Recommended treatment regimens for patients with renal cell carcinoma (RCC) continue to change as novel therapies and combinations are approved by the FDA.

For example, cabozantinib (Cabometyx) was approved in December 2017 based on data from the phase II CABOSUN trial in which the multikinase inhibitor reduced the risk of progression or death by 52% compared with sunitinib (Sutent). The agent also improved progression-free and overall survival.

Immunotherapy combinations are also starting to push the field forward, according to Toni K. Choueiri, MD, director of the Lank Center for Genitourinary Oncology and of the Kidney Cancer Center at Dana-Farber Cancer Institute.

In April 2018, the FDA approved the combination of nivolumab (Opdivo) and ipilimumab (Yervoy) for the frontline treatment of RCC, based on results from the CheckMate-214 study. The combination reduced the risk of death by 37% versus sunitinib in intermediate- and poor-risk RCC (HR, 0.63; 

 on Genitourinary Cancers, Choueiri discussed the recent advancements considered at the event, of which he was the chair, and shared his insight on the future treatment landscape of patients with kidney cancer. 

Please provide an overview of the topics highlighted at the meeting and how they speak to the evolution of genitourinary cancer treatment.

To start, there was a talk about robotic surgery in kidney and bladder cancer. It is very interesting how surgery has evolved from open, to laparoscopic, and now to robotic surgery.

Dr. Lauren C. Harshman discussed the evolving role of adjuvant therapy in high-risk patients with RCC in the era of tyrosine kinase inhibitors (TKIs). There are still some ongoing trials that will read out in the next couple of years. She also spoke about integrating high-risk RCC treatments, both in the adjuvant as well as the neoadjuvant settings, followed by adjuvant therapy.

Dr. Bradley A. McGregor tackled targeted therapy for patients with advanced RCC, and most recently combinations of immunotherapy. Immunotherapies are being looked at in combination with other immunotherapy regimens, such as nivolumab and ipilimumab, or, with VEGF inhibitors. There is a lot to come in that advanced setting because many of the phase III trials against sunitinib have either finished accrual or are ongoing. The field may change again.

We had Dr. Guru P. Sonpavde talk about integrating novel immunotherapy with chemotherapy in advanced bladder cancer in the early-stage setting. Finally, Dr Xiao X. Wei discussed systemic therapy management with the focus on PD-1/PD-L1 inhibitors and the management of adverse events (AEs). Immunotherapy is a specific class of agents with a specific management for AEs.

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

Renal Cell Carcinoma Treatment Evolves as New Therapies are Approved

-positive breast cancers are now incorporating PARP inhibitors more extensively. Success in the ovarian cancer space spurred its application in breast cancer research and treatment, explains Nadine M. Tung, MD, an associate professor of medicine, Harvard Medical School, director, Cancer Risk and Prevention Program, Beth Israel Deaconess Medical Center, Dana-Farber Cancer Institute.

The FDA recently approved the PARP inhibitor olaparib (Lynparza) for the treatment of patients with germline 

-positive, HER2-negative metastatic breast cancer who have previously received chemotherapy. The approval was based on the results from the phase III OlympiAD trial, which showed that olaparib reduced the 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 

Encouraging phase III findings were also demonstrated with the PARP inhibitor talazoparib. In the EMBRACA trial, talazoparib was found to reduce the risk of disease progression or death by 46% in patients with 

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

Tung discussed the role of PARP inhibitors 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 mutation. 2017;377:523-533. 

Litton JK, Rugo HS, Ettl J, et al. A phase 3 trial comparing talazoparib, an oral PARP inhibitor, to physician’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.

Nadine M. Tung, MD, discussed the role of PARP inhibitors for patients with BRCA-positive breast cancer and the importance of genetic testing.

PARP Inhibitor Use in Breast Cancer Treatment Evolves

Recent FDA actions and updated guideline recommendations have taken a once stagnant treatment landscape for nonmetastatic castration-resistant prostate cancer (CRPC) and made it exciting for both patients and treating physicians.

