Mary Caffrey

”One of the big stories in oncology in 2021 has been the tale of “dangling approvals.” These are accelerated approvals that landed in limbo, after follow-up trials failed to confirm the results that prompted the FDA to allow these cancer drugs to reach the market for certain patients.

The FDA held 3 days of hearings in late April to weigh whether some therapies in this category should stay on the market.

However, in some cases, manufacturers voluntarily withdrew indications after talks with the agency. During the hearings, some manufacturers cited the fact that their therapies were already incorporated into the National Comprehensive Cancer Network (NCCN) clinical guidelines, and thus in use.

Two such cases involved the PD-1 inhibitors nivolumab (Opdivo), from Bristol Myers Squibb, and pembrolizumab (Keytruda), from Merck. Indications were withdrawn for some patients with metastatic small cell lung cancer (SCLC),

 a cancer type in which some progress in treatment advances has been made of late, but in which there is still great unmet need.

The question is, what now? For a discussion on how leading clinicians are responding to these announcements, along with other developments in SCLC, Targeted Therapies in Oncology (TTO) spoke with Martin J. Edelman, MD, chair of the Department of Hematology/ Oncology and associate director for translational research at the Fox Chase Cancer Center in Philadelphia, Pennsylvania.

TTO: Over the past year, we’ve seen the voluntary withdrawal of some indications in SCLC after the FDA moved to address what they call “dangling approvals.” What are your thoughts on how this process played out?

: The most important thing to understand is, it’s not that the drugs were not effective. It was that the trial design, [or] probably the nature of the population, had changed. With these immunotherapy drugs, since the initial approvals, similar agents have now been demonstrated to be effective in combination with chemotherapy in the front line. So, the use of them in second and subsequent lines of therapy became more questionable. But it’s not that they were not effective.

The FDA processes continue to evolve over time. They’re not always as clear as we’d like— what’s the basis for approval? In the past, it had to be based upon a fairly hard point of overall survival; then they moved to other issues in terms of progression-free survival and sometimes 

response rate. So, it’s not always obvious as to why something is approved.

But I think in this situation, it’s important to recognize that pembrolizumab and nivolumab in second line for SCLC are, in fact, drugs that do potentially have utility in populations who have not received immunotherapy alone or in combination previously.

I think part of the basis for removing the approval was that, in the future, [the FDA] didn’t want patients who had gotten immunotherapy as part of their initial treatment with one drug to get essentially another anti–PD-1 or anti–PD-L1 in second- or third-line therapy. That’s reasonable, but a number of patients still will not have received immunotherapy as part of their initial treatment; for them, an immunotherapy agent is still reasonable down the road.

How do the recent FDA proceedings affect the NCCN guideline process, specically in SCLC? 

Because I’m actually on that committee, I don’t know to what extent I can discuss deliberations. But an NCCN guideline will still list these as potential agents, in second- or third-line use. I think that, as I said, there’s no question that these are active agents. [As for] the NCCN process…certainly the FDA 

approvals and disapprovals can influence that. But again, it doesn’t take away from the potential guideline, which moves down from being heavily based on evidence in randomized phase 3 studies, to more expert opinion—but certainly a fair amount of published evidence, prospective studies, indicating activity in these drugs.

What kinds of questions do physicians and even patients have about immunotherapy and SCLC relative to other types of treatment? 

Immunotherapy certainly gets a lot of buzz. I can’t think of other [therapies] that have TV commercials. In lung cancer, I kind of knew we had hit the big time when suddenly, there were TV commercials for immunotherapeutics. I was watching one of these, and I said to my wife, “You know, it’s no day at the beach.” And the next thing is they show this guy walking on the beach.

