UVA Cancer Center

Although the standard of care for muscle-invasive bladder cancer (MIBC) is well established, not enough patients are being treated with curative intent, according to Robert Dreicer, MD, MS. Now, Dreicer said, a new paradigm that includes neoadjuvant use of immune checkpoint inhibitors may be emerging, but the impact of fresh approaches in the neoadjuvant setting will hinge on whether clinicians and patients embrace change.

"The data that we [have] in the neoadjuvant setting has been known to us for 30 years, and the uptake broadly in the community has been problematic," said Dreicer, deputy director of the University of Virginia Cancer Center in Charlottesville. "But we are also moving into a new era, hopefully, of the management of urothelial cancer, which includes the neoadjuvant setting."

Dreicer discussed current and future approaches in MIBC during a presentation at NY GU 

 Interdisciplinary Prostate Cancer Congress

 and Other Genitourinary Malignancies hosted by Physicians’ Education Resource

, LLC, which was held as a virtual meeting due to the coronavirus disease 2019 pandemic. He also serves as director of solid tumor oncology in the division of Hematology/Oncology and is a professor of medicine and urology at the University of Virginia.

As it stands now, Dreicer said, there is a disconnect in the treatment of patients with MIBC. The standard of care for patients with MIBC is neoadjuvant cisplatin-based chemotherapy followed by radical cystectomy (RC). If patients are not eligible for cisplatin treatment, they should either proceed to RC or be enrolled in a clinical trial evaluating an immune-oncology therapy.

However, Dreicer cited a recent analysis by Ralph de Vere White, MD, and colleagues that detailed f indings from 2 studies showing that many patients do not receive the standard of care treatment. In 1 study involving 28,691 patients with MIBC in the National Cancer Database, where 80% of patients are treated in academic centers, 41.3% underwent RC, while 7.6% received definitive radiotherapy. Another study used information from the Surveillance, Epidemiology, and End Results Program database, which is more reflective of the general population, to examine care given to 3205 Medicare patients with stage II organ-confined nonmetastatic urothelial carcinoma. Of these patients, 21% underwent RC, whereas 51% received surveillance, resulting in 5-year overall survival rates of 42% and 14.5%, respectively.

The studies suggest a "significant undertreatment" of patients with MIBC, a population with a median age in the low- to mid-70s. "This underutilization of radical cystectomy is representative of perhaps not just an aging population but [also] a mindset about who can be managed with curative intent."

First-line treatment with cisplatin-based chemotherapy followed by RC was established through a phase 3 trial in patients with stage T2 to T4a MIBC who were randomized to receive RC alone or with 3 cycles of prior cisplatin-based chemotherapy of methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC).

Patients treated with the MVAC combination (n = 153) had a median overall survival of 77 months versus 46 months in the RC-alone arm (n = 154; 

 = .06). Those who received RC alone had a 33% greater risk of death than those in the MVACplus-RC group (HR, 1.33; 95% CI, 1.00-1.76). In addition, of the 126 patients in the MVAC group who underwent RC, 38% of the surgical specimens were pathologically free of cancer at the time of surgery; 85% remained alive at 5 years.

Findings from multiple studies conducted over the years confirm the absolute benefit of cisplatin-based chemotherapy is probably in the 10% to 15% range, Dreicer said. "The data have been available to us for 25 to 30 years. Despite that, its uptake broadly in both the community and, to some extent, within the academic medical centers has been less than perhaps we would like," he said. “We all recognize the challenges. There are concerns about tolerability; some-times, there are concerns about moving ahead rapidly with surgery."

Dreicer said any cisplatin-based chemo-therapy regimen is acceptable in patients who are fit to receive it. "This is a very lethal disease and even though neoadju-vant cisplatin-based chemotherapy is a modest benefit, a 5% to 15% improvement in survival is not modest if you are 1 of those 5% to 15% of patients," he said. "This is a well-trodden pathway; we know how to give this therapy safely and effectively, and it remains the standard of care until we evolve beyond that."

Evaluating Patients for Neoadjuvant Therapy

Patients who are deemed unfit for treatment with standard-of-care cisplatin meet 1 or more of the following criteria: Eastern Cooperative Oncology Group performance status of 2 or greater or a Karnofsky Performance Status Scale score of 60% to 70%, creatinine clearance less than 60 mL/min, grade ≥2 hearing loss, grade ≥2 neuropathy, and/or New York Heart Association Class III heart failure.

 Some academic centers are willing to treat patients with creatinine levels in the 50 mL/min range, sometimes with changes in cisplatin dosing, Dreicer said.

