% (95% CI, 0.9%-11.5%) among patients with low or no PD-L1 expression (n = 73). Thirty-one patients achieved a response, including 5 CRs and 26 partial responses (PRs).

Common all-grade AEs included fatigue, musculoskeletal pain, constipation, decreased appetite, nausea, peripheral edema, and urinary tract infection. Immune-related AEs included pneumonitis, hepatitis, colitis, thyroid disease, adrenal insuf ciency, and diabetes.

Next, the FDA granted an accelerated approval to avelumab (Bavencio) on May 9 for patients with locally advanced or mUC with disease progression during or following platinum-containing chemotherapy or within 12 months of neoadjuvant or adju- vant platinum-containing chemotherapy.

The approval was based on data from a cohort of 242 patients with locally advanced or mUC from the single-arm, open-label, phase Ib JAVELIN Solid Tumor trial. Patients who had been fol- lowed for at least 13 weeks (n = 226) had an ORR of 13.3% (95% CI, 9.1%-18.4%), and those who had been followed for at least 6 months (n = 161) had an ORR of 16.1% (95% CI, 10.8%-22.8%).9 The median time to response was 2.0 months (range, 1.3-11.0) and the median DOR was not reached in either group.

Among patients followed for 6 months or more, there were 9 CRs (5.6%) and 17 PRs (10.6%) versus 9 CRs (4%) and 21 PRs (9.3%) among those followed for at least 13 weeks. Response rates did not vary signi cantly according to PD-L1 expression levels.

All-grade AEs frequently reported included fatigue (41%), infusion-related reaction (30%), musculoskeletal pain (25%), nausea (24%), decreased appetite (21%), and urinary tract infection (21%). Serious AEs occurred in 41% of patients and included cases of urinary tract infection/urosepsis, abdominal pain, musculoskeletal pain, increased creatinine levels/renal failure, dehydration, hematuria/urinary tract hemorrhage, intestinal obstruction/small intestine obstruction, and pyrexia. Deaths due to AEs occurred in 14 patients (6%), and these were due to pneumonitis, respiratory failure, sepsis/urosepsis, cerebrovascular accident, or gastrointestinal issues.

The FDA noted that the recommended dose for avelumab is 10 mg/kg intravenously over 60 minutes every 2 weeks, and indicated that the accelerated approval is contingent upon results of a confirmatory trial.

Disrupting the long stream of good news in the field, Genentech, the manufacturer of atezolizumab, announced on May 9 that the drug had failed to meet its primary endpoint in the second-line setting in the con rmatory phase III IMvigor 211 trial, on which the rst approval of atezolizumab in bladder cancer was based.

The trial was unable to show an improvement in OS with atezolizumab therapy compared with chemotherapy for patients with previously treated locally advanced or mUC. Genentech noted that full results from the IMvigor 211 trial will be presented later this year after the data have been further examined.

Most recently, on May 18, pembrolizumab (Keytruda) received FDA approval for use in bladder cancer. The PD-1 inhibitor was approved for the treatment of patients with locally advanced or mUC who have disease progression during or following platinum-containing chemotherapy or within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy. A second accelerated approval was awarded to frontline pembrolizumab for patients with locally advanced or mUC who are ineligible for cisplatin-containing chemotherapy, although this approval is contingent upon results from a con rmatory trial.

Articles

Clinical Articles

The Rapid Uptake of Immunotherapy in Bladder Cancer

With the advent of newer generations of targeted therapies for treating patients with nonsmall cell lung cancer (NSCLC), debate has erupted within the medical community over whether patients should be treated with newer agents upfront, or whether these agents should be held for later use. During the 2017 European Lung Cancer Conference, 2 oncologists took up this debate and offered the rationale for both sides of the argument for/against the upfront use of newer tyrosine kinase inhibitors (TKIs) for patients with ALK-positive or EGFR-mutant NSCLC.