They are drugs that have a role in the treatment of cancer—they are not the only drugs. Patients should understand that these can be potentially valuable agents—in some instances, indispensable agents—but they are part of a larger strategy, which may include chemotherapy, radiation, sometimes even surgery. They are drugs that certainly have potentially significant and even lethal adverse effects [AEs]. For the most part, [they] lack the acute AEs that we are used to seeing with chemotherapy—[however], even those [effects] to a large extent are ameliorated with modern antinausea therapies, etc.

You don’t have that potential for nausea, hair loss, etc, that you still see with chemotherapy, but the AEs of immunotherapy can be quite profound. They are less predictable. I spend a lot of time educating patients about AEs of all therapies: chemotherapy, immunotherapy, radiotherapy, etc, and their combinations. But immunotherapy is no day at the beach. Many patients feel very well until they don’t. Some go through their course of treatment and have remarkably few AEs. Other people can get life-threatening effects. Sometimes, interestingly, those may presage really dramatic and long-term benefit. But people can get life-altering therapy [and have] problems, [such as] diabetes, which requires lifelong insulin. It’s a very unpredictable set of AEs. They are drugs that require a great deal of respect.

After a stretch of time in which comparatively less progress was made in treating SCLC than non–small cell lung cancer (NSCLC), SCLC has seen the recent designation of subtypes.

How do you expect this advance to affect patient care?

A number of subtypes have been described, primarily based upon cell lines and archive tissues. We do not yet have any prospective clinical data on the utility of these types. So, that remains to be seen. If I sound a little cynical about that, it’s because after 30 years or so of work in the fi eld, a lot of stuff that comes from biology doesn’t always translate. On the other hand, if you don’t have the biology, you’ll never get there. So, some of these subtypes, I think, may help to better identify who will respond to immunotherapy. Clearly, that’s one of the subtypes. And, it would be good if we knew—it’s important to know—in whom things will work as well as in whom things will not work. Because if you give somebody immunotherapy and it doesn’t work, then that’s both expensive and potentially dangerous. It’s never good to get AEs with no chance of benefit. So that’s one aspect that I think will be really important. The other side is to figure out who will benefit from chemotherapy, and from which chemotherapy drugs. There does appear to be some evidence that may be useful, but we need to have well-designed, good clinical trials that tell us, “This is better.” I look forward to those studies.

How will the rise of advances in the use of biomarkers affect treatment of SCLC going forward? 

The biomarkers are the clinical subtypes—and to the extent that some of those are already available in SCLC, you will need, number 1, to have an adequate tissue size. So, I think something that will change is that there will be demand for more tissue.

We saw this in NSCLC. Years ago, I ran a prospective study in what was then the Cancer and Leukemia Group B.

 This was NSCLC, and we needed tissue, and people kind of screamed and yelled and said, “There’s just no way we can get tissue and analyze it before we treat people for cancer.” That was unimaginable. And it wasn’t so very long ago—it was about 2006. That problem delayed that study for a couple of years and may have contributed to it failing, because the marker that we had identified was in immunohistochemistry. There are antibodies, they shift, [and] so we never could cross-validate back to the original specimens. But the fact is, that [this work] will require that we get bigger chunks of tissue. Hopefully it will turn out like NSCLC, where it will just become routine. We’ll be able to say, I’ve got a higher probability that this [vs that] will be beneficial.

The issue of SCLC is going to be more complex than NSCLC. In NSCLC, where we have biomarkers like 

, the treatments that we have are extremely effective—basically, 

they’re 80% to 90% effective, and they tend to be durable. The issue in SCLC has never been getting an initial response. The vast majority of patients respond to drugs that have been around for 30 to 40 years. The problem is maintaining the response. So, it will be the durability of response that’s far more crucial. And that’s where I mean no therapy has been remarkable.