According to the American Urological Association (AUA) guidelines, patients with nonmetastatic CRPC should be observed with continued androgen deprivation therapy (ADT). Alternative treatment can include first-generation antiandrogens, such as flutamide, bicalutamide (Casodex), and nilutamide (Nilandron), or first-generation androgen synthesis inhibitors, such as ketoconazole plus a steroid. Clinicians should not offer systemic chemotherapy or immunotherapy to these patients, according to these guidelines.

In February 2018, the FDA approved apalutamide (Erleada) for patients with nonmetastatic CRPC. The approval was based on results from the phase III SPARTAN trial, which showed that apalutamide reduced the risk of metastasis or death by 72% in this patient population. The median metastasis-free survival (MFS) was 40.5 months in the apalutamide arm versus 16.2 months in the placebo arm (HR, 0.28; 95% CI, 0.23-0.35; 

 <.0001). At a median follow-up of 20.3 months, 61% of the apalutamide arm remained on treatment compared with 30% of patients receiving placebo. An interim overall survival (OS) analysis of 24% of events revealed a trend favoring apalutamide.

In March 2018, the FDA granted a priority review to a supplemental new drug application for enzalutamide (Xtandi) for the treatment of men with nonmetastatic CRPC. The decision was based on phase III data of the PROSPER trial, in which the combination of enzalutamide plus ADT reduced the risk of metastases or death by 71% versus ADT alone.

 Additionally, the median MFS was 36.6 months with enzalutamide plus ADT versus 14.7 months with ADT alone (HR, 0.29; 95% CI, 0.24-0.35; 

 State of the Science Summit™ on Prostate Cancer, at which he delivered a lecuture, Mark J. Mann, MD, an assistant professor of urology at Sidney Kimmel Cancer Center, Thomas Jefferson University Hospital. discussed the developing treatment landscape for patients with nonmetastatic CRPC. 

Please provide an overview of your lecture on the treatment of nonmetastatic CRPC.

The definition of nonmetastatic CRPC is a patient with a prostate-specific antigen (PSA) that is 2 over the nadir, or a 25% increase from the nadir while the testosterone is still repressed. The next part of the diagnosis is determining whether it is metastatic. That is done with a CT scan and a bone scan, which are standard, but there are new imaging modalities that are starting to come into play, specifically PET scans.

The next step in surveillance is to make sure the patient [has] nonmetastatic disease. We discussed the AUA recommendations for treatment, or rather the lack of treatment, and the indication where we will then progress to more advanced treatments. I also discussed the latest ASCO [American Society of C] publicized studies, such as enzalutamide in the PROSPER trial and apalutamide in the SPARTAN study.

Can you discuss the current AUA guidelines?

The current AUA guidelines for nonmetastatic CRPC is to continue with ADT. If the patients are not willing or do not accept those recommendations, then you can offer them a first-generation antiandrogen, such as bicalutamide, or a first-generation androgen synthesis inhibitor along with a steroid. The guidelines also are clear that they do not recommend chemotherapy or immunotherapy in those patients.

Can you speak to the importance of the apalutamide approval and the background of the study?

The SPARTAN trial was for nonmetastatic CRPC, where patients could have been clinically N0 or N1, which indicates that they may have had more advanced disease in that trial. This trial randomized patients to apalutamide with ADT or ADT alone. They found that OS endpoints were not met and the time of progression to metastatic disease was approximately 44 months compared with less than 1.5 years in the ADT group alone.

Apalutamide has also recently been added to the National Comprehensive Cancer Network guidelines. Can you discuss this?

Apalutamide is an interesting drug in that it is a next-generation androgen receptor inhibitor. It targets the receptor, the signaling cascade, and DNA, binding with fewer central nervous system toxicities.

What are some of the challenges that remain with apalutamide?

It will be interesting to see its efficacy when broken down into racial differentials to determine how effective it is in patients with different ethnicities. Furthermore, it will be interesting to see how it affects the cascade of drugs that typically follows and how it plays into that role.

Once patients have entered this space where previously docetaxel and abiraterone acetate (Zytiga) were never present before, it will be interesting to see how they affect subsequent outcomes and whether patients have been previously treated with those drugs or not.

What are some other agents that are now being explored in this setting?

