Kidney Cancer Journal – 2017 – Number 4

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Kidney Cancer Journal – 2017 – Number 4

EDITOR’S MEMO

‘Future Shock’? Is That Where We Are in Frontline Treatment for RCC?

When futurist author Alvin Toffler wrote a book in 1970 called Future Shock, the title worked its way into the national lexicon as a way to describe how society was reacting to overwhelming technological change. He described it as a personal perception of “too much change in too short a period of time” or simply, information overload where we are struggling, perhaps even stressed, to keep up with the accelerated pace of new information.

Is it a bridge too far to suggest that in some respects our knowledge base in renal cell carcinoma (RCC) has left more than a few observers in “future shock,” trying to keep up with the velocity of changes that in 2018 could usher in significant changes in the strategies for frontline therapy in RCC? Perhaps “future shock” is an exaggeration, but it is certainly accurate to envision a time a few months from now, perhaps when we are all preparing for the next ASCO meeting in June, when we look forward to a calculus to help us clarify the multitude of changes proposed for frontline and second line therapy for RCC.

Recent meetings of the European Society of Medical Oncology (ESMO) and other scientific sessions such as the Society for Immunotherapy of Cancer (SITC) suggest a key turning point in frontline strategies for renal cell carcinoma (RCC). We are on the cusp of a shift in the paradigm for frontline choices. Now that cabozantinib has been approved (see page 103), and assuming that the ipilimumab-nivolumab combination will be approved in the foreseeable future, there are a wide range of questions that need to be addressed as we grapple with choices in an attempt to apply evidence-based approaches to a shifting paradigm of treatment. The ESMO meeting of 2017 helped to move the needle on several fronts, notably with regard to data on cabozantinib. With previous data compiled by an open-label design, we needed additional evidence to support the findings from the CABOSUN trial. ESMO delivered what was expected in the form of results from an independent review board. Results from the IRC indicated that the response rate for frontline cabozantinib in intermediate and poor-risk patients declined, but that is fairly typical of what might be expected.

We know from experience in other trials that when investigators proceed to an IRC analysis, this phase is likely to reveal a tendency in the earlier stages of the trial to be somewhat sanguine about outcomes. For example, among RCC patients who have shown, let’s say, a 25% reduction in tumor size, investigators may characterize this finding as a “partial response.” However, such responses scrutinized in the IRC analysis may be recategorized because the review suggests otherwise. This is particularly true when evaluations of whether end points have been reached are considered in a relatively subjective context.

The advantage of having an independent review board review all the radiological data was important. With regard to this IRC data, the reviewers are not aware of which patients are assigned to a drug. And they are not aware of what the investigators had said about these patients. The board simply measures the tumors and whether there was progression or reduction. The bottom line is that a major question mark regarding the validity of results previously presented through the CABOSUN trial has essentially been lifted. The robust data translate to an improvement in outcomes for patients in first line therapy who are intermediate to poor risk compared to treatment with sunitinib.

Results presented at ESMO with respect to CABOSUN were important for other reasons as well, particularly as we look for evidence on progression-free survival (PFS) and overall survival OS) to guide clinical decision making. CABOSUN did not produce definitive data on OS because the trial was not large enough for that measure. Nevertheless, CABOSUN did show an overall survival benefit trend. But with all the combinations emerging and undergoing study (such as a new trial investigating ipinivo combined with cabozantinib) we need to question the wisdom of spending years on assessing this end point with monotherapy, whether it achieves improved OS. Practically speaking, it may be superfluous and not a good investment for a pharmaceutical company’s research program to undertake this study. Why? Because it is likely that a combination of agents, including the drug for which OS has not been unequivocally determined, will produce data showing superior OS.

As we evaluate the expanded spectrum of therapy and the overarching excitement for immune-oncologic approaches, the subtext of the debate is also a cautionary tale. As impressive as the OS findings are with IO therapy, not all patients are candidates for IO. The cautionary tale reflects the fact that in many patients IO therapy may not be the appropriate first choice— particularly in those with bone metastases, autoimmune disease and the elderly whose ability to undergo infusions may be limited.

With this issue, we conclude our 15th year of publishing the Kidney Cancer Journal. Who would have known that when this publication was launched in 2003 that we would be talking about “future shock” and an overwhelming volume of information in frontline therapy? At that time there was only one drug approved for RCC Perhaps the new year will bring much in the way of a new paradigm, as much perhaps as what the situation was more than 10 years ago when the current standard of anti-VEGF therapy was about to be approved. On behalf of the journal, its Medical Advisory Board and Editorial Advisory Board, we wish you the best for the new year.