Everybody always loves anecdotes. Here’s one: We had a patient who had progressed and was treated with definitive treatments, chemotherapy and radiation, for a limited-stage SCLC. He relapsed, and he was placed on one of our trials that will be reported in a couple of weeks. Then he was on another study, on the control arm, [but in any case] that was another negative trial. And then he got a few doses of immunotherapy, anti–PD-L1 treatment, and ended up with a rip-roaring colitis after 3 or 4 doses. But he got better—his SCLC got better— from [the immunotherapy], more than 2 years ago, and I have not treated him for that since then. So, here’s a disease where the median life expectancy for recurrent refractory disease is measured in weeks—and yet it’s 2 years later. Actually, his big problems, currently, relate to his other smoking-related illnesses—his heart disease, his lung disease.

You wave a magic wand over a SCLC patient— take away their cancer—and they’re still stuck with their terrible heart and lung disease. That’s really a big rate-limiting step for a lot of this.

1. Beaver JA, Pazdur R. “Dangling” accelerated approvals in oncology. 

. 2021;384(18):e68. doi: 10.1056/NEJMp2104846 

2. FDA in brief: FDA Oncologic Drugs Advisory Committee to review status of six indications granted accelerated approval. News release. FDA; March 11, 2021. Accessed May 8, 2021. https://www.fda.gov/news-events/ fda-brief/fda-brief-fda-oncologic-drugs-advisory-committee-review-status-six-indications-granted-accelerated 

3. Bristol Myers Squibb statement on Opdivo (nivolumab) small cell lung cancer US indication. Bristol Myers Squibb. News release; December 29, 2020. Accessed May 26, 2021. https://news.bms.com/news/details/2020/Bristol-Myers-Squibb-Statement-on-Opdivo-nivolumab-SmallCell-Lung-Cancer-US-Indication/default.aspx 

4. Merck provides update on Keytruda (pembrolizumab) indication in metastatic small cell lung cancer in the US. Merck. News release; March 1, 2021. Accessed May 26, 2021. https://www.merck.com/news/merck-provides-update-on-keytruda-pembrolizumab-indication-in-metastatic-small-cell-lung-cancer-in-the-us/ 

5. Gay CM, Stewart CA, Park EM, et al. Patterns of transcription factor programs and immune pathway activation defi ne four major subtypes of SCLC with distinct therapeutic vulnerabilities. 

. 2021;39(3):346-360. e7. doi:10.1016/j.ccell.2020.12.014 

6. Schilsky RL, McIntyre OR, Holland JF, Frei E. A concise history of the Cancer and Leukemia Group 

. 2006;12(11 Pt 2):3553s-3555s. doi:10.1158/1078-0432.CCR-06-9000

Articles

Targeted Therapies in Oncology spoke with Martin J. Edelman, MD, do uncover what is next for small cell lung cancer after PD-1 inhibitor indication have been withdrawn.

After PD-1 Inhibitor Indications  Are Withdrawn in SCLC, What Now?

Clinical pathways in cancer care are beyond the “new” phase, but oncology practices and health systems are still learning all the ways they can bring greater standardization to care, eliminate unnecessary care, improve data collection, and drive value.

That’s what Mark Wojtowicz, MS, MBA, the administrative director for Oncology Research and Innovation at Geisinger Cancer Institute in Danville, Pennsylvania, shared during a session of the Association of Community Cancer Centers 47th Annual Meeting & Cancer Center Business Summit in March.

Geisinger implemented Elsevier’s ClinicalPath in medical and radiation oncology in April 2019, starting with a “soft demo” and a weeklong training process. The pathways product was rolled out at all sites a month later. The health system decided to integrate ClinicalPath into its Epic electronic health record (EHR) management system because incorporation into the workflow was seen as critical to getting physicians to adopt pathways.

Pharmacists oversaw a process in which the pathway regimen library was “harmonized” with Epic to systematically update new workflows in hematology and oncology. This was a key process because Geisinger actively takes part in clinical trials.

“Accruing to clinical trials is an important part of what we do, and we know that it means a great deal that our clinicians have clinical trial information at that decision-making point,” Wojtowicz said. To have all options available when clinicians were talking to patients, “we wanted to implement across all these specialties, and we wanted to do it as rapidly as possible.