For patients who fit 1 or more of these criteria, immune checkpoint inhibitors may hold the most promise as future neoadjuvant treatment, according to Dreicer. Five agents that inhibit the PD-1/PD-L1 checkpoint are approved for patients with locally advanced or metastatic urothelial carcinoma; 1 of these drugs, pembrolizumab (Keytruda), is also indicated in patients with high-risk nonmuscle-invasive bladder cancer unresponsive to bacillus Calmette-Guérin therapy. Dreicer highlighted trials with the potential to change the neoadjuvant standard of care (

Table. Ongoing Phase 1/2 Trials Evaluating Neoadjuvant Therapy in MIBC

Atezolizumab (Tecentriq) is being examined as a neoadjuvant option in the phase 2 ABACUS trial (NCT02662309). Ninety-five patients received 2 cycles of atezolizumab at a dose of 1200 mg every 3 weeks. Regardless of PD-L1 status, the pathological complete response rate was 31% (95% CI, 21%-41%).

 In previously reported data of 68 patients, 39% of patients were downstaged to nonmuscle invasive disease.

“These are small studies, but they suggest that there is the potential for significant utility of checkpoint inhibitor therapy,” Dreicer noted. He added that some patients in the pembrolizumab study were eligible to receive cisplatin, making the decision whether to enroll participants in trials “somewhat controversial.”

“One of the questions that remains is whether or not the responders represent similar patients who might respond to cisplatin neoadjuvant therapy. If we identify the same group of patients who respond, we would still potentially be offering less-toxic therapy,” he said. “Our priority is identifying biomarkers to guide whether or not a chemotherapeutic neoadjuvant therapy is better for patient X versus patient Y, remains to be seen.”

The phase 3 ENERGIZE trial (NCT03661320) is an ongoing 3-arm study comparing chemotherapy with gemcitabine and cisplatin alone, in combination with the anti—PD-1 agent nivolumab (Opdivo) plus placebo, or with nivolumab plus linrodostat mesylate (BMS-986205), an IDO1 inhibitor. After neoadjuvant therapy, all patients will undergo RC, followed by similar adjuvant treatment for those in the 2 nivolumab arms. The combination of nivolumab and linrodostat showed a favorable safety and efficacy profile in heavily pretreated patients with advanced bladder cancer in a prior phase 1/2 study (NCT02658890).

These data are encouraging, Dreicer said, but he acknowledged that change to the standard of care is not going to occur overnight. “We’re going to look at new data that may change the paradigm and may make this a far less challenging kind of therapeutic intervention, but until that data become standard of care, we are left with what we need to do tomorrow. And what we need to do tomorrow is use cisplatin-based chemotherapy in the settings that we can.”

Dreicer noted that there are many unanswered questions about using immunotherapy regimens in the neoadjuvant setting. “All of these issues will present us with challenges, but they will be nice challenges to have, given the fact that we have not moved forward in a long period of time,” Dreicer concluded. “Neoadjuvant paradigm management is moving rapidly, hopefully to a new place.”

Dreicer R. Management of muscle-invasive bladder cancer. Presented at: 

); March 13-14, 2020; New York, NY.       

de Vere White R, Lara PN Jr, Black PC, Evans CP, Dall’Era M. Framing pragmatic strategies to reduce mortality from bladder cancer: an endorsement from the Society of Urologic Oncology [published online January 17, 2020]. 

Grossman HB, Natale RB, Tangen CM, et al. Neoadjuvant chemotherapy plus cystectomy compared with cystectomy alone for locally advanced bladder cancer. 

. 2003;349(9):859-866. doi: 10.1056/NEJMoa022148

Galsky MD, Hahn NM, Rosenberg J, et al. Treatment of patients with metastatic urothelial cancer "unfit" for cisplatin-based chemotherapy. 

 2011;29(17):2432-2438. doi: 10.1200/JCO.2011.34.8433

Sonpavde G, Necchi A, Gupta S, et al. ENERGIZE: a phase III study of neoadjuvant chemotherapy alone or with nivolumab with/without linrodostat mesylate for muscle-invasive bladder cancer. 

. 2020;16(2):4359-4368. doi: 10.2217/fon-2019-0611

Powles T, Kockx M, Rodriguez-Vida ALuke JL, et al. Clinical efficacy and biomarker analysis of neoadjuvant atezolizumab in operable urothelial carcinoma in the ABACUS trial. 

. 2019;25(11):1706-1714. doi: 10.1038/s41591-019-0628-7

Luke J, Tabernero J, Joshua A, et al. BMS-986205, an indoleamine 2, 3-dioxygenase 1 inhibitor (IDO1i), in combination with nivolumab (nivo): updated safety across all tumor cohorts and efficacy in advanced bladder cancer (advBC). 

 2019;37(suppl 7; abstr 358). doi: 10.1200/JCO.2019.37.7_suppl.358

The phase 2 PURE-01 trial (NCT02736266) is examining the benefit of neoadjuvant pembrolizumab in patients with MIBC who had residual disease after transurethral resection and are eligible for RC. A total of 50 patients received 3 cycles of pembrolizumab at 200 mg every 3 weeks prior to surgery. The pathological complete response rate, the primary end point, was 42% (95% CI, 28.2%-56.8%). Disease downstaging was also observed to clinical stage lower than T2 in 54% of patients (95% CI, 39.3%-68.2%), which Dreicer said is in the “ballpark of cisplatin.”

