Danielle Bucco

Patients with renal cell carcinoma (RCC) have seen a change in standard of care as novel therapies and combinations are quickly approved, says Toni K. Choueiri, MD.

In December 2017, the FDA approved cabozantinib (Cabometyx) based on practice-changing data from the phase II CABOSUN trial. The multikinase inhibitor reduced risk of progression or death by 52% compared with sunitinib (Sutent) while the median progression-free survival was 8.6 months with cabozantinib versus 5.3 months for sunitinib (HR, 0.48; 95% CI, 0.31-0.74;

Median overall survival (OS) after a 30.8 month follow-up was 26.6 months (95% CI, 14.6-not evaluable) versus 21.2 months (95% CI, 16.3-27.4) in cabozantinib and&nbsp;sunitinib arms, respectively. There was a nonstatistically significant 20% reduction in the risk of death (HR, 0.80; 95% CI, 0.53-1.21;

The field is also pushing toward immunotherapy combinations, Choueiri adds. Combination nivolumab (Opdivo) plus ipilimumab (Yervoy) reduced risk of death by 37% compared with sunitinib in patients with intermediate- and poor-risk RCC (HR, 0.63;

<.0001), according to results from the CheckMate-214 trial.

In April 2018, this regimen was approved by the FDA for frontline treatment of this patient population.

, Choueiri, director of the Lank Center for Genitourinary Oncology and of the Kidney Cancer Center at Dana-Farber Cancer Institute, discussed the recent advancements in RCC. He also shared his insight on the future outlook of this treatment landscape.

: Can you speak to the success of the CABOSUN trial?

We are beyond single-agent VEGF receptors and TKIs. We still use other single agents, such as nivolumab or cabozantinib. In the frontline setting against sunitinib, cabozantinib showed superior response rates and an improved PFS.

This randomized phase II trial was essentially for patients in the poor- and intermediate-risk subgroups. Cabozantinib was approved in December 2017 in the frontline setting.

: What does the future look like? Will it include combinations of immunotherapies and targeted therapies?

Almost all of the large phase III trials are comparing combinations, such as immunotherapy plus VEGF inhibition, plus another immunotherapy regimen, or plus sunitinib. However, these studies are not head to head, so hopefully we will eventually have a head-to-head study. It is extremely important to compare combinations with the new standard of care. The combinations, especially with the high response rates that we are seeing, are going to be a significant part of the standard of care. However, the combination of nivolumab and ipilimumab has a higher response rate than sunitinib.

Also, with earlier studies, we are seeing TKIs such as axitinib (Inlyta) and lenvatinib (Lenvima). Additionally, the combination of pembrolizumab (Keytruda) and [axitinib] was very well tolerated, resulting in response rates between 50% to 70% and higher. There are also studies with 2 antibodies, the PD-L1 inhibitor atezolizumab (Tecentriq) and bevacizumab (Avastin), which were presented at the 2018 Genitourinary Cancers Symposium. The PD-L1positive population demonstrated a higher response rate with the combination when compared with sunitinib. However, it is still too early to determine the OS benefit.

: Can you discuss any new biomarker development?

We are still trying to come up with a biomarker for single-agent PD-1/PD-L1 inhibitors as well as VEGF TKIs. It is not easy, as we do not have anything to guide our clinical decision in practice. PD-L1 via immunohistochemistry was prognostic for nivolumab but when it was combined with ipilimumab in the CheckMate-214 study, it responded differently when looking at PD-L1 status. There was a much higher benefit for patients who were PD-L1 positive. This biomarker could tell us something. It has been integrated in most phase III trials but is still not ready for prime time.

Choueiri TK, Hessel C, Halabi S, et al. Progression-free survival (PFS) by independent review and updated overall survival (OS) results from Alliance A031203 trial (CABOSUN): Cabozantinib versus sunitinib as initial targeted therapy for patients (pts) with metastatic renal cell carcinoma (mRCC). In: Proceedings from the 2017 ESMO Congress; September 8-12, 2017; Madrid, Spain. Abstract LBA38.

Escudier B, Tannir NM, McDermott DF, et al. CheckMate214: efficacy and safety of nivolumab plus ipilimumab vs sunitinib for treatment-naive advanced or metastatic renal cell carcinoma, including IMDC risk and PD-L1 expression subgroups. In: Proceedings from the 2017 ESMO Congress; September 8-12, 2017; Madrid, Spain. Abstract LBA5. 2013;369(18):1691-1703. doi:10.1056/NEJMoa1304369.

