TargetedOnc Staff Writer

According to a statement from the FDA, the agency has issued a draft guidance proposing labeling recommendations for breast implant manufacturers that would help patients understand the benefits and risks of implants. The labeling recommendations would include the addition of a boxed warning.

The draft guidance includes measures to help ensure women have access to the information on the benefits and risks of breast implants, including recommendations that manufacturers incorporate a patient decision checklist in the device&rsquo;s labeling, and updated guidelines for patient screening for ruptured devices.

&ldquo;We have heard from many women that they are not fully informed of the risks when considering breast implants. They&rsquo;ve stated that they need more information to facilitate meaningful conversations with their doctors and to make appropriate decisions for themselves. Many stakeholders suggested that a boxed warning and patient decision checklist could provide this information,&rdquo; the agency stated in a press release. &ldquo;The agency appreciates this important feedback and, in today&rsquo;s draft guidance, has proposed a number of recommendations designed to help inform conversations between patients and healthcare professionals when breast implants are being considered.&rdquo;

In the proposed labeling recommendations, the FDA recommends that boxed warnings be included in the labeling for breast implants, with information including that breast implants are not lifetime devices and the risk of developing complications increase the longer a patient has the implant and, therefore, additional surgery may be required to address such complications.

The agency also stated that implants have been associated with the risk of developing breast implant-associated anaplastic large cell lymphoma (ALCL) and may be associated with systemic symptoms, such as fatigue or joint pain. In 2017, the FDA released a warning advisory that breast implants may increase an individual&rsquo;s risk of developing ALCL.

Another recommendation listed in the draft guidance is that manufacturers include a patient decision checklist at the conclusion of a patient informational booklet or brochure to help guide discussion during a patient consultation with a surgeon, as well allowing the patient to acknowledge all of the associated risks.

Regarding rupture screening for patients with silicone gel-filled breast implants, the FDA also proposed revising these recommendations. The existing opinion states that labeling include the method(s) and frequency of rupture screening, and current approved labeling recommends MRI screenings for patients starting 3 years after getting implants and every other year thereafter.

With the latest draft guidance, the agency proposed that patients without symptoms be screened using either ultrasound or MRI at 5 to 6 years after receiving implants and then every 2 years thereafter. If a patient has symptoms at any time or uncertain ultrasound results for breast implant rupture, an MRI is recommended, the FDA stated. The update to these recommendations is based on results of increased rupture rates at 5 to 6 years after implantation, as well as data suggesting that ultrasound is an effective screening method. Recommendations were also provided by the American College of Radiology and from an FDA panel meeting that was held earlier in 2019.

The FDA also recommended, in the draft guidance, that breast implant manufacturers include product ingredient information in the device&rsquo;s labeling so that it is simplified enough for patients to understand. The abridged information could better information patients of the number and types of chemicals and heavy metals that are in these devices.

The final recommendation in the draft guidance proposes that manufacturers include more information on the patient device card to include the unique device identifier&nbsp;of the product, the boxed warning, and also provide web links to the patient decision checklist, boxed warning and labeling for the specific implant so that patients may easily access any updated information on the manufacturer&rsquo;s website, the agency stated in the press release.

&ldquo;Taken as a whole we believe this draft guidance, when final, will result in better labeling for breast implants that will ultimately help patients better understand breast implant benefits and risks, which is a critical piece in making healthcare decisions that fit patients&rsquo; needs and lifestyle,&rdquo; the agency concluded in the press release. &ldquo;After a period of public comment, once the guidance is finalized, manufacturers may choose to follow the recommendations in the final guidance or they may choose other methods of labeling their devices, so long as the labeling complies with applicable FDA laws and regulations.&rdquo;

When final, the recommendations in the guidance will supplement or, in some cases, replace recommendations in FDA&rsquo;s Guidance Saline, Silicone Gel, and Alternative Breast Implants guidance, which were published in 2006.

Statement on the Agency&rsquo;s Continued Efforts to Protect Women&rsquo;s Health and Enhance Safety Information Available to Patients Considering Breast Implants. FDA. Published October 23, 2019. https://bit.ly/35WzONY. Accessed October 23, 2019.