Enzalutamide is the other major agent that was presented at the 2018 Genitourinary Cancers Symposium. They did a very similar design [to SPARTAN], except that was just in a nodal-negative [N0] and in an M0 population. They also had an increase in time to development of metastasis. It was not quite as long [as apalutamide] but still impressive. That is another drug that has shown efficacy in this space.

There are other drugs being explored. There is potential for PARP inhibitors and immunotherapies that are currently being explored, as well.

What are your thoughts on immunotherapy trying to make a breakthrough in this landscape?

Immunotherapy hit the prostate cancer market far too early. Sipuleucel-T [Provenge] was far ahead of the immunotherapy game when it was first developed and approved. We know from the approval of many other immunotherapies that PSA progression and evaluating outcomes purely based on PSA values can be misleading. For example, in PD-1/PD-L1 inhibitors, you will often see a response, but radiographically you will see the opposite. It is reasonable to expect that from immunotherapies as well, which is why I suspect that sipuleucel-T may not have been adopted early on.

The more recent immunotherapies have shown some efficacy, but that activity is limited in prostate cancer. There are some interesting viral gene transfection therapies that are currently in the very early stages of being explored that may have some potential.

Now that we understand how immunotherapies work and whether there is a flare phenomenon radiographically or by PSA, they may still be effective. We may be able to evaluate more important outcome markers, such as the MFS that the apalutamide and enzalutamide trials use as one of their primary endpoints.

What are the differences in treatment for a patient with nonmetastatic CRPC versus nonmetastatic castration-sensitive prostate cancer?

The difference with nonmetastatic castration-sensitive prostate cancer is that the treatment options [for that setting] have been standardized for a long time. ADT has been the mainstay of therapy. However, if a patient has CRPC, the difficulty is that the studies have not shown many effective treatment options until recently. They have looked at denosumab (Xgeva), which did not show any efficacy, and zoledronic acid, which showed a similar response.

With the newer imaging modalities, the question is whether a patient is really nonmetastatic. [Techniques such as] Gallium-68 PSMA (prostate-specific membrane antigen)—PET/CT scans identify metastatic disease when we did not think there was any. That is likely to change the nonmetastatic castration-sensitive and nonmetastatic CRPC playing fields. [For castration-sensitive disease], physicians should potentially use drugs from the STAMPEDE and LATITUDE trials.

The greater problem that this presents is that trials have been based on the same imaging diagnostic modalities. A large part of them have already been metastatic, so we are going to realize now that some of them are nonmetastatic. Should we look again at denosumab and zoledronic acid based on these new imaging modalities? I am not sure.

American Urological Association. Castration-resistant prostate cancer. American Urological Association website. auanet.org/guidelines/castration-resistant-prostate-cancer-(2013-amended-2015). Published 2013. Accessed March 22, 2018.

Small EJ, Saad F, Chowdhury S et al. SPARTAN, a phase 3 double-blind, randomized study of apalutamide (APA) versus placebo (PBO) in patients (pts) with nonmetastatic castration-resistant prostate cancer (nmCRPC). 

2018;36(suppl 6s;abstr 161). ascopubs.org/doi/abs/10.1200/JCO.2018.36.6_ suppl.161.

Hussain M, Fizazi K, Saad F, et al. PROSPER: a phase 3, randomized, double-blind, placebo (PBO)-controlled study of enzalutamide (ENZA) in men with nonmetastatic castration-resistant prostate cancer (M0 CRPC). 

. 2018;36(suppl 6S;abstr 3). ascopubs.org/doi/abs/10.1200/JCO.2018.36.6_suppl.3.

Mark J. Mann, MD, discusses the developing treatment landscape for patients with nonmetastatic castration-resistant prostate cancer.

Promising Developments Spark Excitement in Nonmetastatic CRPC Treatment

Precision medicine is vital in delivering optimal and individualized care for patients with HER2-positive breast cancer.

Specifically, this type of approach was investigated in the NSABP B-47 trial, which aimed to determine the value of trastuzumab (Herceptin) plus standard adjuvant chemotherapy in patients with low levels of HER2 protein. This trial’s findings showed no significant efficacy, demonstrating the importance of targeting treatments for patients based on their genetic mutations, explained Mothaffar Fahed Rimawi, MD, in an interview during the 2017 San Antonio Breast Cancer Symposium (SABCS).