On the pro side, David Carbone, MD, PhD, first raised the issue of sequencing TKIs to achieve a greater overall survival (OS) than would be achieved with 1 agent alone. Fabrice Barlesi, MD, PhD, who spoke against using newer agents upfront, supported sequencing but advocated for using the first-generation agents first in the sequence.

Barlesi is head of multidisciplinary oncology and therapeutic innovations at Assistance Publique Hôpitaux De Marseille, coordinator of the Center of Early Phase Cancer Trials of Marseille, and professor of medicine at Aix-Marseille University in France. He pointed out that according to the results of retrospective analyses, responses and treatment durations are better when agents are used in succession rather than alone.

He acknowledged that the survival advantage with newer agents has exceeded that of the first-generation agents, such as when comparing alectinib (Alecensa) or ceritinib (Zykadia) with the first-generation agent crizotinib (Xalkori) in patients with an ALK rearrangement. In the J-ALEX study of patients without prior ALK inhibitor treatment, for example, the progression-free survival (PFS) was 25.9 months in the alectinib arm (95% CI, 20.3 months to not reached) and was 10.2 months (95% CI, 8.2-12.0) with crizotinib (HR, 0.34; 95% CI, 0.17-0.71; P <.0001).

&ldquo;If you look only at the short term, at the PFS, yes, it&rsquo;s true, you have an advantage to PFS in the ALK-rearranged patients for alectinib and you can see that the PFS is increased,&rdquo; Barlesi said.

However, sequential treatment of these ALK inhibitors, starting with crizotinib followed by alectinib, led to a median OS of 51.1 months and a median combined PFS of 18.2 months, according to a retrospective study.

According to the IFCT-1302 CLINALK trial, a French retrospective study, OS outcomes would be best when, following crizotinib, patients were treated in the second line with a next-generation ALK inhibitor rather than with an alternative treatment, usually chemotherapy, or best supportive care.

Carbone, the Barbara J. Bonner Chair in Lung Cancer Research, director of the James Thoracic Center, and professor of medicine at The Ohio State University Comprehensive Cancer Center, alternatively suggested that 2 median PFS values could not be added together to come up with an estimated &ldquo;time on TKI&rdquo; calculation. A patient who achieves the median PFS with 1 drug may not achieve the median PFS with a subsequent drug, or vice versa, he noted.

Carbone also noted that this rough calculation does not account for treatment beyond progression. Evidence from clinical trials have shown that there is an added clinical benefit to continuing to treat beyond progression by RECIST criteria. In the ASPIRATION trial, patients with EGFR-mutant NSCLC were treated with first-line erlotinib beyond which are common in NSCLC, the change of treatment can also be delayed to stay on the first-line targeted agent longer, thereby increasing the patient&rsquo;s OS.

In addition, Carbone said that saving the next-generation TKIs for later makes no sense, and it is better to treat patients with the best treatments first. &ldquo;History has taught us that in oncology, using the best treatment first results in the best survival,&rdquo; he stated.

With newer agents that demonstrate prolonged PFS rates, clinicians can pre-empt the development of known resistance mutations, such as T790M in EGFR-mutant disease, and provide a rapid and more reliable relief of symptoms, according to Carbone.

However, Barlesi contended that the use of newer agents instead cuts off additional treatment options down the line. If, for example, a patient were to be treated frontline with the second-generation ALK inhibitor alectinib, the patient would be more likely to develop a G1202R resistance mutation, and none of the ALK inhibitors are sensitive to this resistance mutation by the half maximal inhibitor concentration, mean IC. Even the next-generation agent lorlatinib, which shows the highest sensitivity to this mechanism of resistance of the ALK inhibitors, has a sensitivity very close to the 50 nmol/L IC50 cutoff, at 49.9 nmol/L.

Without any additional ALK inhibitors available to use in this situation in the second line, the next treatment approach would be chemotherapy.

In EGFR-positive NSCLC, the T790M resistance mutation can be treated with the third-generation EGFR TKI osimertinib (Tagrisso), but what can be done when the patient develops a resistance mutation from treatment with osimertinib? Targeted agents are not currently available to treat these new resistance mechanisms, including MET amplification, HER2 amplification, and more.