Breast Implants-Certain Labeling Recommendations to Improve Patient Communication: Draft Guidance for Industry and Food and Drug Administration Staff. FDA. Published October 23, 2019. https://bit.ly/33V42z1. Accessed October 23, 2019.

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According to a statement from the FDA, the agency has issued a draft guidance proposing labeling recommendations for breast implant&nbsp;manufacturers that would help patients understand the benefits and risks of implants. The labeling recommendations would include the addition of a boxed warning.

FDA Considers New Warning and Label Recommendations for Breast Implants

live case-based peer perspectives discussion, Aiwu Ruth He, MD, PhD, discussed with a group of physicians the considerations she makes when deciding on treatment for patients with hepatocellular carcinoma (HCC). Dr He, a medical oncologist at Medstar Georgetown University Hospital, explained the treatment options based on 2 case studies of patients with HCC.

An otherwise healthy, 77-year-old Caucasian woman with a history of alcohol use presented to her primary care physician complaining of abdominal pain and fatigue. Her ECOG performance status was 1 and she weighed 65 kg.

A CT scan of the chest, abdomen, and pelvis, with triphasic liver evaluation revealed a 4.5-cm hepatic mass in the right lobe plus multiple small nodules in the lung. She had a Child-Pugh score of A. Her alpha-fetoprotein (AFP) level was 380 ng/mL.

What are the first-line therapeutic options for this patient?

In our practice, we would do systemic therapy whether we do local control or not. There is a lot of controversy regarding how to manage hepatocellular carcinoma (HCC), particularly as the landscape is changing so much. This patient received lenvatinib 12 mg daily.

Lenvatinib (Lenvima) 12 mg twice a day was initiated. She experienced modest weight loss and reported loss of appetite for which she was referred for nutritional therapy. Imagining at 16 weeks showed she had a partial response.

Eight months after initiation of therapy, her treatment was discontinued due to disease

Can you discuss the selection of lenvatinib for this patient and your own experiences with lenvatinib in this setting?

The REFLECT trial was a global, randomized, phase III study with close to 1000 patients.

Patients had to have Barcelona Clinic Liver Staging System B or C, Child-Pugh A, an ECOG performance status of 1 or 0, adequate liver function, and no prior systemic therapy. The patients on the REFLECT trial also did not have more than 50% of liver occupation from the tumor or blockage of the main portal vein.

There were 2 dose levels for the lenvatinib arm based on weight. For patients who weighed less than 60 kg, they received 8 mg once daily. If they weighed more than 60 kg, they received 12 mg once daily. The lenvatinib arm was compared to sorafenib (Nexavar), which was given at 400 mg twice daily. The primary endpoint was overall survival (OS).

The lenvatinib arm was twice that of the sorafenib arm in terms of the secondary endpoint, progression-free survival, suggesting that lenvatinib is probably the more active agent. If you look at the OS data, there is a trend toward benefit with lenvatinib, but it is in the noninferiority range. The conclusion is that lenvatinib has a very similar OS compared to sorafenib in the frontline setting, however, it may be trending towards to OS. At this point, we would say that lenvatinib in noninferior to sorafenib in terms of OS. Independent reviewed overall response rate (ORR) based on RECIST 1.1 was close to 20% for lenvatinib. Additionally, the independently-reviewed modified RECIST criteria ORR was quite impressive, which was 40.6% compared to 12.4% in the sorafenib arm.

What are the most common adverse events (AEs) associated with lenvatinib?

Hypertension, diarrhea, decreased appetite, decreased weight, and fatigue are all common AEs associated with lenvatinib. We have a dozen to 2 dozen patients on lenvatinib at our practice because we began to treat patients with this agent prior to its approval through the compassionate program. If you educate the patients on the symptoms I just mentioned, once they come in we stop it and it goes away or we can start the patient at a lower dosage and a lot of those symptoms will go away. In my experience, the patient can experience significant fatigue. It is a tyrosine kinase inhibitor (TKI), so it is not significantly better or worse than sorafenib in terms of AEs.