In the NSABP B-47 study, which was presented at the meeting, results showed that the 5-year invasive disease-free survival rate was 89.6% among the 1640 patients who received trastuzumab and 89.2% among the 1630 patients who did not (95% CI, 0.77-1.26; 

 = .9). Investigators said the findings were no different whether patients were subdivided by HER2 immunohistochemistry level, extent of lymph node involvement, or hormone receptor status.

Rimawi, associate professor, Baylor College of Medicine, medical director and director of clinical research at Baylor's Lester and Sue Smith Breast Center and the Smith Clinic/Ben Taub Hospital, and co-leader of the breast program at Baylor's Dan L. Duncan Cancer Center, discussed the significance of precision medicine in HER2-positive breast cancer, as well as the possible role of immunotherapy for this specific population.

 What is the importance of precision medicine in HER2-positive breast cancer?

[At SABCS] I discussed the research that is shedding light on HER2-positive breast cancer, including mechanisms of resistance, sensitivity, and the efforts to tailor treatments to the individual patient.

I moderated 2 sessions where a panel of experts received challenging cases from the audience and provided treatment recommendations based on the latest available evidence. These contributions show the strength of this [medical] meeting, where science and clinical medicine come together to push forward patient care by utilizing the best possible care models and the best science.

From your perspective, what was the most exciting advancement in the field of breast cancer in 2017?

It is hard to pinpoint 1 thing. In my opinion, the most impressive thing about breast cancer is the incremental improvement in patient outcomes that have been ongoing year after year. Although a small increment does not sound exciting, when you add those up with different treatment modalities for years, we are seeing the mortality from breast cancer going down and women are living longer, healthier lives. 

You see 3 different levels of improvements or achievements. One involves very robust meta-analyses where clinical trials from all over the world pool their data together. When that happens, there are 10,000 women treated with similar treatments and followed for 10 to 20 years. Powerful data have shown us that giving patients the treatments that we know work, such as chemotherapy for higher-risk patients and endocrine therapy for estrogen receptor (ER)-positive patients, are continuing to make a difference in the lives of women. We know that giving the chemotherapy on a more dose-dense schedule has robustly demonstrated to improve outcomes for these patients. The power of collective knowledge is one area of achievement. 

The other area is the strength that we are seeing in precision medicine. Multiple trials have reported showing that we need to target the right treatment to the right person. The NSABP B-47 trial that was reported at SABCS sought to determine whether anti-HER2 therapy with trastuzumab would be beneficial to women who have lower levels of HER2 expression.

This trial would be considered negative under clinical standards but, the question was, “If they have some level of HER2 expression, would they benefit from anti-HER2 treatment?” This trial showed conclusively that it is not the case. You need to target anti-HER2 treatment to those who are HER2-positive and extending a treatment that works well for 1 group of patients to other patients may not work. That is a win for precision medicine and for the idea that it is important to tailor treatment to the patients.

The third area that is exciting is we are still seeing a robust flow of data from new agents that are in development. We are seeing many trials focusing on the immune system and how to best stimulate it or reprogram it to fight cancer with a lot of promise. There are many other agents for other pathways that are being explored. We need to understand the biology of the tumor and the patient, and then focus the treatment that way. Hopefully, those achievements will continue year after year.

Moving forward, what role will immunotherapy have in the treatment of patients with HER2-positive breast cancer?

The idea of using, or reprogramming, the immune system or stimulating it to fight cancer has been a dream that many people were following. The introduction of checkpoint inhibitors in many cancers over the last few years has been making a difference for the treatment of patients with cancer.

In breast cancer, there has been a robust interest in the immune system and immuno-oncology agents. Due to the clinical unmet need in triple-negative breast cancer, there is a focus of immunotherapy there because, biologically, those tumors have a higher mutational load and are more immunogenic. There is also interest in other subsets of breast cancer like ER-positive breast cancer.

There is going to be a role for immunotherapy for HER2-positive breast cancer. There are many agents that are being studied in several settings and in combination with other agents. We will see that there is a subset of patients with breast cancer who benefit from immunotherapy. Who those patients are with HER2-positive disease is something that remains to be determined based on our understanding of the biology and the impact the treatment is making. I am optimistic that the future of immune-oncology is bright. 