Articles

Although the standard of care for muscle-invasive bladder cancer is well established, not enough patients are being treated with curative intent.

Immunotherapy Regimens May Expand Use of Neoadjuvant Therapy in MIBC

Linda R. Duska, MD, professor of obstetrics and gynecology and gynecologic oncologist at the University of Virginia, discusses primary debulking surgery in ovarian cancer.

Primary debulking surgery has demonstrated improved overall survival for patients. However, the procedure can lead to surgical complications. For example, primary debulking surgery has been associated with an increased rate of surgical morbidity or mortality in some patients, says Duska.

As such, patient-related factors including performance status, serum albumin levels, BMI, and other medical comorbidities may lead a surgeon to discuss neoadjuvant chemotherapy with the patient as a less morbid alternative to surgery, concludes Duska.

Videos

Linda R. Duska, MD, discusses primary debulking surgery in ovarian cancer.

Dr. Duska on Primary Debulking Surgery in Ovarian Cancer

Linda R. Duska, MD, professor of obstetrics and gynecology and gynecologic oncologist at the University of Virginia, explains whether the Fagotti score provides an accurate assessment of whether a patient with newly diagnosed, advanced ovarian cancer can achieve a complete resection in surgery.

The Fagotti score can be useful in determining whether a patient with newly diagnosed, advanced ovarian cancer can undergo optimal debulking surgery in the hands of an experienced surgeon, explains Duska. However, it is not the sole way to assess resectability. A small laparotomy could be performed instead, in addition to performing imaging, a CT scan, a PET scan, or an MRI, says Duska.

Ultimately, resectability should be assessed by a trained gynecologic oncologist. Having a gynecologic oncologist involved in the care of women with advanced disease from the onset of treatment is important, says Duska. However, that is not always possible, especially in community practices where general surgeons or gynecologists are more likely to perform the surgery. When that happens, the patient’s likelihood of receiving an appropriate surgery decreases, concludes Duska.

Dr. Duska on the Utility of the Fagotti Score in Advanced Ovarian Cancer

Although upfront debulking surgery is standard for most patients with advanced ovarian cancer, neoadjuvant chemotherapy potentially offers a less morbid alternative for those who are ineligible for the procedure, said Linda R. Duska, MD.

"I know all of our patients want surgery because it feels like that's the right thing to do. But in some patients, a big surgery might actually be more harmful than helpful," said Duska. "We need to be honest with ourselves, and with our patients, about what we can and can't do. An older, frailer, sick patient may benefit from a neoadjuvant approach. It's important that we share the data with those patients so that they can make informed choices."

 State of the Science Summit™ on Ovarian Cancer, Duska, a professor of obstetrics and gynecology at the University of Virginia, discussed the ongoing debate between upfront surgery and neoadjuvant chemotherapy in ovarian cancer and the data that support both options.

 What trials have evaluated the use of neoadjuvant chemotherapy in ovarian cancer?

Most people would agree that upfront surgical debulking is the best option for most—but not all&mdash;women with ovarian cancer. However, some women may actually benefit from neoadjuvant chemotherapy as an alternative approach. There are 2 published, randomized trials&mdash;both of which have been critiqued for a variety of reasons&mdash;that suggest that in a certain population of women, neoadjuvant chemotherapy is equivalent to primary debulking surgery and may actually be less morbid.

Those studies enrolled women who are older, had bulkier disease, and had a poorer performance status than some of the other trials that we have done with primary debulking surgery. Therefore, this is a slightly different population than what we're used to looking at. There has been some criticism regarding the low debulking rates, depending on which study one is referring to. However, it's meaningful to know that a certain subgroup of women—for example, women with bulky stage IV disease&mdash;actually seem to benefit from neoadjuvant chemotherapy over primary debulking surgery.

Beyond bulky disease, what other features indicate that a patient may be better suited for neoadjuvant chemotherapy?

We know that primary debulking surgery has a higher rate of surgical morbidity, but again, this depends on the patient. There are certain patient factors that we can look at, such as performance status, serum albumin, body mass index, and the presence of multiple other medical comorbidities, among others. [These factors could] point to a likelihood of significant surgical morbidity and therefore might make a surgeon more likely to discuss neoadjuvant chemotherapy as a less morbid option with the patient in a shared decision-making way. Of course, we have to keep in mind that upfront surgical debulking has been shown to improve overall survival. The problem, however, is that if [a patient's] surgery is so morbid that [they're] never able to receive chemotherapy, or if [they] die from surgical debulking, then that did not help as we would have liked.

Does the Fagotti score provide an accurate assessment of whether or not a patient can achieve a complete resection in surgery?

That is a tough question; Fagotti would say, "Yes." In the hands of an expert who has used the Fagotti score a lot, it can be. Others would argue that perhaps there are better ways to assess resectability. You could do a very small laparotomy to assess this—not a big one, but a smaller exploration of the upper abdomen to make a decision. You can use imaging, CT scan, PET scan, or MRI; there are a whole variety of [tools] that you can use.