A 63-year-old man with chronic hepatitis C (HCV) infection was referred for further imaging studies after suspicious finding on routine ultrasound surveillance for HCC. His AFP level was 420 IU/mL.

He had a Child-Pugh score of A due to: prothrombin time/International Normalized Ratio of 1.1, bilirubin of 1.0 mg/dL, albumin of 3.5 g/dL, no hepatic encephalopathy, and no present ascites.

A CT scan revealed 2 lesions in the right hepatic lobe measuring 2 cm and 5 cm; no extrahepatic disease; no cirrhosis. The patient underwent liver resection with an R0 margin. Pathology showed grade 2 HCC with moderate fibrosis.

Thirty months after progression, a routine follow-up imaging showed a new lesion in the liver measuring 2.3 cm. A chest CT showed 3 small lesions (<1 cm) in the left upper lobe of the lung.

The patient was started on sorafenib 400 mg every other day, and tolerated therapy well after management of grade 1 diarrhea.

What is your reaction to the use of sorafenib for this patient?

This patient has metastatic disease to the lung. In this case, I would start this patient on a lower dose of sorafenib and, if they tolerate, escalate the dose. It is important for this case that surgeons, hepatologists, medical oncologists, etc. are all in the room when deciding treatment for this patient.

What if he was Child-Pugh class B, instead of A?

For Child-Pugh C, we need to be cautious because there are no data. We do have some data on Child-Pugh B. In CheckMate 040, there was a fifth cohort that enrolled patients with Child-Pugh B liver function for safety data.

I would try immuno-oncology therapy if the patient had a stable Child-Pugh, and they are not dropping quickly from A to B. Again, I would not try this for Child-Pugh C because there are really no data.

What are the options for second-line therapy?

Eight months after the treatment was initiated, a follow-up CT scan showed new lesions in the lung and his ECOG performance status was 1 at this point. The AFP also increased to 820 IU/L. In this case, we could use cabozantinib (Cabometyx), nivolumab (Opdivo), [pembrolizumab (Keytruda)], or regorafenib.

Nivolumab is an option based on the Checkmate 040 study, which was a phase I/II trial starting with a 20-patient dose-escalation cohort and then went to 48 patients.

After a durable ORR of 20%, the FDA decided to allow an expansion and 200 additional patients were added to the cohort. With this cohort, the durable ORR was 15% and the median OS was 28 months. Based on these data, the FDA approved nivolumab for either the frontline or second-line setting, however, pending the proof of OS efficacy in future studies. As you can see, they have a contingency there. In this trial, the survival curves continue to remain high and a lot of these patients have had disease control for a long time, even without therapy.

We have regorafenib based on the RESORCE data.

If you count survival from the start of sorafenib, the median OS is 2 years. For patients who have tolerated sorafenib and responded for some time, those are probably the best candidates for regorafenib. I do have patients who do well with this treatment. It is an approved therapy and a lot of people use it.

Cabozantinib was [studied in] a randomized study compared to placebo.

Three-fourths of the patients were second-line and a quarter of the patients were third-line. From this, we can say that cabozantinib is quite an active agent and is similar to other TKIs in terms of toxicities.

What are the AEs associated with immuno-oncology therapy?

Any inflammation of the organ can present a number of symptoms. I educate my patient and tell them to let me know of any abnormalities. The most common symptoms that I see are rash-related. If they have a rash, I start with topical steroids and, if that doesn't work, I will do 20 mg of prednisone. Usually, these treatments are sufficient enough to cool down the rash.

The other common ones are autoimmune hepatitis or immune-mediated hepatitis. In this case, before each infusion, we have the patient do a liver and kidney function test. If the transaminitis is 5 times or more above their normal level, and I will have them repeat the test within 72 hours, and if it doesn't come down or it reaches even higher levels, I start them on 1 mg of prednisone right away.

Eight months after sorafenib was initiated, follow-up CT scans showed new lesions in the lung nodules. He had an ECOG performance status of 1 and his AFP had increased to >820 IU/L.

The patient was started on regorafenib (Stivarga) 160 mg. He complained of intermittent diarrhea and grade 2 hand-foot syndrome.