Articles

Patients with renal cell carcinoma have seen a change in standard of care as novel therapies and combinations are quickly approved, says Toni K. Choueiri, MD.

Expert Highlights Changes in the Treatment Landscape of RCC

The frontline treatment of patients with ovarian cancer may potentially change in the near future, with targeted and immunotherapy strategies showing promising signals of activity.

For example, the combination of chemotherapy plus the PD-1 inhibitor pembrolizumab (Keytruda) followed by pembrolizumab maintenance&nbsp;appeared to be safe and feasible for patients with advanced ovarian cancer, according to preliminary data from a small clinical trial that were presented at the 2018 Society for Gynecologic Oncology Annual Meeting.

In the study, 6 of 10 patients exhibited no evidence of disease during follow-up for as long as 14 months after debulking surgery, including 1 patient who had suboptimal results. No new or unexpected adverse events (AEs) occurred.

However, further data need to be collected before knowing what role immunotherapy should have in the frontline setting, Heather Dalton, MD, says. Other strategies being explored include PARP inhibitors, checkpoint inhibitor monotherapy, and bevacizumab (Avastin). In October 2017, the FDA accepted a supplemental biologics license application for bevacizumab, in combination with carboplatin and paclitaxel, followed by bevacizumab alone, for the first-line treatment of advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer. The FDA is expected to make a decision on the application by June 25, 2018.

, Dalton, a gynecologic oncologist at Arizona Oncology, discussed the developing standard of care for the frontline treatment of patients with ovarian cancer.

What is the standard first-line treatment option for patients with ovarian cancer?

This is a controversial subject. There were many times where we thought we had it all figured out. With every trial, the water seems to get muddier regarding the standard of care. With the initial dose-dense regimen, we were excited about the improvement in overall survival that we saw that rivaled intraperitoneal (IP) chemotherapy. Everyone was understandably embracing of that regimen, but the results of the GOG 252 trial complicated that significantly as there was no difference in survival between the regimens.

I would say, for suboptimally debulked patients, most would agree that the dose-dense regimen or an appropriate clinical trial are good choices. For patients who are not the most robust, consideration of fractionated treatments, such as dose-dense carboplatin and paclitaxel, are good options. For patients with a good performance status, IP chemotherapy is still a reasonable option, although there is no true standard of care. There are lots of controversies there.

Are there emerging strategies that could be looked at as a frontline option?

A lot of exciting things are going on right now in ovarian cancer. There are 6 new FDA appointment dates for potential approvals for drugs in the frontline setting. The addition of PARP inhibitors in the frontline setting [could be] exciting. We are seeing that in multiple clinical trials and it will be exciting to see the results.

Additionally, we are seeing the introduction of checkpoint inhibitors in the frontline setting. Those are all very exciting, so it will be interesting to see what comes out of those trials because there are [encouraging] data in the second-line setting.

Are there any concerns or unanswered questions that we have with PARP inhibitors or immunotherapy in the frontline setting?

We are learning more about these medications and the class-specific AEs associated with them. With regimens such as PARP inhibitors, some patients have more hematologic or gastrointestinal-related toxicities, but those are generally manageable. We are getting better at making appropriate adjustments to dosing as we become familiar with these regimens.

With checkpoint inhibitors, we are at a time where there is potential with modulating the immune system, but these also have anticipated AEs. Those are often serious, but are usually manageable and can be recognized earlier. As time goes on, we can learn more about these medications so that we can handle things more effectively.

What are your thoughts on pembrolizumab (Keytruda) being combined with chemotherapy in the frontline setting?

I do not think that there are enough data with that combination to say that patients shouldn&rsquo;t get the standard of care, which is cytotoxic chemotherapy. As we learn more about these trials with checkpoint inhibitors and PARP inhibitors, we will have more data on how efficacious those can be in the frontline setting. It is too early to abandon the treatments that we know work without definitive evidence. Certainly, in some cancer types, we are moving to immunotherapy as a frontline setting and hopefully for patients with ovarian cancer that will be an optionbut we are not there yet.

Have we defined the role of adding bevacizumab (Avastin) to the treatment landscape?

There is definitely a benefit in patients who are suboptimally debulked, which has been supported by numerous data. As far as its addition in the frontline setting, there are new data coming out demonstrating the potential benefit of it in the frontline setting. Although those studies have been criticized, there is a pending FDA evaluation of the regimen in the frontline setting. We will see how the indication changes, but many people are using it.