Barlesi suggested that tumors with actionable targets are heterogeneous, and that each patient and mechanism of resistance is different and should be treated individually.

He also said that the safety profile of the newer agents can be slightly better than that of the first-generation TKIs, but not significantly so. Pointing to the rates of grade 3/4 dyspnea among the different ALK inhibitors, Barlesi cited 4% with crizotinib, 5.7% with ceritinib, 3% with alectinib, and 7% with brigatinib (Alunbrig).

For both EGFR and ALK TKIs, the central nervous system is a frequent site of disease progression, but the newer drugs have substantial activity in the brain, Carbone said. In the J-ALEX trial, patients with brain metastases at baseline who were treated with alectinib had a significant improvement compared with those treated with crizotinib; the median PFS was not reached in the alectinib arm, while it was 10.2 months in the crizotinib arm.

In patients without brain metastases at baseline, the median PFS was 20.3 versus 10.0 months, respectively.

However, Carbone and Barlesi pointed out that these patients&rsquo; brain metastases will usually be pretreated, and in this case, the difference in central nervous system activity is not as significant. The objective response rate of patients with pretreated brain metastases with crizotinib was 33% versus 36% with ceritinib and 28% with brigatinib.

&ldquo;When we look at the safety, there is maybe a slight advantage, if any, but absolutely not for all the newer targeted agents, and the safety profile should not drive our decision with the data we have to date,&rdquo; Barlesi stated.

Carbone suggested that the best way to end this debate would be to conduct a clinical trial, rather than adding PFS values together. He pointed to the ongoing randomized, 3-arm APPLE trial that is investigating patients with an EGFR T790M mutation treated with either osimertinib in the first line, gefitinib (Iressa) followed by osimertinib upon RECIST progression, or gefitinib followed by osimertinib upon molecular progression. He said that this will answer questions around whether first-generation or newer agents are better in the frontline, and whether RECIST progression or molecular progression is the right indication for switching treatment.

&ldquo;I think that a long first PFS really matters, that toxicity matters, that brain penetration matters. And we need to do the right studies with planned crossovers with time on TKI and OS endpoints, as well as paying attention to quality of life,&rdquo; Carbone concluded.

Takiguchi Y, Hida T, Nokihara H, et al. Updated e cacy and safety of the j-alex study comparing alectinib (ALC) with crizo- tinib (CRZ) in ALK-inhibitor naïve ALK fusion positive non-small cell lung cancer (ALK+ NSCLC).. J Clin Oncol. 2017;35(suppl; abstr 9064).

Watanabe S, Hayashi H, Okamoto K, et al. Progression-free and overall survival of patients with ALK rearrangement-positive non-small cell lung cancer treated sequentially with crizotinib and alectinib. Clin Lung Cancer. 2016;17(6):528-534. doi: 10.1016/j. cllc.2016.05.001.

Duruisseaux M, Besse B, Cadranel J, et al. Overall survival with crizotinib and next-generation ALK inhibitors in ALK-positive non-small-cell lung cancer (IFCT-1302 CLINALK): a French nationwide co- hort retrospective study. Oncotarget. 2017;8(13):21903-21917. doi: 10.18632/oncotarget.15746.

Park K, Ahn M, Yu C, et al. ASPIRATION: rst-line erlotinib (E) until and beyond RECIST progression (PD) in Asian patients (pts) with EGFR mutation-positive (mut+) NSCLC. Presented at: 2014 ESMO Annual Congress; September 27-29, 2014; Madrid, Spain. Abstract 1223O.

Gainor JF, Dardaei L, Yoda S, et al. Molecular mechanisms of resistance to rst- and second-gen- eration ALK inhibitors in ALK-rearranged lung cancer. Cancer Discov. 2016;6(10):1118-1133. doi: 10.1158/2159-8290.CD-16-0596.

Facchinetti F, Tiseo M, Di Maio M, et al. Tackling ALK in non-small cell lung cancer: the role of novel inhibitors. Transl Lung Cancer Res. 2016;5(3):301-321. doi: 10.21037/tlcr.2016.06.10.