Fehrenbacher L, Cecchini RS, Geyer CE, et al. NSABP B-47 (NRG Oncology) phase III RCT comparing adjuvant chemotherapy ACweekly paclitaxel (WP) or TC x 6 with or without trastuzumab for 1 year in high-risk, invasive breast cancer, negative for HER2 by ISH and with IHC 1+ or 2+ (HER2-Low IBC). Presented at: SABCS; December 5-9, 2017; San Antonio, Texas.

Mothaffar Fahed Rimawi, MD, explains the importance of targeting treatments for patients with low levels of HER2 protein based on their genetic mutations, and the possible use of immunotherapy for these patients.
 

Precision Medicine in HER2+ Breast Cancer Treatment Is Essential

Combination regimens, like combining checkpoint inhibitors with chemotherapy, continue to gain interest for the treatment of patients with squamous non—small cell lung cancer (NSCLC).

Beyond the May 2017 FDA approval of pembrolizumab (Keytruda) plus carboplatin/pemetrexed for nonsquamous patients regardless of PD-L1 status, researchers are turning their focus to immunotherapy combinations in squamous patients in ongoing clinical trials. For example, the randomized, open-label, phase III IMpower131 study is evaluating the safety and efficacy of atezolizumab (Tecentriq) in combination with carboplatin/paclitaxel or carboplatin/nab-paclitaxel (Abraxane) versus carboplatin/nab-paclitaxel in chemotherapy-naïve patients with stage IV squamous NSCLC (NCT02367794). The trial, which has a primary endpoint of progression-free survival, is expected to enroll 1021 patients.

This immunotherapy plus chemotherapy combination is one of many being studied in squamous NSCLC. “Immunotherapy is a new option for patients and is well established,” said George R. Blumenschein, MD. “We are refining how we use it. There will be a number of additional refinements as we have the new data that will be coming forward in the next few months.”

at the 2017 State of the Science SummitTM on Advanced Non—Small Cell Lung Cancer, Blumenschein, a professor in the Department of Thoracic/Head and Neck Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, discussed the current treatment landscape for patients with squamous cell lung cancer.

What did you highlight in your presentation on advanced squamous cell carcinomas?

Blumenschein: I spoke about the current state of affairs regarding immunotherapy for the advancement of patients with squamous cell carcinoma of the lung. I touched on strategies for identifying patients, the activity of the approved compounds in the space, as well as potential future approaches to refine selection of patients for therapies with immunotherapy. 

How do you determine the sequencing of treatments for these patients?

In terms of the standard of care, what we do when patients present with newly diagnosed metastatic disease is we take into account the patient’s comorbidities. Are they candidates for immunotherapy? We also look at their PD-L1 status and whether that patient will be able to receive pembrolizumab or another option.

If their comorbidities preclude treatment with immunotherapy, or they do not have the 50% tumor proportion score, then patients should review systemic chemotherapy [options]. Subsequently, for second-line therapy—provided they have no medical contraindications&mdash; patients can receive 1 of the 3 approved immunotherapy agents.

Is there potential for durvalumab (Imfinzi) to play a role in squamous cell carcinoma?

Currently, it is not playing a role; although, it has recently had positive news in the adjuvant setting after patients receive concurrent chemoradiation for locally advanced NSCLC. Based on that data, I anticipate it will be utilized in that setting. There are a number of other ongoing trials with it in combination with a CTLA-4 inhibitor. We will see [what the data show], as it may become a compound that is utilized in combination in NSCLC.

What is the current unmet need for patients with squamous NSCLC?

The most pressing unmet needs are options for patients who cannot get immunotherapy. Another unmet need is the management of patients who have progression on immunotherapy and the various tyrosine kinase inhibitors for the different translocations or mutations. How do we best serve them to continue to provide a high-level of benefit from these compounds?

Is the future of immunotherapy likely to be with combinations?

Immunotherapy is being inserted into various spaces in NSCLC and in numerous combinations, whether they are immunotherapy plus immunotherapy combinations or chemotherapy plus immunotherapy regimens. Different types of checkpoint inhibitors are being studied as single agents, as well.