If we get to a point where PARP inhibitors are looked at in the frontline setting, will we run into sequencing challenges?

As more patients are exposed to PARP inhibitors, it will be interesting to see the data that have come out on the efficacy of these agents. Hopefully, depending on how long it has been since the patient received a PARP inhibitor, it could be given to them again, but those data are forthcoming.

Uyar D, Bishop EA, Bradley WH, Rader JS. Preliminary data on the use of combination carboplatin, paclitaxel and pembrolizumab therapy for ovarian cancer. In: Proceedings from the 2018 SGO Annual Meeting; March 24-27, 2018; New Orleans, LA. Abstract 100.

Expert Discusses Evolving Treatment of Ovarian Cancer in the Frontline Setting

While PARP inhibitors have demonstrated success in ovarian cancer previously, they are finally impacting the treatment paradigm for patients with

-positive breast cancers, according to Nadine M. Tung, MD.

The FDA approved olaparib (Lynparza) in January 2018 for treatment of patients with germline

-positive, HER2-negative metastatic breast cancer who have received a prior treatment of chemotherapy. Based on results from the phase III OlympiAD trial, olaparib reduced risk of disease progression or death by 42% and improved progression-free survival (PFS) by 2.8 months versus standard chemotherapy in previously treated patients

-positive, HER2-negative disease. These promising results led to the FDA approval.

Phase III findings also demonstrated potential benefit with talazoparib, another PARP inhibitor. Talazoparib was reduced the risk of disease progression or death by 46% in patients with

-positive advanced breast cancer in the EMBRACA trial.

At a median follow-up of 11.2 months, the median PFS was 8.6 months with talazoparib versus 5.6 months with physician&rsquo;s choice of therapy (HR, 0.54; 95% CI, 0.41-0.71;

Tung, associate professor of medicine at the Harvard Medical School and director of the Cancer Risk and Prevention Program at Beth Israel Deaconess Medical Center, Dana-Farber Cancer Institute, discussed the emerging role PARP inhibitors have for patients with

-positive breast cancer and the importance of genetic testing.

What is the current treatment landscape of PARP inhibitors for patients with breast cancer?

The newest development is the OlympiAD trial and the FDA approval of olaparib for patients with germline

mutations who have metastatic, HER2-negative breast cancer. The FDA approved use of olaparib in January 2018, so that is available now for patients who have metastatic HER2-negative breast cancer. Those patients also have a germline

mutation and have seen chemotherapy at some pointeither in the initial setting, adjuvant, neoadjuvant, or metastatic setting

What other PARP inhibitors are being investigated?

Firstly, the OlympiAD trial investigated olaparib compared with nonplatinum standard chemotherapy. Olaparib led to a significant improvement in PFS.

A similar study was presented at the 2017 San Antonio Breast Cancer Symposium using a different PARP inhibitor, talazoparib, in the EMBRACA trial. It was a very similar design with the same population, comparing the PARP inhibitor monotherapy with standard chemotherapy choices. Interestingly, the results were very similar with a significant improvement in PFS by approximately 3 months. It will be interesting to see if a second PARP inhibitor does get FDA approval.

Are there any thoughts of bringing PARP inhibitors to earlier lines of therapy?

Both of the studies I mentioned were for patients who had seen standard chemotherapyanthracyclines or taxanes&mdash;either in the initial or metastatic setting. Now, PARP inhibitors are also being studied in an earlier setting. There are studies, such as OlympiA, looking at [olaparib in] the adjuvant setting for patients with germline

mutations who have higher risk of disease after they complete standard chemotherapy and local therapy.

Could this benefit patients without BRCA mutations?

That is an important goal we are working on. We want to find patients who do not have germline

mutations, but whose tumors may be sensitive to PARP inhibitors. The way that investigators are trying to approach that topic is to identify breast cancers that also have the same DNA repair defect as the breast cancers in patients with germline

-associated breast cancers have a defect in homologous recombination. That is the pathway that repairs double-strand DNA breaks. How can we identify other breast cancers that have this defect? There are various tools being developed. None of them are in clinical use yet, but some of them are interesting. Some look at genomic loss in the tumor, whereas others look at mutational signatures to find those with a defect in homologous recombination. The other approach is to look at patients who either have a germline mutation or whose tumors have a somatic mutation in other genes that work with

In metastatic prostate cancer, patients with germline or somatic mutations in the other genes, such as

, respond to PARP inhibitors. That approach is being looked at with breast cancer. We are looking at patients who have some other mutations, such as

How do you typically identify these mutations?