Kim Y, Hida T, Nokihara H, et al. MA07.03 Alectinib (ALC) versus crizotinib (CRZ) in ALK-positive non-small cell lung cancer (ALK+ NSCLC): primary results from phase III study (J-ALEX). J Thorac Oncol. 2017;12(1 Suppl):S378-S379. doi: 10.1016/j.jtho.2016.11.427.

Two oncologists&nbsp;offer rationale for both sides of the argument for/against the upfront use of newer tyrosine kinase inhibitors for patients with ALK-positive or EGFR-mutant NSCLC.

The Debate Over Upfront Use of Newer Targeted Agents in NSCLC

Options for treating patients with hepatocellular carcinoma (HCC) may currently be limited, with most physicians turning to a tyrosine kinase inhibitor (TKI) for advanced disease, but physicians may soon be able to choose between a TKI and immunotherapy. In the future, oncologists will need to make an informed choice between these 2 modalities as more information on immunotherapy treatment in HCC comes to light, according to Aiwu Ruth He, MD, PhD.

Dr He, associate professor of medicine at Georgetown University School of Medicine, explored this issue during the 2nd Annual School of Gastrointestinal Oncology hosted by Physicians&rsquo; Education Resource (PER) on April 29 in New York City. She used results from the randomized, international, phase III RESORCE trial to illustrate the state of TKIs in HCC.

RESORCE evaluated the efficacy and safety of regorafenib (Stivarga) versus placebo in patients with HCC who progressed while taking sorafenib (Nexavar). Patients (n = 573) were treated at 152 medical centers in 21 countries around the world. In the study, 379 patients were assigned to 160 mg of daily regorafenib on a 3-weeks-on/1-week-off cycle. Another 194 patients were assigned to placebo. Overall survival (OS) was the primary endpoint.

Median OS was 10.6 months for regorafenib compared with 7.8 months for placebo (HR, 0.63; 95% CI, 0.50-0.79; P <.0001).

&ldquo;There is an improvement of 3 months in median OS with a 37% reduction in the risk for death,&rdquo; Dr He said. &ldquo;In almost [all] groups of patients, they benefit from regorafenib treatment.&rdquo;

She added that patients in the treatment group had significantly improved progression-free survival (PFS; 3.1 vs 1.5 months) and time to progression rates. Regorafenib patients also had a significantly higher response rate (65.2% vs 36.1%) and a disease control rate nearly double that of placebo.

Patients spent a median of 3.6 months on regorafenib treatment compared with 1.9 months for placebo. Half of patients treated with regorafenib reported grade 3/4 treatment-related adverse events (AEs) compared with 16.5% of placebo patients. However, only 10% of regorafenib patients discontinued treatment, compared with 4% in the placebo group, an outcome Dr He declared &ldquo;pretty good.&rdquo;

&ldquo;AEs were manageable and consistent with the known regorafenib safety profile,&rdquo; she said.

Dr He then moved into a review of developments in immunotherapy, which she called &ldquo;the next very exciting treatment for patients with liver cancer,&rdquo; in a review of the available results of the ongoing Checkmate-040 trial,

a phase I/II study of nivolumab (Opdivo) in advanced HCC. The study is planning to add cohorts to further evaluate nivolumab, including in a combi- nation arm with ipilimumab (Yervoy).

Based on available data from the study, the FDA recently granted a priority review designation to nivolumab for patients with HCC following prior sorafenib. The FDA is scheduled to make its final decision on or before September 24.

The phase I/II CheckMate-040 trial accrued 262 patients with advanced HCC with or without hepatitis C virus (HCV) or hepatitis B virus (HBV) infection, including 48 patients in the dose-escalation phase and 214 in the dose-expansion phase. Seventy-seven percent of patients in the dose-escalation phase and 68% of patients in the expansion phase had received prior sorafenib.