Another question is, “How do you help with the populations that are currently not considered candidates for immunotherapy?” There will be a number of different studies that will be reported over the next 12 months in the frontline space. These will look at immunotherapy combinations, as well as chemotherapy plus immunotherapy combinations that will hope to answer this question. There will be a shift toward more utilization of immunotherapy in the frontline setting if these studies are positive—as we hope they will be. 

“Immunotherapy is a new option for patients and is well established,” said George R. Blumenschein, MD. “We are refining how we use it. There will be a number of additional refinements as we have the new data that will be coming forward in the next few months.”

Expert Examines Immunotherapy's Role in Squamous Cell Lung Cancer

Following the FDA approval of high-intensity focused ultrasound (HIFU) for prostate tissue ablation, there are ongoing clinical trials attempting to determine how effective the technology can be for the treatment of patients with prostate cancer, explains Jonathan Warner, MD.

“Are there ways that we can optimize the cure rates with HIFU? When are people recurring? What are we missing when they recur? What are the true rates of complications? We do not know the answer to most of these questions,” Warner adds.

There is currently an ongoing phase II/III European trial (NCT022651590) attempting to evaluate cancer control and general overall health-related quality-of-life outcomes and effectiveness of HIFU for patients with localized prostate cancer. This trial, which is expected to be completed in 2020, is evaluating the proportion of men who are free of clinically significant prostate cancer 36 months after focal therapy with HIFU.

Researchers are exploring novel approaches with cryotherapy and focal therapy. In addition, with the implementation of the active surveillance and novel agents for more aggressive disease, the roles of surgery and radiation therapy could be changing.

In an interview during the 2017 OncLive® State of the Science Summit on Genitourinary CancersTM, Warner, an assistant professor in the Division of Urology and Urologic Oncology, Department of Surgery, City of Hope, discussed the evolving role of surgery and radiation therapy in the treatment landscape for patients with prostate cancer.

What are some of the side effects of local definitive therapies for prostate cancer? 

Warner: If we look at the 2 curative therapies for prostate cancer, radiation and surgery have been the long-term options available for patients. The primary side effects that come with surgery are erectile dysfunction and urinary incontinence. When a patient has surgery and they suffer from one of those consequences, the outcomes and the treatments are very predictable.

When you have radiation for prostate cancer, whether that is in the salvage setting or as a primary modality, unfortunately, the nature of the radiation creates a lot of unpredictability as far as the treatment options go. 

For example, for urinary incontinence, if a patient has had an operation and the prostate is removed, many patients can be cured or improved with a male sling procedure, which is a non-manipulated device that helps them restore their continence. However, in the radiated patients, the slings are just not as successful. Only about 50% of men will have some improvement.

Another big part of my practice is with strictures after radiation therapy. Again, this can be either from a patient who has had a prostatectomy and then had to undergo salvage radiation therapy or a patient who had primary radiation therapy. This comprises about 25% of my practice. It can be a devastating problem, since sometimes we must remove the whole bladder when these complications occur. Again, the treatment options are there but they are unpredictable as far as the success rates go. 

Some people are doing focal therapies for prostate cancer either with HIFU or focal cryotherapy, which is when they freeze the lesion that is found on the MRI. We are stepping into new realm of treatments that are going to develop into new complications. Firstly, with HIFU, the cure rates are not quite as good as the first 2 therapies that I mentioned. We are seeing a lot of recurrences and those patients need to face a decision about what to go through, whether that is removing the prostate or radiation therapy. Most of these patients are surgery averse, so they often go to radiation therapy. We compound the effects and the patients often have worse complications.

With cryotherapy, we see a lot of fistula formations, which are holes between the rectum and the prostate that develop after cryotherapy. Those can be devastating complications with significant risks that are difficult to repair. 

Are there ongoing trials with focal therapy looking to further explore the treatment?

There are trials actively ongoing. The biggest change that has happened with focal therapy is the advent of MRI. MRIs have been around for a long time, but the new protocols that are utilized have allowed us to isolate significant lesions found on prostate cancers. 