Robert A. Figlin,
MDEditor-in-Chief

2017-1

INLYTA® (axitinib) is indicated for the treatment of advanced renal cell carcinoma (RCC) after failure of one prior systemic therapy.

Important Safety Information

Hypertension including hypertensive crisis has been observed. Blood pressure should be well controlled prior to initiating INLYTA. Monitor for hypertension and treat as needed. For persistent hypertension, despite use of antihypertensive medications, reduce the dose. Discontinue INLYTA if hypertension is severe and persistent despite use of antihypertensive therapy and dose reduction of INLYTA, and discontinuation should beconsidered if there is evidence of hypertensive crisis.

Arterial and venous thrombotic events have been observed and can be fatal. Use with caution in patients who are at increased risk or who have a history of these events.

Hemorrhagic events, including fatal events, have been reported. INLYTA has not been studied in patients with evidence of untreated brain metastasis or recent active gastrointestinal bleeding and should not be used in those patients. If any bleeding requires medical intervention, temporarily interrupt the INLYTA dose.

Cardiac failure has been observed and can be fatal. Monitor for signs or symptoms of cardiac failure throughout treatment with INLYTA. Management of cardiac failure may require permanent discontinuation
of INLYTA.

Gastrointestinal perforation and fistula, including death, have occurred. Use with caution in patients at risk for gastrointestinal perforation or  stula. Monitor for symptoms of gastrointestinal perforation or  stula periodically throughout treatment. Hypothyroidism requiring thyroid hormone replacement has been reported. Monitor thyroid function before initiation of, and periodically throughout, treatment. No formal studies of the effect of INLYTA on wound healing have been conducted. Stop INLYTA at least 24 hours prior to scheduled surgery.

Reversible Posterior Leukoencephalopathy Syndrome (RPLS) has been observed. If signs or symptoms occur, permanently discontinue treatment.

PP-INL-USA-0390

© 2016 Pfizer Inc.

2017-2

Monitor for proteinuria before initiation of, and periodically throughout, treatment. For moderate to severe proteinuria, reduce the dose or temporarily interrupt treatment.

Liver enzyme elevation has been observed during treatment with INLYTA. Monitor ALT, AST, and bilirubin before initiation of, and periodically throughout, treatment.

For patients with moderate hepatic impairment, the starting dose should be decreased. INLYTA has not been studied in patients with severe hepatic impairment.

Women of childbearing potential should be advised of potential hazard to the fetus and to avoid becoming pregnant while receiving INLYTA.

Avoid strong CYP3A4/5 inhibitors. If unavoidable, reduce the dose. Grapefruit or grapefruit juice may also increase INLYTA plasma concentrations and should be avoided.

Avoid strong CYP3A4/5 inducers and, if possible, avoid moderate
CYP3A4/5 inducers.

The most common (≥20%) adverse events (AEs) occurring in patients receiving INLYTA (all grades, vs sorafenib) were diarrhea (55% vs 53%), hypertension (40% vs 29%), fatigue (39% vs 32%), decreased appetite (34% vs 29%), nausea (32% vs 22%), dysphonia (31% vs 14%), handfoot syndrome (27% vs 51%), weight decreased (25% vs 21%), vomiting (24% vs 17%), asthenia (21% vs 14%), and constipation (20% vs 20%).

The most common (≥10%) grade 3/4 AEs occurring in patients receiving INLYTA (vs sorafenib) were hypertension (16% vs 11%), diarrhea (11% vs 7%), and fatigue (11% vs 5%).

The most common (≥20%) lab abnormalities occurring in patients receiving INLYTA (all grades, vs sorafenib) included increased creatinine (55% vs 41%), decreased bicarbonate (44% vs 43%), hypocalcemia (39% vs 59%), decreased hemoglobin (35% vs 52%), decreased lymphocytes (absolute) (33% vs 36%), increased ALP (30% vs 34%), hyperglycemia (28% vs 23%), increased lipase (27% vs 46%), increased amylase (25% vs 33%), increased ALT (22% vs 22%), and increased AST (20% vs 25%).

All rights reserved.

November 2016

References

1. Rini BI, Escudier B, Tomczak P, et al. Comparative effectiveness of axitinib versus sorafenib in advanced renal cell carcinoma (AXIS): a randomised phase 3 trial. Lancet. 2011;378(9807):1931-1939.
2. Rini BI, Escudier B, Hariharan S, et al. Long-term safety with axitinib in previously treated patients with metastatic renal cell carcinoma. Clin Genitourin Cancer. 2015;13(6):540-547. mRCC=metastatic renal cell carcinoma; TKI=tyrosine kinase inhibitor.