To me, it comes down to surgical judgment. This is why it's really important to have a trained gynecologic oncologist evaluating these patients in order to make an informed decision about whether or not a surgery would likely be successful. Having a gynecologic oncologist involved in the care of women with advanced disease from the beginning of their therapy is important.

It doesn't always happen. In the community, some women are operated on either by general surgeons or a gynecologist with general surgeons. We know that when that happens, the chance of [patients] having an appropriate surgery decreases. Therefore, ideally, if a patient is going to the operating room, she should go with a trained gynecologic oncologist who understands the complexity of the disease and knows how to perform these complex surgeries.

What efforts can be made to ensure that this happens?

That's a good question. One way that has been suggested is having all patients with ovarian cancer referred to centers of excellence. However, I'm not sure that this is always feasible for several reasons. Another way that we've managed to do this as a society in gynecologic oncology is to increase the number of fellowships, and to, at least in the United States, train more gynecologic oncologists to be able to take care of some of these women. I don't know what the solution is; [perhaps the answer lies in] education and training, and just ensure that patients know [about how important this is], so that they can be advocates for themselves.

What do you anticipate from the ongoing TRUST trial?

I worry that if it doesn't show that [primary debulking is superior to neoadjuvant chemotherapy], then we won't believe it for whatever reason. [I fear] that we'll criticize it or that we'll find something wrong with it. The people who believe that surgery is important, [also] believe that this study will show that primary debulking surgery is superior. Again, I do believe we have to be mindful of the populations of patients who get entered into these studies; there is investigator bias and patient bias. When we're applying the results of these studies [to practice], we have to remember to make sure that the patients in the trial are representative of those who are sitting in front of us.

What would you identify as the biggest remaining challenges in the field?

We need to ensure that women are seen by gynecologic oncologists. If that's possible, we will have an adequate surgical assessment and an appropriate surgery; that would be the first thing. Right now, we're not doing this across the board, at least in this country.

We don't have prospective randomized data supporting upfront debulking surgery; it's all retrospective and it's all biased because it is retrospective. I don't believe that we will ever have prospective data about [this approach]. However, I'm hopeful that when we get the results of the TRUST study, we'll add to the data that we already have to help us best advise our patients.

Linda R. Duska, MD, discusses the ongoing debate between upfront surgery and neoadjuvant chemotherapy in ovarian cancer and the data that support both options.

Neoadjuvant Chemo Safer Alternative for Certain Patients With Ovarian Cancer

Linda R. Duska, MD, professor of obstetrics and gynecology, University of Virginia, discusses neoadjuvant chemotherapy versus upfront surgical debulking in patients with advanced ovarian cancer.

Many physicians believe that upfront surgical debulking is the best option for most patients with ovarian cancer; however, research is showing that there are subgroups of patients who benefit from neoadjuvant chemotherapy, explains Duska. Some studies suggest that neoadjuvant chemotherapy is equivalent to primary debulking surgery and may be less morbid, according to Duska.

Two studies examining neoadjuvant chemotherapy versus upfront surgical debulking enrolled women who were older, had bulkier disease, and poorer performance status. Duska says this is a different patient population than typical studies, and these studies have been criticized for low debulking rates. However, these data show that a certain subgroup of patients, such as those with stage IV disease, seem to benefit from neoadjuvant chemotherapy over primary debulking surgery, concludes Duska.

Linda R. Duska, MD, discusses neoadjuvant chemotherapy versus upfront surgical debulking in patients with advanced ovarian cancer.

Dr. Duska on Neoadjuvant Chemo Vs Upfront Surgery in Ovarian Cancer

The National Colorectal Cancer Roundtable’s 80% by 2018 initiative has been publicized for several years as a commitment to improving colorectal cancer (CRC) screening rates among adults 50 years and older, and this initiative will continue beyond 2018. Approximately 1 of every 20 Americans will be diagnosed with CRC at some point in their life, and the American Cancer Society estimates that most CRC deaths can be prevented by screening. Screening has been shown to save lives both by decreasing the incidence of CRC via the detection and removal of precancerous polyps and by increasing the likelihood of survival, which involves identifying CRC at an earlier stage when treatment is usually more effective.

CRC screening is cost-effective. For the cost of treating 1 case of advanced CRC, hundreds or even thousands of people could be screened for this disease type. Screening for CRC is obviously the right thing to do, yet locally and nationally we are not meeting this goal. Improving the screening rate has been challenging for many organizations, including the University of Virginia (UVA). Why does something that sounds so simple require so much effort, and what makes that effort worthwhile?

As a nationally ranked health system that includes a National Cancer Institute—designated cancer center, the UVA Health System is committed to leading in this arena through the development and implementation of a robust CRC screening program. Our vision is a system that allows us to (1) consistently offer patients appropriate options for CRC screening, (2) educate patients and providers about CRC screening, (3) remove barriers to screening, and (4) ensure that patients are supported appropriately after screening occurs.