There are trials attempting to localize steam therapy to the region of prostate cancer. They are looking at focal therapy with cryotherapy, so they will freeze the area where the lesions are identified. We can use those MRIs to focus on the areas where the lesions are seen. Again, we are probably going to miss some of the cancer, but the MRI will show us the most aggressive cancers. It might not show us all of the low-grade cancers, but the low-grade cancers are not usually the ones that cause the problems. There are active trials in those areas, as well as with HIFU, since it has achieved FDA approval status.

What questions are the HIFU trials trying to answer?

Now that it has reached FDA approval, people are trying to see how useful it will be. We do not know the answer to most of these questions. Many patients left the United States to get their treatments and have come back. We do not know what the long-term complications will be.

With the introduction of active surveillance, what will be the role of surgery moving forward?

My hope is that we will see less prostate cancer surgery and radiation. MRIs have helped us identify whether the cancer is significant, which has been useful. Genomic markers are groundbreaking. Analyzing prostate biopsy tissue and analyzing patients’ blood are ways that we are going to detect those genes that are more or less aggressive.

Prostate cancer, at baseline, is a slow-growing process. There is obviously the collection of patients who have an aggressive cancer and we need to figure out how to find those that need treatment versus those that can be observed. We are making headway and we have made improvements over the last several years, but there is still a long way to go. 

How do you determine when a patient should receive surgery or radiation therapy?

Half of my practice is devoted to radiation complications. I am clearly biased against radiation. Patients need to make this decision, but they should be well educated. The complications of radiation tend to develop years down the road. Many people do not realize that 5 or 10 years [after therapy] is when we are starting to see the complications of radiation. We need to prepare patients for that and help the younger patients understand that, if they receive radiation, there are going to be issues down the road. We need to focus our efforts on younger patients to move away from radiation. Hopefully, through education, we can make sure people understand what the consequences are.

Is there anything else you would like to add regarding surgery for prostate cancer?

There are side effects from radiation and surgery for prostate cancer treatment, but it is important to recognize that we can treat those side effects. The first goal is curing cancer and then we can deal with any of the complications. I do not think patients should let the worry of urinary incontinence or erectile dysfunction guide their decision. We can fix those problems. It is important to focus on whether the patient needs treatment and, if they do, then we will help with the complications.

“Are there ways that we can optimize the cure rates with HIFU? When are people recurring? What are we missing when they recur? What are the true rates of complications? We do not know the answer to most of these questions,” says Jonathan Warner, MD.

Expert Discusses Treatment Options for Prostate Cancer

Medicine is becoming more personalized for patients with breast cancer as physicians continue to understand both the disease itself and genomic testing that can lead to more optimal treatment plans.

Francisco J. Esteva, M.D., Ph.D. discussed genomic testing at the 16th Annual International Congress on the Future of Breast Cancer® (East).

In an interview during the meeting, Esteva, a professor in the Department of Medicine at NYU Langone Medical Center, discussed the clinical implications of genomic testing for patients with metastatic breast cancer.

What are the clinical implications of genomic testing in breast cancer?

There are different technologies that are being used to profile both primary and metastatic breast cancer tumors including next-generation sequencing, circulating-free DNA in the plasma and other technologies looking at the microenvironment. In my presentation, I just focused on next-generation sequencing and liquid biopsies. 

The most important area right now in terms of research is the profiling of metastatic tumors. In breast cancer, there are not as many mutations in cancer-related genes as we have seen in other tumor types, such as melanoma or others where the mutational load is not as big.

In The Cancer Genome Atlas study published in 

a few years ago, they profiled 500 tumors and found that around 10 percent of all tumors had more than six mutations. Most tumors either had no mutations identified in the top-40 cancer-related genes or just had very few mutations. I don’t think we have the whole story about cancer drivers using genomic sequencing today. It is important information, but it remains a research tool to direct patients to clinical trials targeting those mutations.

These are all major challenges that we need to deal with. If we find a specific mutation, whether that mutation is a driver of the cancer or whether it is a passenger — meaning it is not driving the tumor phenotype &mdash; is still unclear. There are several examples where this technology may be useful in the future. We have found mutations in 

that may predict a response to Nerlynx (neratinib). For example, in one of the studies presented by Dr David Hyman at Memorial Sloan Kettering Cancer Center at the 2017 AACR Annual Meeting, findings demonstrated a promising approach to sequencing tumors.