The median age of patients in the escalation phase was 62 years (range, 55-69), 75% of patients were male, 58% were white, and 40% had an ECOG performance status (PS) of 1. Seventy-five percent had surgical resection and 21% had received radiotherapy.

In the expansion phase, the median age was 64 years (range, 56-70), 80% of patients were male, 49% were white, 47% were Asian, and 36% had an ECOG PS of 1. Sixty percent of patients had surgical resection and 19% had received radiotherapy.

In the escalation phase, patients received 0.1 to 10 mg/kg of intravenous nivolumab every 2 weeks. Patients in the expansion phase received nivolumab at 3 mg/kg every 2 weeks.

The overall objective response rate (ORR) in the escalation phase was 15% (95% CI, 6%-28%), including 3 complete responses (CRs) and 4 partial responses (PRs). Five of the 7 responses occurred within 3 months of initiating nivolumab. The median duration of response was 17 months (95% CI, 6-24) and the median time to progression was 3.4 months (95% CI, 1.6-6.9). The disease control rate was 58% (95% CI, 43%-72%).

The 6- and 9-month OS rates were each 66% (95% CI, 51%-78%). In the dose-escalation phase, the median OS was 15.0 months (95% CI, 9.6-20.2).

The ORR in the expansion group was 20% (42 of 214 patients; 95% CI, 15%-26%), including 3 CRs and 39 PRs. Combining these responses with 96 patients (45%) who had stable disease, the disease control rate was 64% (138 of 214). The 3 CRs occurred in 2 patients without viral hepatitis and in 1 patient with HBV infection. All 3 of those patients had prior sorafenib.

Twenty-nine (69%) of the 42 responses occurred before 3 months. The median duration of response was 9.9 months and the median time to progression was 4.1 months (95% CI, 3.7-5.5).

The 6- and 9-month OS rates in the expansion cohort were 83% (95% CI, 78%-88%) and 74% (95% CI, 67%-79%), respectively. The 6- and 9-month PFS rates were 37% (95% CI, 30%-43%) and 28% (95% CI, 22%-35%), respectively.

The researchers reported that nivolumab was tolerable with a manageable safety profile during the dose-escalation phase. A maximum-tolerated dose was not reached. Twenty-five percent (12 of 48) of patients had grade 3/4 treatment-related AEs. There were 3 treatment-related serious AEs: pemphigoid, adrenal insuficiency, and liver disorder.

Safety in the expansion cohort was similar to that of the escalation cohort. Grade 3/4 and serious treatment-related AEs occurred in 19% and 4% of patients, respectively. The incidence of symptomatic treatment-related AEs was comparable, regard- less of whether patients had HCV or HBV. Twenty-four patients discontinued treatment due to AEs, and there were no deaths related to treatment.

Given the continued reporting of positive data with both treatment modalities, determining the optimal sequence of immuno- therapy and targeted agents in HCC is a critical challenge.

&ldquo;The sequence of treating patients with TKIs or immunotherapy needs to be tested in randomized clinical trials,&rdquo; Dr He said in summary.

Bruix J, Qin S, Merle P, et al; RESORCE Investigators. Regorafenib for patients with hepatocellular car- cinoma who progressed on sorafenib treatment (RESORCE): a randomised, double-blind, placebo-con- trolled, phase 3 trial. Lancet. 2017;389(10064):56-66. doi: 10.1016/S0140-6736(16)32453-9.

El-Khoueiry AB, Sangro B, Yau T, et al. Nivolumab in patients with advanced hepatocellular carci- noma (CheckMate 040): an open-label, non-comparative, phase 1/2 dose escalation and expansion trial [published online April 20, 2017]. Lancet. 2017. doi: 10.1016/S0140-6736(17)31046-2.

Options for treating patients with hepatocellular carcinoma may currently be limited, with most physicians turning to a tyrosine kinase inhibitor for advanced disease, but physicians may soon be able to choose between a TKI and immunotherapy.