For some patients, we do germline testing. If they have a personal or family history that is suggestive of having an inherited

mutation, we do multigene panels. For many patients, we are rarely just testing for

. We are looking for these other DNA repair genes.

In metastatic patients, we do a lot of tumor somatic testing that looks at targets of therapy. You pick up a lot of germline mutations by testing the tumor in the metastatic setting. There are about 4% of patients with breast cancer whose tumors will have a

mutation that do not have an inherited germline mutation.

mutation is found in the tumor, that should trigger germline testing so that it is known whether the patient has an inherited mutationas that has other implications for risk management for other cancers and family members. It is also important to say that even if the tumor testing does not show a

mutation, a patient should undergo germline testing if they qualify for it.

When is it best to conduct germline testing?

Even though PARP inhibitors are not yet approved in an earlier setting, if a patient qualifies for germline

testing, they should always have it at initial diagnosis. It has implications for their local treatment, surgery, what chemotherapy is being chosen, prophylactic mastectomies, and risk management. In the initial setting, if someone meets criteria for germline testing, they should always have it.

At recurrence or at metastatic disease, we are almost always doing tumor testing. If the patient missed it or qualifies for germline testing and never had it, they should get it at that point.

Is there anything else you would like to add?

There is a lot of debate about how much genetic testing to do in a patient who is diagnosed with breast cancer. Should it just be the high-risk breast cancer genes? Should it be high- and moderate-risk breast cancer genes? Should it be a multigene panel that looks for cancer susceptibility genes for other cancers? I do not think there is complete agreement among experts in this field, but we are increasingly using panels. Identifying the breast cancer susceptibility genes has implications for treatment and surveillance in our own patients, identifying their risks for other cancers, and also for their relatives.

Now that there are some new ovarian cancer susceptibility genes, such as

identifying those mutations warrants a discussion about prophylactic mastectomy in our patients with breast cancer. For me, I am virtually always testing for the breast and ovarian cancer susceptibility genes. However, if the patient and the clinician feel that there is merit in finding other cancer susceptibility genes, then a multigene panel for established cancer risk genes is appropriate.

We know now that when we test patients with breast cancer, we do find Lynch syndrome genes in patients who do not have a personal or family history that would have suggested it. If the patient and clinician feel this is important information, then a multigene panel makes sense.

Robson M, Im SA, Senkus E, et al. Olaparib for metastatic breast cancer in patients with a germline BRCA&nbsp;mutation. 2017;377:523-533.&nbsp;

Litton JK, Rugo HS,&nbsp;Ettl J, et al. A phase 3 trial comparing talazoparib, an oral PARP inhibitor, to physician&rsquo;s choice of therapy in patients with advanced breast cancer and a germline BRCA-mutation. In: Proceedings from the 2017 San Antonio Breast Cancer Symposium; December 5-9, 2017; San Antonio, Texas. Abstract GS6-07.

While PARP inhibitors have demonstrated success in ovarian cancer previously, they are finally impacting the treatment paradigm for patients with <em>BRCA</em>-positive breast cancers, according to Nadine M. Tung, MD.&nbsp;

Expert Highlights Advancements With PARP Inhibitors in Breast Cancer

While relapsed/refractory mantle cell lymphoma (MCL) is considered an aggressive disease, new findings show patients may benefit from adding chimeric antigen receptor (CAR) T-cell therapy to their treatment regimen. ZUMA-2, a currently ongoing trial, aims to understand the potential benefits with axicabtagene ciloleucel (axi-cel; Yescarta), an anti-CD19 CAR T-cell product, for&nbsp;patients with relapsed/refractory MCL (NCT02601313).

The ZUMA-2 trial set a primary endpoint of safety and efficacy of axi-cel, measured by overall response rate (ORR). Secondary endpoints were selected as duration of response, best objective response, and progression-free survival. It was required that patients in the trial had prior therapy with an anthracycline- or bendamustine-containing chemotherapy, anti-CD20 monoclonal antibody therapy, and either ibrutinib (Imbruvica) or acalabrutinib (Calquence). Researchers estimate a primary completion date for this study in July 2018.