The logical place to begin was to determine which screening methods to include within our program. The American Cancer Society recognizes 6 different options for CRC screening. Offering patients different test options significantly increases adherence to CRC screening recommendations. A review of outcomes, risks, costs, and benefits of all screening methods led to our decision to build our program around 4 tests: fecal immunochemical (FIT), colonoscopy, computed tomography colonography, and multitarget stool DNA.

To increase awareness, our goal was to educate both patients and providers about the options for CRC screening, with an emphasis on informed and shared decision making. We created patient-friendly literature to educate patients on specific test options and the lifesaving benefits of CRC screening. These materials are available in print form, on our website, and through our electronic health record (EHR), to provide easy access for our patients and providers.

To further educate providers in our state, UVA Health System is partnering with the American Cancer Society to create a webinar focused on a review of the current guidelines and the pros and cons of various CRC screening options. The literature validates that education alone will not result in improved screening rates. Logistical and systems-based obstacles must be identified and reduced to realize a consistently effective program. Within our institution, we have identified several important barriers. These include variability in the use of the EHR and health maintenance tabs among different offices and specialties, prioritization and time constraints that prevent consistent discussion of CRC screening between the primary care provider (PCP) and the patient, lack of clarity about ordering specific screening tests, and absence of processes to ensure that ordered screening tests are completed.

Over the past year at UVA Health System, we have formed a multidisciplinary team to coordinate and support removal of these barriers, one by one. Physician and nursing leaders from our Cancer Center and Digestive Health, Radiology, and Primary Care departments formed a CRC screening steering committee with multiple projects aimed at addressing specific process gaps. Our initiatives include using the EHR to better identify unscreened patients; managing screening intervals using health maintenance tools; developing 1-stop referral access for CRC screening order sets that include all screening modalities, to ease the administrative burden on PCPs and creating standard processes to follow up on positive screening tests.

As further evidence of the institutional commitment to this mission, UVA recently hired a CRC screening navigator who is an integral member of our team. She met with members from each specialty to understand and optimize the processes involved in ordering, performing, and following up on each CRC screening test. She developed several initiatives at our institution, including an annual FluFIT program, which combines flu shots with CRC screening promotions; a service line competition for CRC screening; and special March Colorectal Cancer Awareness Month activities. In addition, she actively promotes CRC screening at community health-focused events and has provided education and outreach to large area employers. As our CRC screening program expands, we plan to enhance patient-specific navigation by assisting with scheduling screening tests, reminding patients of their next screening interval, and initiating consults with colorectal surgeons and oncologists.

Although the initiatives mentioned above focus on improving screening for the population in the UVA Health System, there are other significant barriers to CRC screening in our region and state. These include lack of health insurance, poor access to regular-care providers, remote geographic locations, and educational and cultural barriers. Uninsured and underserved populations deserve special attention within a CRC screening program because failure to screen will result in a higher incidence of advanced CRC in these groups. Our strategies to reach these individuals include seeking grants to financially support affordable, simple, accessible FIT screening; partnering with regional organizations that serve specific uninsured and underserved communities; and uniting with other healthcare institutions to create pathways to screening.

Screening for CRC is an obvious need, but it requires a strategic plan to be successful. What is your organization doing to improve CRC screening rates? By asking that simple question, you can start the process to save lives.

Approximately 1 of every 20 Americans will be diagnosed with colorectal cancer at some point in their life, and the American Cancer Society estimates that most colorectal cancer deaths can be prevented by screening.

UVA Screening Program Seeks to Get Ahead of Colorectal Cancer

Ryan D. Gentzler, MD, assistant professor, Division of Hematology/Oncology, University of Virginia Health System, discusses combination therapies in non—small cell lung cancer (NSCLC).

Multiple combinations of immunotherapy and chemotherapy have been looked at, explains Gentzler. The KEYNOTE-189 trial looked at pembrolizumab (Keytruda) plus chemotherapy in patients with nonsquamous NSCLC and showed a survival benefit with the addition of pembrolizumab. The KEYNOTE-407 trial was a similar study that enrolled patients with squamous cell lung cancer that looked at platinum-doublet chemotherapy plus pembrolizumab. That study also showed a survival improvement. The combination of chemotherapy plus atezolizumab (Tecentriq) plus bevacizumab (Avastin) has also shown an improvement in overall survival compared with chemotherapy alone, notes Gentzler.

Physicians also have data from immunotherapy combinations. The CheckMate-227 trial compared ipilimumab (Yervoy) and nivolumab (Opdivo) with chemotherapy alone in a subset of patients who have a high tumor mutational burden. The trial showed an improvement in progression-free survival (PFS) with the combination. The CheckMate-227 trial had multiple arms, and one of the subsets that was looked at was the low PD-L1 expression group in which chemotherapy plus nivolumab was compared with chemotherapy alone. There was also an improvement in PFS within that comparison group, adds Gentzler.