The Choice Between Immunotherapy and TKIs for Liver Cancer

While HER2-targeted therapy has transformed the treatment of patients with breast cancer with HER2-positive tumors, this success is dampened by acquired and de novo resistance to these therapies. Current strategies for overcoming resistance to HER2-targeted agents in early breast cancer were outlined by C. Kent Osborne, MD, during the 2017 St. Gallen International Breast Cancer Conference.

Osborne, director of the Dan L. Duncan Cancer Center at the Baylor College of Medicine, cited the likely determinants of the initial response to endocrine therapy as HER2 oncogene addiction, deregulation of the PI3K pathway, and the tumor microenvironment, including lymphocyte infiltration.

&ldquo;Acquired resistance is much more complex and is driven by clonal selection or adaptive mechanisms,&rdquo; he commented.

According to Osborne, &ldquo;escape routes&rdquo; involving increased expression or signaling in growth factor receptor pathways are major factors of resistance. He emphasized the importance of eliminating these escape routes, especially the EGFR/HER2 pathway, by using combined therapies that simultaneously target both the estrogen receptor (ER) and growth factor receptor signaling.

&ldquo;Oncogene addiction implies that a single genomic abnormality in a tumor drives tumor growth and, consequently, that complete inhibition of this pathway therapeutically should then provide an effective treatment for the patient,&rdquo; he said, using HER2 amplification/overexpression as an example. Osborne pointed out that a 3-year disease-free survival (DFS) rate of 98.7% (P <.0001) was achieved in women with HER2-positive, node-negative cancer and tumors less than 3 cm in the APT trial of trastuzumab (Herceptin) and paclitaxel.

&ldquo;Therapies targeting HER2, such as trastuzumab, are very effective; however, complete blockade of the HER receptor layer by dual blockade is an improvement, especially in the absence of chemotherapy,&rdquo; Osborne explained. &ldquo;The HER2 receptor is a member of a family of 4 receptors, all of which can activate the same downstream pathways, so incomplete blockade of the receptor family by a drug like trastuzumab, which binds to and blocks HER2, might be a mechanism for resistance to that thera- py by leaving other receptors in the family active to compensate.&rdquo;

Osborne referenced neoadjuvant trials of anti-HER2 agents in combination with trastuzumab and compared the pathological complete response (pCR) rates of the combination compared with trastuzumab alone. The NeoSphere2 trial of pertuzumab (Perjeta) demonstrated a pCR rate of 29% with trastuzumab alone that was increased to 46% with dual pertuzumab/trastuzumab inhibition of HER2. In the NeoALTTO3 and NSABP B414 trials, the pCR rates with trastuzumab were 30% and 52% versus 51% and 62% with combined trastuzumab plus lapatinib (Tykerb), respectively. The TRYPHAENA5 trial did not have a sole trastuzumab comparator, but a pCR of 55% to 64% was achieved with trastuzumab/pertuzumab combination therapy.

Osborne noted that the relatively high pCR rates seen in neoadjuvant trials with drug combinations indicate that there is a subset of patients who may be treated with targeted therapy alone. He cited neoadjuvant clinical trials in patients not receiving chemotherapy, including the TBCRC 0066 and PAMELA7 trials of lapatinib and trastuzumab, that demonstrated pCR in 20% to 35% of patients.

&ldquo;Many of these patients had large primary tumors. These data suggest that a significant fraction of patients with HER2-amplified tumors, if they can be identified before treatment, might not need chemotherapy at all, only therapy targeting this potent oncogene,&rdquo; Osborne commented.

He cited patient selection as crucial to this strategy, and observed that, to date, there is no prognostic marker, although the CALGB 40601 and PAMELA trials both showed more patients with a HER2-enriched subtype achieved pCR. PI3K activation is implicated in resistance to HER2 therapy, and the TRYPHAENA8 and NeoALTTO9 trials showed greater pCR rates in patients with wild-type versus mutant PIK3CA.

However, the TBCRC 006 trial6 of lapatinib plus trastuzumab with and without letrozole failed to show an association by flu- orescence in situ hybridization criteria between pCR rate and PIK3CA mutation status, PTEN level, and ER expression.