The FDA has approved axi-cel for patients with non-Hodgkin lymphoma (NHL) based on findings from the ZUMA-1 trial. The approval was specified for patients with large B-cell lymphoma that had received 2 prior lines of therapy, also including diffuse large B-cell lymphoma (DLBCL). An ORR of 82% was reached with Axi-cel, as well as a CR rate of 54%. With an 8.7 month follow-up, 39% of the patients in the ZUMA-1 trial remained in CR. Median duration of response was not reached, though, at the time of assessment (95% CI, 8.1-not estimable).

In an interview with Targeted Oncology,&nbsp;Frederick L. Locke, MD, a medical oncologist at Moffitt Cancer Center, investigator on ZUMA-2, and co-lead investigator on ZUMA-1, discussed the ongoing ZUMA-2 trial investigating axi-cel for patients with MCL. He also highlights the impact this trial and its results will have on the treatment landscape of this disease.

Can you discuss the rationale behind conducting the ZUMA-2 trial for patients with MCL?

The ZUMA-2 trial is a Kite Pharma/Gilead Sciences-sponsored multicenter clinical trial to evaluate the anti-CD19 CAR T-cell therapy called axi-cel as a treatment for patients with MCL.&nbsp;

MCL is a B-cell cancer that can act indolently or aggressively. When the disease becomes refractory, it can grow very quickly. Newer FDA-approved medications with efficacy for late-stage MCL, such as the oral medication ibrutinib, have proven very effective to control disease for many patients. Unfortunately, for patients whose lymphoma grows while on ibrutinib, or the similar medication acalabrutinib, there are not many good options. This trial is attempting to investigate if that set of patients could go into remission for a prolonged period of time with axi-cel.

What are the main challenges that exist for this patient population?

Once ibrutinib stops working or if patients come off ibrutinib, we know that the disease may progress rapidly. These patients have very little time to be referred and enrolled onto the trial, so they could get CAR T cells manufactured.ery quickly. That is one of the big challenges for patients with MCL refractory to ibrutinib; patients need treatment [right away].

If this trial investigating axi-cel is successful, what impact could this type of therapy have on the MCL landscape?

We saw the FDA-approved indication for axi-cel in patients with DLBCL who have relapsed after 2 lines of therapy, but MCL is another lymphoma [that expresses CD19]. There are clearly patients who die of progressive MCL and need new therapies. If we can prove that axi-cel is safe and effective to use, the study has the potential to save lives.

Is it possible for axi-cel to be brought into the frontline setting for patients with MCL?

This is also a question that we have in DLBCL. I would not say that it is impossible, but we have to be deliberate and first answer the question of its safety and efficacy in refractory patients. We can then compare it to other earlier lines of therapy, which is the logical next step.

Patients with MCL can be in remission for many years with upfront chemotherapy, anti-CD20 monoclonal antibodies. If patients are in CR and are consolidated with an autologous stem cell transplant, they could potentially remain in remission for a decade. To say that CAR T-cell therapy can compete with those preexisting responses in MCL is a big leap so we have a ways to go.

It is important that people are aware of existing trials, not only for MCL but also for DLBCL, so they can determine whether their patients are eligible for a referral to a center that has clinical trials, especially in the CAR T-cell space and at first relapse. Referring patients at first relapse is important. Waiting for a second relapse or third relapse creates issues of getting those patients onto trials. There are study eligibility criteria, including while blood cell count and platelet count, which can be quite low for patients with MCL, especially if the patients have a large spleen or bone marrow involvement. Early referral is always better.

Locke FL, Neelapu SS, Bartlett NL, et al. Primary results from ZUMA-1: a pivotal trial of axicabtagene ciloleucel (Axi-cel; KTE-C19) in patients with refractory aggressive non-Hodgkin lymphoma (NHL). In: Proceedings from the 2017 AACR Annual Meeting; April 1-5, 2017; Washington, DC. Abstract CT019.

While relapsed/refractory mantle cell lymphoma (MCL) is considered an aggressive disease, new findings show patients may benefit from adding chimeric antigen receptor T-cell therapy to their treatment regimen. ZUMA-2, a currently ongoing trial, aims to understand the potential benefits with axicabtagene ciloleucel, an&nbsp;anti-CD19 CAR T-cell product, for&nbsp;patients with relapsed/refractory MCL.

Danielle Bucco | Authors

Articles

Expert Highlights Changes in the Treatment Landscape of RCC

Expert Discusses Evolving Treatment of Ovarian Cancer in the Frontline Setting

Expert Highlights Advancements With PARP Inhibitors in Breast Cancer

Expert Discusses ZUMA-2 Trial Investigating CAR T-Cell Therapy in MCL