INLYTA® (AXITINIB) TABLETS FOR ORAL ADMINISTRATION Initial U.S. Approval: 2012

Brief Summary of Prescribing Information

INDICATIONS AND USAGE: INLYTA is indicated for the treatment of advanced renal cell carcinoma (RCC) after failure of one prior systemic therapy.

DOSAGE AND ADMINISTRATION

Recommended Dosing. The recommended starting oral dose of INLYTA is 5 mg twice daily. Administer INLYTA doses approximately 12 hours apart with or without food. INLYTA should be swallowed whole with a glass of water. If the patient vomits or misses a dose, an additional dose should not be taken. The next prescribed dose should be taken at the usual time.

Dose Modification Guidelines. Dose increase or reduction is recommended based on individual safety and tolerability. Over the course of treatment, patients who tolerate INLYTA for at least two consecutive weeks with no adverse reactions >Grade 2 (according to the Common Toxicity Criteria for Adverse Events [CTCAE]), are normotensive, and are not receiving anti-hypertension medication, may have their dose increased. When a dose increase from 5 mg twice daily is recommended, the INLYTA dose may be increased to 7 mg twice daily, and further to 10 mg twice daily using the same criteria. Over the course of treatment, management of some adverse drug reactions may require temporary interruption or permanent discontinuation and/or dose reduction of INLYTA therapy [see Warnings and Precautions]. If dose reduction from 5 mg twice daily is required, the recommended dose is 3 mg twice daily. If additional dose reduction is required, the recommended dose is 2 mg twice daily. Strong CYP3A4/5 Inhibitors: The concomitant use of strong CYP3A4/5 inhibitors should be avoided (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, and voriconazole). Selection of an alternate concomitant medication with no or minimal CYP3A4/5 inhibition potential is recommended. Although INLYTA dose adjustment has not been studied in patients receiving strong CYP3A4/5 inhibitors, if a strong CYP3A4/5 inhibitor must be co-administered, a dose decrease of INLYTA by approximately half is recommended, as this dose reduction is predicted to adjust the axitinib area under the plasma concentration vs time curve (AUC) to the range observed without inhibitors. The subsequent doses can be increased or decreased based on individual safety and tolerability. If co-administration of the strong inhibitor is discontinued, the INLYTA dose should be returned (after 3–5 half-lives of the inhibitor) to that used prior to initiation of the strong CYP3A4/5 inhibitor. Hepatic Impairment: No starting dose adjustment is required when administering INLYTA to patients with mild hepatic impairment (Child-Pugh class A). Based on the pharmacokinetic data, the INLYTA starting dose should be reduced by approximately half in patients with baseline moderate hepatic impairment (Child-Pugh class B). The subsequent doses can be increased or decreased based on individual safety and tolerability. INLYTA has not been studied in patients with severe hepatic impairment (Child-Pugh class C).

DOSAGE FORMS AND STRENGTHS

1 mg tablets of INLYTA: red, film-coated, oval tablets, debossed with “Pfizer” on one side and “1 XNB” on the other side.

5 mg tablets of INLYTA: red, film-coated, triangular tablets, debossed with “Pfizer” on one side and “5 XNB” on the other side.

CONTRAINDICATIONS: None

WARNINGS AND PRECAUTIONS

Hypertension and Hypertensive Crisis. In a controlled clinical study with INLYTA for the treatment of patients with RCC, hypertension was reported in 145/359 patients (40%) receiving INLYTA and 103/355 patients (29%) receiving sorafenib. Grade 3/4 hypertension was observed in 56/359 patients (16%) receiving INLYTA and 39/355 patients (11%) receiving sorafenib. Hypertensive crisis was reported in 2/359 patients (<1%) receiving INLYTA and none of the patients receiving sorafenib. The median onset time for hypertension (systolic blood pressure >150 mmHg or diastolic blood pressure >100 mmHg) was within the first month of the start of INLYTA treatment and blood pressure increases have been observed as early as 4 days after starting INLYTA. Hypertension was managed with standard antihypertensive therapy. Discontinuation of INLYTA treatment due to hypertension occurred in 1/359 patients (<1%) receiving INLYTA and none of the patients receiving sorafenib. Blood pressure should be well-controlled prior to initiating INLYTA. Patients should be monitored for hypertension and treated as needed with standard anti-hypertensive therapy. In the case of persistent hypertension despite use of anti-hypertensive medications, reduce the INLYTA dose. Discontinue INLYTA if hypertension is severe and persistent despite anti-hypertensive therapy and dose reduction of INLYTA, and discontinuation should be considered if there is evidence of hypertensive crisis. If INLYTA is interrupted, patients receiving antihypertensive medications should be monitored for hypotension.