Osborne outlined a validation study of these and other markers in which his group plans to evaluate samples from the TBCRC 006 and 023 studies and the SOLTI Group by RNA sequence, copy number, targeted DNA mutations, and intrinsic subtypes, including HER2 and PTEN by immunohistochemistry.

&ldquo;If validated, these markers could be used to select patients for a definitive de-escalation trial of HER2-targeted therapy alone in the future. Resistant patients would be candidates for trials of downstream inhibitors or other strategies to overcome resis- tance,&rdquo; Osborne commented.

Tolaney SM, Barry WT, Dang CT, et al. Adjuvant paclitaxel and trastuzumab for node-negative, HER2-positive breast cancer. N Engl J Med. 2015;372(2):134-141. doi: 10.1056/NEJMoa1406281.

Gianni L, Pienkowski T, Im YH, et al. 5-year analysis of neoadjuvant pertuzumab and trastuzumab in patients with locally advanced, in ammatory, or early-stage HER2-positive breast cancer (Neo- Sphere): a multicentre, open-label, phase 2 randomised trial. Lancet Oncol. 2016;17(6):791-800. doi: 10.1016/S1470-2045(16)00163-7.

de Azambuja E, Holmes AP, Piccart-Gebhart M, et al. Lapatinib with trastuzumab for HER2-positive early breast cancer (NeoALTTO): survival outcomes of a randomised, open-label, multicentre, phase 3 trial and their association with pathological complete response. Lancet Oncol. 2014;15(10):1137- 1146. doi: 10.1016/S1470-2045(14)70320-1.

Robidoux A, Tang G, Rastogi P, et al. Lapatinib as a component of neoadjuvant therapy for HER2-positive operable breast cancer (NSABP protocol B-41): an open-label, randomised phase 3 trial. Lancet Oncol. 2013;14(12):1183-1192. doi: 10.1016/S1470-2045(13)70411-X.

Schneeweiss A, Chia S, Hickish T, et al. Pertuzumab plus trastuzumab in combination with stan- dard neoadjuvant anthracycline-containing and anthracycline-free chemotherapy regimens in pa- tients with HER2-positive early breast cancer: a randomized phase II cardiac safety study (TRYPHAE- NA). Ann Oncol. 2013;24(9):2278-2284. doi: 10.1093/annonc/mdt182.

Rimawi MF, Mayer IA, Forero A, et al. Multicenter phase II study of neoadjuvant lapatinib and tras- tuzumab with hormonal therapy and without chemotherapy in patients with human epidermal growth factor receptor 2-overexpressing breast cancer: TBCRC 006. J Clin Oncol. 2013;31(14):1726-1731. doi: 10.1200/JCO.2012.44.8027.

Prat AA, Cortes Castan J, Pare L, et al. PAM50 intrinsic subtype as a predictor of pathological complete response following neoadjuvant dual HER2 blockade without chemotherapy in HER2-pos- itive breast cancer: rst results of the PAMELA clinical trial. Presented at: 2016 San Antonio Breast Cancer Symposium; December 8, 2016; San Antonio, TX. Abstract S3-03. https://www.sabcs.org/ Portals/SABCS2016/Documents/SABCS-2016-Abstracts.pdf?v=1.

Schneeweiss A, Chia S, Hegg R, et al. Evaluating the predictive value of biomarkers for e cacy outcomes in response to pertuzumab- and trastuzumab-based therapy: an exploratory analysis of the TRYPHAENA study. Breast Cancer Res. 2014;16(4):R73. doi: 10.1186/bcr3690.

Majewski IJ, Nuciforo P, Mittempergher L, et al. PIK3CA mutations are associated with decreased bene t to neoadjuvant human epidermal growth factor receptor 2-targeted therapies in breast can- cer. J Clin Oncol. 2015;33(12):1334-1339. doi: 10.1200/JCO.2014.55.2158.

C. Kent Osborne, MD, outlines&nbsp;current strategies for overcoming resistance to HER2-targeted agents in early breast cancer.

June 2017

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