Ryan D. Gentzler, MD, assistant professor, Division of Hematology/Oncology, University of Virginia Health System, discusses combination therapies in non–small cell lung cancer (NSCLC).

Dr. Gentzler on Combination Therapies in NSCLC

The heterogeneity of stage III NSCLC means there is not a one-size-fits-all strategy for patients. Rather, a multidisciplinary approach is required to optimally utilize the available tools of chemoradiation, immunotherapy, and surgery.

“We’ll have to figure out how to leverage all the benefits of all those therapies and time them appropriately [versus] a magic bullet or monotherapy that works well for these [patients],” said Dustin M. Walters, MD.

Exciting new data continue to expand the treatment options available for these multidisciplinary strategies. For example, following the readout of the PACIFIC trial, the use of durvalumab (Imfinzi) after chemoradiotherapy became a standard option in the treatment paradigm for patients with unresectable stage III NSCLC. Results of the study demonstrated an 11.2-month improvement in progression-free survival (PFS) with durvalumab versus placebo (16.8 vs 5.6; HR, 0.52; 95% CI, 0.42-0.65; 

 <.0001). The 18-month PFS rate was 44.2% compared with 27.0% in favor of the durvalumab arm.

Additionally, a clinical trial expected to open in October will examine the PD-L1 inhibitor in a phase II, single-arm study (NCT03589547). Patients with locally advanced stage III NSCLC will receive chemoradiation followed by concurrent durvalumab and consolidative stereotactic body radiation therapy. The trial has an estimated completion date of October 2025.

: What is the approach to treating stage III NSCLC?

 State of the Science Summit™ on Advanced Non—Small Cell Lung Cancer, Walters, assistant professor of Thoracic and Cardiovascular Surgery, University of Virginia Health System, provided perspective on the treatment landscape of stage III NSCLC.

: In general, stage III NSCLC is a pretty challenging disease. It's the most heterogeneous of all the stages that we deal with. Early-stage is very straightforward, and stage IV lung cancer is pretty straightforward. Stage III really necessitates a true multidisciplinary approach.

At the University of Virginia, that means a team of radiation oncologists, medical oncologists, surgical oncologists, radiologists, and pathologists. Everyone gets together, we discuss these patients, and we try to determine the best individualized treatment plan for them.

I looked at the context of the PACIFIC trial and how that changes the treatment landscape for stage III lung cancer. PACIFIC was a randomized phase III study that looked at patients who were surgically unresectable with stage III disease. About half of patients had stage IIIa disease and half had stage IIIb disease. It looked at the effects of durvalumab, which is a PD-L1 antibody on survival; it showed a pretty nice benefit in PFS. The overall survival data aren’t quite out yet.

What does the multidisciplinary approach at the University of Virginia look like?

Who is making sure that those approaches are carried out?

What is the role of chemoradiotherapy for these patients?

Is there potential for neoadjuvant immunotherapy?

What does the future hold for stage III disease?

Are these therapies going to be equal players?

A lot of folks have interpreted that trial [by questioning] the role of surgery moving forward. Most of us still think there is a pretty good role for surgery for these patients. The ultimate outcome is to cure these folks, and surgery will play a huge role, particularly for stage IIIa patients.

We have a weekly tumor board that meets every Tuesday morning. We try to discuss every lung cancer case that is brought to all of our clinics, but certainly all of the very challenging cases. The cases are presented, and everyone gives their opinion. We come up with a consensus recommendation. It's really an individualized approach. We take everything into account, such as the stage of disease, the patient themselves, what they want, and what the options are. Based on that, we try to come up with as close of a consensus as we can.

If it's one of my patients that I'm presenting, we'll discuss and come up with a consensus. I'll call the patient, and we will talk about what the different options are and what our recommendations are. Then we’ll decide, in conjunction with the patient, how to move forward.

Certainly, for all stage III patients, chemoradiotherapy is one of the major parts [of treatment] regardless of whether they’re going to have surgery, durvalumab, or other therapy. For resectable patients, our typical approach is to give them induction chemoradiation, restage them, and then operate on them. For unresectable patients, they get definitive chemoradiation in conjunction with durvalumab.

Absolutely. In fact, we just got approval for a clinical trial here at the University of Virginia. We expect it to open in the next 1 to 2 months. It's a phase II, single-arm study where folks are going to get induction chemoradiation with durvalumab. Then, they will get restaged, have surgery, and then get consolidation durvalumab for 1 year afterwards.

It's going to be defining the real role of surgery, particularly in light of immunotherapy. Most of us at the University of Virginia—and most oncologists in general&mdash;will agree that the best approach is going to be some combination of chemoradiation, immunotherapy, and surgery.

That is hard to say. I don't foresee any of those therapies being effective as monotherapy. The multimodality approach is going to be the best for these patients who need local control of their disease. The only options there are radiation and surgery. [Patients] also need systemic therapy because if they have metastasized to lymph nodes, we expect that they have micrometastases and circulating cancer cells.