Arterial Thromboembolic Events. In clinical trials, arterial thromboembolic events have been reported, including deaths. In a controlled clinical study with INLYTA for the treatment of patients with RCC, Grade 3/4 arterial thromboembolic events were reported in 4/359 patients (1%) receiving INLYTA and 4/355 patients (1%) receiving sorafenib. Fatal cerebrovascular accident was reported in 1/359 patients (<1%) receiving INLYTA and none of the patients receiving sorafenib [see Adverse Reactions]. In clinical trials with INLYTA, arterial thromboembolic events (including transient ischemic attack, cerebrovascular accident, myocardial infarction, and retinal artery occlusion) were reported in 17/715 patients (2%), with two deaths secondary to cerebrovascular accident. Use INLYTA with caution in patients who are at risk for, or who have a history of, these events. INLYTA has not been studied in patients who had an arterial thromboembolic event within the previous 12 months.

Venous Thromboembolic Events. In clinical trials, venous thromboembolic events have been reported, including deaths. In a controlled clinical study with INLYTA for the treatment of patients with RCC, venous thromboembolic events were reported in 11/359 patients (3%) receiving INLYTA and 2/355 patients (1%) receiving sorafenib. Grade 3/4 venous thromboembolic events were reported in 9/359 patients (3%) receiving INLYTA (including pulmonary embolism, deep vein thrombosis, retinal vein occlusion and retinal vein thrombosis) and 2/355 patients (1%) receiving sorafenib. Fatal pulmonary embolism was reported in 1/359 patients (<1%) receiving INLYTA and none of the patients receiving sorafenib. In clinical trials with INLYTA, venous thromboembolic events were reported in 22/715 patients (3%), with two deaths secondary to pulmonary embolism. Use INLYTA with caution in patients who are at risk for, or who have a history of, these events. INLYTA has not been studied in patients who had a venous thromboembolic event within the previous 6 months.

Haemorrhage. In a controlled clinical study with INLYTA for the treatment of patients with RCC, haemorrhagic events were reported in 58/359 patients (16%) receiving INLYTA and 64/355 patients (18%) receiving sorafenib. Grade 3/4 haemorrhagic events were reported in 5/359 (1%) patients receiving INLYTA (including cerebral haemorrhage, hematuria, hemoptysis, lower gastrointestinal haemorrhage, and melena) and 11/355 (3%) patients receiving sorafenib. Fatal haemorrhage was reported in 1/359 patients (<1%) receiving INLYTA (gastric haemorrhage) and 3/355 patients (1%) receiving sorafenib. INLYTA has not been studied in patients who have evidence of untreated brain metastasis or recent active gastrointestinal bleeding and should not be used in those patients. If any bleeding requires medical intervention, temporarily interrupt the INLYTA dose. Cardiac Failure. In a controlled clinical study with INLYTA for the treatment of patients with RCC, cardiac failure was reported in 6/359 patients (2%) receiving INLYTA and 3/355 patients (1%) receiving sorafenib. Grade 3/4 cardiac failure was observed in 2/359 patients (1%) receiving INLYTA and 1/355 patients (<1%) receiving sorafenib. Fatal cardiac failure was reported in 2/359 patients (1%) receiving INLYTA and 1/355 patients (<1%) receiving sorafenib. Monitor for signs or symptoms of cardiac failure throughout treatment with INLYTA. Management of cardiac failure may require permanent discontinuation of INLYTA.

Gastrointestinal Perforation and Fistula Formation. In a controlled clinical study with INLYTA for the treatment of patients with RCC, gastrointestinal perforation was reported in 1/359 patients (<1%) receiving INLYTA and none of the patients receiving sorafenib. In clinical trials with INLYTA, gastrointestinal perforation was reported in 5/715 patients (1%), including one death. In addition to cases of gastrointestinal perforation, fistulas were reported in 4/715 patients (1%). Monitor for symptoms of gastrointestinal perforation or fistula periodically throughout treatment with INLYTA.

Thyroid Dysfunction. In a controlled clinical study with INLYTA for the treatment of patients with RCC, hypothyroidism was reported in 69/359 patients (19%) receiving INLYTA and 29/355 patients (8%) receiving sorafenib. Hyperthyroidism was reported in 4/359 patients (1%) receiving INLYTA and 4/355 patients (1%) receiving sorafenib. In patients who had thyroid stimulating hormone (TSH) <5 μU/mL before treatment, elevations of TSH to 10 μU/mL occurred in 79/245 patients (32%) receiving INLYTA and 25/232 patients (11%) receiving sorafenib. Monitor thyroid function before initiation of, and periodically throughout, treatment with INLYTA. Treat hypothyroidism and hyperthyroidism according to standard medical practice to maintain euthyroid state.