Kudo M, Finn RS, Qin S, et al. Lenvatinib versus sorafenib in first-line treatment of patients with unresectable hepatocellular carcinoma: a randomised phase 3 non-inferiority trial.

2018;391(10126):1163-1173. doi: 10.1016/S0140-6736(18)30207-1.

El-Khoueiry AB, Sangro B, Yau T, et al. Nivolumab in patients with advanced hepatocellular carcinoma (CheckMate 040): an open-label, non-comparative, phase 1/2 dose escalation and expansion trial.

2017;389(10088):2492-2502. doi: 10.1016/S0140-6736(17)31046-2.

Bruix J, Qin S, Merle P, et al; RESORCE Investigators. Regorafenib for patients with hepatocellular carcinoma who progressed on sorafenib treatment (RESORCE): a randomised, double-blind, placebo-controlled, phase 3 trial.

2017;389(10064):56-66. doi: 10.1016/S0140-6736(16)32453-9.

Abou-Alfa GK, Meyer T, Cheng AL, et al. Cabozantinib in patients with advanced and progressing hepatocellular carcinoma.

2018;379(1):54-63. doi: 10.1056NEJMoa1717002.

Aiwu Ruth He, MD, PhD, discusses treatment options in a&nbsp;<em>Targeted Oncology </em>live case-based peer perspectives discussion&nbsp;based on 2 case studies of patients with hepatocellular carcinoma.&nbsp;

Expert Considers First- and Second-Line Liver Cancer Treatment Options in 2 HCC Case Studies

Copanlisib (Aliqopa) has been granted with a breakthrough therapy designation from the FDA for the treatment of adult patients with relapsed marginal zone lymphoma (MZL) who have received at least 2 prior therapies.

The designation, which will expedite the development and review of copanlisib in MZL, is based on data from the phase II CHRONOS-1 study, according to Bayer, the manufacturer of the PI3K inhibitor. In a subgroup of 23 patients with MZL, the overall response rate (ORR) was 69.6% (n = 16) in the primary analysis. A follow-up analysis at 18 months showed an ORR of 78.3% (n = 18) in these patients.

"The clinical evidence suggests that Aliqopa may address an unmet medical need by providing physicians and MZL patients with a therapy in a relapsed setting," Scott Z. Fields, MD, senior vice president and head of oncology development at Bayer's Pharmaceutical Division, said in a statement. "We will continue working closely with the FDA in order to bring Aliqopa to these underserved patients as soon as possible."

Safety data for the MZL subgroup showed that the most common (&ge;20%) all-grade treatment-emergent adverse events (TEAEs) were hyperglycemia and fatigue (47.8%), hypertension and diarrhea (43.5%), nausea (26.1%), and pyrexia and cough (21.7%). The most common grade 3 TEAEs were hypertension (39.1%) and hyperglycemia (34.8%).

Overall, the CHRONOS-1 study examined copanlisib in 142 patients across several lymphoma subtypes, including follicular lymphoma (grades 1-3a), MZL, small lymphocytic lymphoma, and lymphoplasmacytic lymphoma/Waldenstrom macroglobulinemia. Eligible patients had relapsed or refractory disease and failure of at least 2 prior lines of therapy.

Patients received copanlisib at 60 mg on days 1, 8, and 15, repeated every 28 days until disease progression or development of unacceptable toxicity. The primary endpoint was objective response by central review after a minimum of 16 weeks of treatment. Secondary endpoints included progression-free survival (PFS), duration of response, overall survival, safety, and quality of life.

The median patient age was 63  years. The median time since the most recent disease progression was 8.3 months, and the study population had received a median of 3 prior regimens. All of the patients had prior exposure to rituximab (Rituxan) and 1 or more alkylating agents, and 60.6% had disease that was refractory to the last regimen received.

Across the lymphoma subgroups, 80.3% of the patients had advanced disease (stage III or IV) at enrollment. Follicular lymphoma was the dominant lymphoma subtype, accounting for 73.2% of the study population.