 However, in that study, researchers looked at breast cancer and other types of cancers. In mostly breast cancer with 

 genome implication, they saw responses to Nerlynx. Not all mutations are the same, and not all mutations have the similar results in all tumor types as we may have thought. 

is another interesting gene where mutations have been associated with a better prognosis in breast cancer. The question is, “Can we use them to predict response to PI3K inhibitors or mTOR inhibitors?” To date, the data are inconclusive.

Another thought is the estrogen receptor (ER) mutations that may predict responses to different types of endocrine therapies, such as Faslodex (fulvestrant) compared with aromatase inhibitors. There are studies also looking at Faslodex versus CDK 4/6 inhibitors, such as Ibrance (palbociclib), suggesting that they do not predict [responses with] CDK 4/6 inhibitors, but they may be predictive of response to some of the basic endocrine therapies. 

That research applies more to the liquid biopsies where we have been able to find mutations in circulating-free DNA in the plasma, which may be predictive but it is still an area of investigation. 

What are the current guidelines for genetic testing?

In patients with metastatic breast cancer, the biomarkers we always test for are ER, HER2 and perhaps 

. Now, since we are more interested in identifying 

mutations, it is standard of care — or at least recommended by national guidelines &mdash; to sequence the 

 genes in patients with triple-negative breast cancer in which the ER, progesterone receptor, and HER2 tests are negative.

Next-generation sequencing, meaning sequencing an entire tumor, is not recommended as a standard of care yet. It is done whenever possible, and especially at the major academic institutions, with the goal being to direct those patients to clinical trials—single-institution trials, big institutions, and also the National Cancer Institute (NCI) MATCH trial, for example. This is where there are more than 20 arms depending on the mutations identified, so patients may be directed to those trials. 

The NCI-MATCH trial screened about 10,000 patients with metastatic cancer of many types and they closed the screening step. Now, they are only allowing patients to enter those trials if sequencing is done by different laboratories. 

How are these genomic tests personalized for patients?

For patients with metastatic breast cancer, those tests are relatively easily accessible and available. There are many companies now where you can send them the tissue or the plasma, and they can look for mutations in the tissue or mutations in circulating-free DNA in the plasma. The question is, “What do you do with that information to be able to personalize these therapies?” That goes into the area of clinical utilities. Technology is ahead of the clinical utility of personalized medicine. We can identify mutations in tumors or in the plasma, but what we do with that information is not clear. That is why it is important to continue to use clinical trials. 

 In clinical trials available today, patients with ER-positive breast cancer were randomized to endocrine therapy with or without PI3K inhibitors or mTOR inhibitors. In some trials, particularly with the mTOR inhibitor Afinitor (everolimus), for example, 

mutations were prognostic, but not very predictive of response to the mTOR inhibitor. With PI3K inhibitors, there is a study that showed that those patients may respond better to a PI3K inhibitor in addition to the endocrine therapy. However, that inhibitor was too toxic. Therefore, we are now looking at more selective inhibitors, such as PI3K inhibitors. 

We need to continue to test those. I don’t think we are at the point to be able to personalize and use this information in the clinic—to select one therapy versus the other.

Over the last 15 years or so, we have been focused on protein coding genes. We even tend to focus on larger genomic testing, but each human cell has 20,000 genes—making it a large and complex system. There are thousands more noncoding genes, which we don’t know much about, and that is another area where we are trained to focus on if they are expressed, what they regulate, and what they do.

Additionally, we have the microenvironment, which relates to the immune system and many other things that are not directly in the cancer cell. We need to be able to understand all of this to truly develop personalized medicine in the future. 


Francisco J. Esteva, M.D., Ph.D. discussed genomic testing at the 16th Annual International Congress on the Future of Breast Cancer® (East).
 

Expert Discusses Genomic Testing in Breast Cancer

Robotic surgery has been moving into the treatment realm for patients with renal cell carcinoma (RCC) who are undergoing a partial nephrectomy, and the procedure has shown to have many benefits.

A patient can experience less pain, a quicker healing time and potentially more normal kidney function, due to the minimally invasive aspect of robotic surgery, according to Ketan K. Badani, M.D.

Danielle Bucco