Wound Healing Complications. No formal studies of the effect of INLYTA on wound healing have been conducted. Stop treatment with INLYTA at least 24 hours prior to scheduled surgery. The decision to resume INLYTA therapy after surgery should be based on clinical judgment of adequate wound healing.

Reversible Posterior Leukoencephalopathy Syndrome. In a controlled clinical study with INLYTA for the treatment of patients with RCC, reversible posterior leukoencephalopathy syndrome (RPLS) was reported in 1/359 patients (<1%) receiving INLYTA and none of the patients receiving sorafenib. There were two additional reports of RPLS in other clinical trials with INLYTA. RPLS is a neurological disorder which can present with headache, seizure, lethargy, confusion, blindness and other visual and neurologic disturbances. Mild to severe hypertension may be present. Magnetic resonance imaging is necessary to confirm the diagnosis of RPLS. Discontinue INLYTA in patients developing RPLS. The safety of reinitiating INLYTA therapy in patients previously experiencing RPLS is not known.

Proteinuria. In a controlled clinical study with INLYTA for the treatment of patients with RCC, proteinuria was reported in 39/359 patients (11%) receiving INLYTA and 26/355 patients (7%) receiving sorafenib. Grade 3 proteinuria was reported in 11/359 patients (3%) receiving INLYTA and 6/355 patients (2%) receiving sorafenib. Monitoring for proteinuria before initiation of, and periodically throughout, treatment with INLYTA is recommended. For patients who develop moderate to severe proteinuria, reduce the dose or temporarily interrupt INLYTA treatment.

Elevation of Liver Enzymes. In a controlled clinical study with INLYTA for the treatment of patients with RCC, alanine aminotransferase (ALT) elevations of all grades occurred in 22% of patients on both arms, with Grade 3/4 events in <1% of patients on the INLYTA arm and 2% of patients on the sorafenib arm. Monitor ALT, aspartate aminotransferase (AST) and bilirubin before initiation of and periodically throughout treatment with INLYTA.

Hepatic Impairment. The systemic exposure to axitinib was higher in subjects with moderate hepatic impairment (Child-Pugh class B) compared to subjects with normal hepatic function. A dose decrease is recommended when administering INLYTA to patients with moderate hepatic impairment (Child-Pugh class B). INLYTA has not been studied in patients with severe hepatic impairment (Child-Pugh class C).

Pregnancy. INLYTA can cause fetal harm when administered to a pregnant woman based on its mechanism of action. There are no adequate and well-controlled studies in pregnant women using INLYTA. In developmental toxicity studies in mice, axitinib was teratogenic, embryotoxic and fetotoxic at maternal exposures that were lower than human exposures at the recommended clinical dose. Women of childbearing potential should be advised to avoid becoming pregnant while receiving INLYTA. If this drug is used during pregnancy, or if a patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to the fetus.

ADVERSE REACTIONS

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. The safety of INLYTA has been evaluated in 715 patients in monotherapy studies, which included 537 patients with advanced RCC. The data described reflect exposure to INLYTA in 359 patients with advanced RCC who participated in a randomized clinical study versus sorafenib. The following risks, including appropriate action to be taken, are discussed in greater detail in other sections of the label: hypertension, arterial thromboembolic events, venous thromboembolic events, haemorrhage, gastrointestinal perforation and fistula formation, thyroid dysfunction, wound healing complications, RPLS, proteinuria, elevation of liver enzymes, and fetal development.

Clinical Trials Experience. The median duration of treatment was 6.4 months (range 0.03 to 22.0) for patients who received INLYTA and 5.0 months (range 0.03 to 20.1) for patients who received sorafenib. Dose modifications or temporary delay of treatment due to an adverse reaction occurred in 199/359 patients (55%) receiving INLYTA and 220/355 patients (62%) receiving sorafenib. Permanent discontinuation due to an adverse reaction occurred in 34/359 patients (9%) receiving INLYTA and 46/355 patients (13%) receiving sorafenib. The most common (20%) adverse reactions observed following treatment with INLYTA were diarrhea, hypertension, fatigue, decreased appetite, nausea, dysphonia, palmar-plantar erythrodysesthesia (hand-foot) syndrome, weight decreased, vomiting, asthenia, and constipation. The following table presents adverse reactions reported in 10% patients who received INLYTA or sorafenib.

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