At the primary analysis, the ORR across all 142 patients was 59.2%, including complete responses in 12.0% of patients and partial responses in 47.2% of patients.2 The ORR rose to 60.6% in the full analysis set population analysis at 18 months. The median PFS was 11.2 months.

Based on the primary analysis, the FDA granted copanlisib an accelerated approval in September 2017 as a treatment for patients with relapsed follicular lymphoma who have received at least 2 least prior systemic therapies.

The accelerated approval is contingent on data from a confirmatory trial. Bayer has 2 ongoing phase III studies (CHRONOS-3 [NCT02367040] and CHRONOS-4 [NCT02626455]) exploring copanlisib in combination with other treatments in patients with relapsed indolent non-Hodgkin lymphoma.

Bayer Receives U.S. FDA Breakthrough Therapy Designation for Aliqopa&trade; (copanlisib) for the Treatment of Marginal Zone Lymphoma. https://bit.ly/2W42puG. Published May 29, 2019. Accessed May 30, 2019.

Dreyling M, Santoro A, Mollica L, et al. Copanlisib in patients with relapsed or refractory indolent B-cell lymphoma: primary results of the pivotal CHRONOS-1 study. Presented at: 2017 AACR Annual Meeting; April 1-5, 2017; San Washington, DC. Abstract CT149.

Copanlisib has been granted with a breakthrough therapy designation from the FDA for the&nbsp;treatment of adult patients with relapsed marginal zone lymphoma who have received at least 2 prior therapies.

Copanlisib Given FDA Breakthrough Designation for Marginal Zone Lymphoma

The review period on the new drug application (NDA) for quizartinib as a treatment for adult patients with relapsed/refractory

-ITDpositive acute myeloid leukemia (AML) has been extended by the FDA by 3 months. This provides the FDA with additional time to review more data supplied by Daiichi Sankyo, the manufacturer of the FLT3 inhibitor.

Based on findings from the phase III QuANTUM-R trial, there was a 24% reduction in the risk of death compared to salvage therapy in patients with

-ITDpositive relapsed/refractory AML after frontline treatment with or without hematopoietic stem cell transplantation (HSCT).

At a median follow-up of 23.5 months, the median OS was 6.2 months (95% CI, 5.3-7.2) with quizartinib compared with 4.7 months (95% CI, 4.0-5.5) with salvage chemotherapy (HR, 0.76; 95% CI, 0.58-0.98; stratified log-rank test, 1-sided

"We look forward to continued dialogue with the FDA throughout the review process of quizartinib," Arnaud Lesegretain, vice president, Oncology Research and Development and head, AML Franchise, Daiichi Sankyo, said in a press release. "We remain confident in the data supporting our NDA submission and are committed to bringing quizartinib forward as a potential treatment for relapsed or refractory

-ITD AML, a particularly aggressive and difficult-to-treat subtype of AML, where patients need additional targeted treatment options."

The OS benefit with quizartinib in QuANTUM-R was upheld across 3 prespecified sensitivity analyses. In the first, which censored for the effect of transplant, the median OS with quizartinib versus salvage chemotherapy was 5.7 versus 4.6 months (HR, 0.79; 95% CI, 0.59-1.05;

= 0.519). An analysis censoring for the use of other FLT3 inhibitors showed a median OS of 6.6 versus 5.0 months, respectively (HR, 0.74; 95% CI, 0.55-0.99;

The third sensitivity analysis examined the per-protocol set (patients who were randomized and treated without significant protocol deviations). For this assessment, the median OS was 6.2 months with quizartinib versus 4.6 months with salvage chemotherapy (HR, 0.75; 95% CI, 0.57-1.00;

The OS benefit was also demonstrated across several patient subgroups. Among patients with prior allogeneic HSCT, the median OS was 5.3 months with quizartinib versus 4.0 months with salvage chemotherapy. The medians were 6.9 versus 5.2 months in those without prior allogeneic HSCT. The OS benefit was also shown across subgroups defined by AML risk scores, including intermediate (6.2 vs 4.6 months) and unfavorable (9.4 vs 5.8 months).