Antonia SJ, Villegas A, Daniel D, et al. Durvalumab after chemoradiotherapy in stage III non—small-cell lung cancer. 

. 2017;377(20):1919-1929 doi: 10.1056/NEJMoa1709937.

Dustin M. Walters, MD, provides perspective on the treatment landscape of stage III non–small cell lung cancer.

Expert Explains Successes, Challenges in Stage III Lung Cancer

Although immunotherapy and targeted agents are revolutionizing the treatment paradigm in metastatic non—small cell lung cancer (NSCLC), chemotherapy retains a vital role for the majority of patients, according to Ryan D. Gentzler, MD.

“The data that we have now suggest that chemotherapy plus immunotherapy is the only combination strategy we have that has shown an overall survival (OS) improvement. The chemotherapy backbone is still an important one for patients,” said Gentzler.

 and presented at the 2018 AACR Annual Meeting, the first-line combination of pembrolizumab (Keytruda) with standard chemotherapy reduced the risk of death by more than 50% in patients with nonsquamous NSCLC without 

 mutations in the phase III KEYNOTE-189 trial.

In the study, patients were randomized to frontline pembrolizumab or placebo in combination with pemetrexed and either cisplatin or carboplatin. The estimated 12-month OS rate at a median follow-up of 10.5 months was 69.2% (95% CI, 64.1%-73.8%) in the pembrolizumab arm versus 49.4% (95% CI, 42.1%-56.2%) in the control arm (HR, 0.49; 95% CI, 0.38-0.64; 

 <.001). Notably, an OS benefit was seen regardless of PD-L1 status. The median PFS was 8.8 months (95% CI, 7.6-9.2) versus 4.9 months (95% CI, 4.7-5.5) in the pembrolizumab and placebo arms, respectively (HR, 0.52; 95% CI, 0.43-0.64; 

In August 2018, the FDA granted a full approval to the combination based on these phase III data. However, Gentzler explained that there are patients with NSCLC who may benefit from combination immunotherapy, such as nivolumab (Opdivo) and ipilimumab (Yervoy) as seen in the CheckMate-227 trial. Until physicians see greater standardization of biomarkers such as tumor mutational burden (TMB), the decision of which combination to use should be individualized to each patient, he added.

: Does chemotherapy have a role in the frontline treatment of metastatic NSCLC?

 on Advanced Non—Small Cell Lung Cancer, Gentzler, assistant professor, Division of Hematology/Oncology, University of Virginia Health System, highlighted how chemotherapy remains a critical component of the metastatic NSCLC treatment paradigm.

: This has been an evolving field, particularly in the last several years—maybe even just the last 6 to 12 months. The theme of my talk was what role chemotherapy has in our treatment of this disease. There has been a lot of progress in the last decade or so of moving away from chemotherapy. We've now identified multiple oncogenic driver mutations that exist in lung adenocarcinoma [that we’re] able to successfully pair a targeted therapy to. We have been able to delay the need for chemotherapy in a large portion of patients.

More recently, we have identified that immunotherapy can be quite effective in the rest of the population. This includes those who were smokers and those who don't have these oncogenic driver mutations. Our hope has always been that we can get away from cytotoxic chemotherapy and the side effects that come along with those treatments and replace it with a single-agent tyrosine kinase inhibitor or an immunotherapy drug.

What chemoimmunotherapy combinations are we looking at? 

What we found in the data that have been released over the last year or so is that chemotherapy still seems to have an important role. When we add chemotherapy to an immunotherapy regimen it seems as though there may be a better chance of response or a longer duration of response. Several studies have looked at chemotherapy as a backbone with immunotherapy. Now, trials are showing OS improvement by adding PD-1/PD-L1 drugs to standard chemotherapy.

There are several immunotherapy/chemotherapy combinations that have been looked at. The KEYNOTE-189 trial looked at pembrolizumab plus chemotherapy. There was a similar trial that was for patients with squamous cell lung cancer that looked at platinum-doublet chemotherapy plus pembrolizumab; that was the KEYNOTE-407 trial. That study also showed a survival improvement in that group. There has been a combination of chemotherapy plus atezolizumab (Tecentriq) plus bevacizumab (Avastin) that has also resulted in an OS improvement compared with chemotherapy alone.

How will you decide which combination to give? 

We have data from immunotherapy combinations, such as ipilimumab and nivolumab, that have been compared with chemotherapy alone, particularly in a subset of patients who have a high TMB. That was the CheckMate-227 trial, which showed an improvement in PFS with the combination. The CheckMate-227 trial had multiple arms, and one of the subsets that was looked at was the low PD-L1 expression group in which chemotherapy plus nivolumab was compared with chemotherapy alone. There was also an improvement in PFS within that comparison group.

The data that we have now suggest that chemotherapy plus immunotherapy is the only combination strategy we have that has shown an OS improvement. The chemotherapy backbone is still an important one for patients. Certainly, in subsets of patients who may have PD-L1—negative or TMB-high tumors, there may be a role for combination immunotherapy. However, that regimen has not been compared head-to-head with chemotherapy plus immunotherapy with an OS endpoint.