In subgroups defined by response to prior therapy, the median OS was 6.5 vs 4.7 months in patients who relapsed, with no HSCT; 7.9 vs 5.4 months in refractory patients; and 5.1 versus 4.0 months in patients who relapsed, post HSCT.

The benefit with quizartinib versus salvage chemotherapy was also observed across subgroups defined by varying allelic ratio, age, sex, and AML history.

Patients on QuANTUM-R were randomized in a 2:1 ratio to once-daily quizartinib at 60 mg, with a 30-mg lead-in (n = 245) or to receive investigators&rsquo; choice of salvage chemotherapy that was selected prior to randomization. Chemotherapy choices included low-dose cytarabine (n = 29); the combination of mitoxantrone, etoposide, and cytarabine, (MEC; n = 40); or the combination of fludarabine, cytarabine and GCSF with idarubicin (FLAG-IDA; n = 53).

Baseline patient characteristics were well balanced across the treatment arms. The median patient age in the quizartinib arm was 55 years (range, 19-81) and 89% had and ECOG performance status of 0-1. Thirty-three percent of patients were refractory to prior therapy, 23% had relapsed after remission with HSCT, and 45% had relapsed after remission without HSCT.

Also among patients receiving quizartinib, the

-ITD variant allele frequency ranges included <3% (1%); &ge;3% to &le;25% (27%); >25% to &le;50% (35%), and >50% (37%). Cytogenetic risk status included favorable (5%), intermediate (78%), unfavorable (9%), and unknown (8%).

The overall response rate was 69% with quizartinib versus 30% with salvage chemotherapy. The composite complete remission (CRc) rate was 48% versus 27% and the partial response rate was 21% versus 3%, respectively. The median duration of CRc was 12.1 weeks versus 5.0 weeks, respectively.

The median event-free survival was 1.4 months (95% CI, 0.0-1.9) with quizartinib versus 0.9 months (95% CI, 0.4-1.3) with salvage chemotherapy (HR, 0.90; 95% CI, 0.70-1.16; 1-sided, stratified log-rank

Single-agent quizartinib was well tolerated in the trial. Grade 3 QT prolongation was uncommon and there were no grade 4 cases. The most common grade &ge;3 hematologic adverse events (AEs) in the quizartinib arm included thrombocytopenia (35% vs 34% in the salvage chemotherapy arm), anemia (30% vs 29%, respectively), neutropenia (32% vs 25%), febrile neutropenia (31% vs 21%), and leukopenia (17% vs 16%).

The most common grade &ge;3 nonhematologic AEs in the quizartinib arm were nausea (3% vs 1% in the salvage chemotherapy arm), fatigue (8% vs 1%, respectively), pyrexia (3% vs 4%), musculoskeletal pain (4% in each arm), vomiting (3% vs 1%), hypokalemia (12% vs 9%), and diarrhea (2% vs 3%).

Quizartinib is also being explored in the phase III QuANTUM-First study (NCT02668653), which is examining the FLT3 inhibitor in patients with newly-diagnosed

Jorge E. Cortes, MD1, Samer K. Khaled, MD2, Giovanni Martinelli, MD. Efficacy and safety of single-agent quizartinib (Q), a potent and selective FLT3 inhibitor (FLT3i), in patients (pts) with FLT3-Internal Tandem Duplication (FLT3-ITD)mutated relapsed/refractory (R/R) acute myeloid leukemia (AML) enrolled in the global, phase 3, randomized controlled Quantum-R Trial. Presented at: ASH Annual Meeting and Exposition; December 4-8, 2018; San Diego, California. Abstract 563.

The FDA initially granted a priority review designation to the NDA in November 2018, with an action date set for May 25, 2019. Under the new timeframe, the FDA is now scheduled to make a final decision on the NDA by August 25, 2019.

The review period on the new drug application for quizartinib as a treatment for adult patients with&nbsp;relapsed/refractory <em>FLT3</em>-ITD&ndash;positive acute myeloid leukemia has been extended by the FDA by 3 months.&nbsp;This provides the FDA with additional time to review more data supplied by&nbsp;Daiichi Sankyo, the manufacturer of the FLT3 inhibitor.

Author | TargetedOnc Staff Writer

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