There are also patients with high PD-L1 status at ≥50%. Data from the KEYNOTE-024 trial showed a consistent OS benefit with pembrolizumab alone versus chemotherapy [in this population].

The side effects that are associated with chemotherapy plus immunotherapy are largely additive side effects rather than synergistic. You get all of the traditional side effects from platinum-doublet chemotherapy, and you have side effects from single-agent PD-1/PD-L1 inhibitors. Most of the time, those are not overlapping toxicities. A lot of this is what we are accustomed to with chemotherapy. You add on some additional side effects with immune-related adverse events (irAEs).

What is the biggest challenge you have encountered? 

The combination of nivolumab and ipilimumab is similar to the side effects that we see with single-agent PD-1/PD-L1 inhibitors, except they occur at a much higher frequency. Therefore, with that combination, we are looking at irAEs. Things such as colitis and pneumonitis occur at a little bit of a higher frequency than with single-agent immunotherapy. When you give that regimen, you don’t have any of the hematologic toxicity that we see with chemotherapy.

One of the challenges is that TMB is not a well-standardized and readily available test that can be turned around in a fast enough time for most patients. If it takes 3 to 4 weeks to get those results, sometimes patients need to get started on treatment before that. That is one limitation with using first-line ipilimumab/nivolumab.

One of the challenges that we have with all of these new chemotherapy and immunotherapy regimens is knowing which to choose for an individual patient. If a patient has an intermediate PD-L1 status and an unknown or low TMB status, should they get chemotherapy plus pembrolizumab or should they get ipilimumab/nivolumab if they have a high TMB and high PD-L1 [expression]?

What clinical trials or combinations are you looking forward to hearing about?

Will chemotherapy have a role in the treatment paradigm 10 years from now?

Even in the high PD-L1 expression group, there are some patients who may derive some benefit from getting chemotherapy plus pembrolizumab. We saw that with the KEYNOTE-189 trial, in which there appears to be a response rate of 60% compared with the KEYNOTE-024 response rate of 45%. Individualizing all of these options for a specific patient is a challenge. Is the patient highly symptomatic and needs the best chance of response upfront? Or, do they have more time to wait and try a monotherapy regimen that has a lesser chance of responding upfront but has the same durability?

I'm anxious to see the OS results from the CheckMate-227 trial. If we can show that TMB [determines that using an immunotherapy combination] improves OS, that would make that regimen much more appealing.

I'm hopeful that other combinations [will come forward], whether it's immunotherapy combinations or targeted therapy plus immunotherapy combinations so we can continue to save the side effects of chemotherapy for a larger proportion of patients. There will be subsets of patients where even chemotherapy alone will still be an important tool in our armamentarium.

Gandhi L, Rodgríguez-Abreu D, Gadgeel S, et al. KEYNOTE-189: Randomized, double-blind, phase 3 study of pembrolizumab (pembro) or placebo plus pemetrexed (pem) and platinum as first-line therapy for metastatic NSCLC. In: Proceedings from the 2018 AACR Annual Meeting; April 14-18, 2018; Chicago, Illinois. Abstract CT075.

Gandhi L, Rodgríguez-Abreu D, Gadgeel S, et al. Pembrolizumab plus chemotherapy in metastatic non—small-cell lung cancer [published online April 16, 2018]. 

Ryan D. Gentzler, MD, highlights how chemotherapy remains a critical component of the metastatic non–small cell lung cancer treatment paradigm.

Despite Treatment Advances, Chemotherapy Retains Role in Metastatic NSCLC

Richard D. Hall, MD, assistant professor, Hematology/Oncology, University of Virginia Health System, discusses combination approaches in advanced non—small cell lung cancer (NSCLC).

One of the main themes following the 2018 AACR Annual Meeting and the 2018 ASCO Annual Meeting is the use of combination therapies in patients with advanced NSCLC, says Hall. These include pembrolizumab (Keytruda) or atezolizumab (Tecentriq) in combination with standard chemotherapy.

The KEYNOTE-189 trial showed a significant improvement in overall survival (OS) and progression-free survival (PFS) for treatment-naïve patients with stage IV NSCLC who are 

-negative. Additionally, the KEYNOTE-407 trial showed a prolonged median OS in patients with squamous cell carcinoma in the frontline setting. Similarly, there was an improvement in OS and PFS in the IMpower150 trial, which looked at atezolizumab plus bevacizumab (Avastin), carboplatin, and paclitaxel versus chemotherapy alone. Finally, CheckMate-227 showed a benefit with the combination of ipilimumab (Yervoy) and nivolumab (Opdivo).

Combination therapies are defining the treatment paradigm of lung cancer, explains Hall, giving physicians more therapeutic options that reflect better outcomes.

Richard D. Hall, MD, assistant professor, Hematology/Oncology, University of Virginia Health System, discusses combination approaches in advanced non–small cell lung cancer (NSCLC).