“A lot of the credit goes to the team that really made that happen.”

The soft demo was key, Wojtowicz said. “Everybody was at the starting line, [and] the tool was actually launched; it just wasn’t promoted to the broad practice that it was live and accessible.”

During this period, the physician champions worked with the pathways to achieve buy-in among the others—and allow time for adjustments and integration with other workflows. A month later the new program was ready to go live. Over 1 week, the pathways team met with clinicians and let them try the pathways system to give them opportunities for training and practice. Wojtowicz shared a decision-tree slide that showed each step, starting with whether a diagnosis was or was not on a pathway. The mapping system was critical, he said.

“We know that clinical pathways oftentimes will not cover every single scenario that’s out there or every decision that an oncologist needs to make,” Wojtowicz said. “So you have to be able to map that out—what’s that pathway look like? Or what do those workflows look like when it’s a nonpathway-related decision versus pathway related?”

This visualization process allowed the team— and by extension, physicians—the chance to think through what the workflow would look like and helped with implementation.

Integrating workflows in medical oncology with the EHR definitely presented some challenges, but physicians were determined to have one way to interact with the system. In the beginning, extra information had to be tailored and removed. “And that did require that [for] some regimens, they had to differentiate, and we had to build new ones. But I think that was a worthwhile exercise because everyone required consensus, discussion, and agreement around that direction.”

The final step was to ensure that the pathways were multidisciplinary—that physicians could work with a system that would allow transparency between medical and radiation oncology so that treatment options could be presented together to patients. “What worked for us was that the system allowed for this transfer of data,” so if a decision was made in medical oncology, it was shared with radiation oncology.

“That was a huge thing as far as workflow goes because we really had to be prepared to have not only the individual clinician be able to handle the workflow but then you kind of get to that next level where it’s, ‘How about the multidisciplinary workflow?’” he said. “You’ve got to make it simpler for those things to happen.”

The next step is to make use of new data on the pathway system by allowing artificial intelligence to use predictive analytics to inform decision makers in the practice.

“It doesn’t really stop there,” he said. More value will come from investments that health systems are making in predictive analytics.

“We started bringing our clinical pathways decision data to the discrete elements that come out of that decision. We started bringing that into data tables and linking it back with our clinical information to gain better insights about when decisions were made and what’s happening after that.” This allows clinicians to decide what care plans should look like and how much monitoring should occur.

Geisinger also opted to include prognostic questions. Tough as it is, physicians are asked if they would be surprised if the patient were to die in the next year. The answer helps drive more palliative care referrals.

The health system is cognizant that it is asking doctors to take time to gather data and to add clicks to their day, Wojtowicz said. Adoption rates have been good, and the process continues to improve.

From the health system’s perspective, “they’re extracting data in discrete fashion and merging [the data] back with some of our clinical data to make the most out of it.”

Clinical Pathways Expanded to Include Data Collection, EHR Management at Geisinger

Both cancer and its treatments are highly symptomatic, making it difficult at times for clinicians to closely monitor every symptom a patient experiences outside the office walls. But advances in technology are making It easier to use patient-reported outcomes (PROs) as a tool for remote symptom management (RSM). A presentation at the Association of Community Cancer Centers 47th Annual Meeting & Cancer Center Business Summit titled, “The Role of Remote Cancer Symptom Management in an Evolving Reimbursement Landscape,” gave virtual attendees an overview of the latest research on PROs and how RSM can be incorporated into an oncology practice.

The discussion began with a presentation from Ethan Basch, MD, MSc, director of the Cancer Outcomes Research Program at University of North Carolina (UNC) Lineberger Comprehensive Cancer Center, chief of the Division of Oncology and physician in chief at NC Cancer Hospital, and professor of health policy and management at the UNC Gillings School of Global Public Health. The panel also included Nadia Still, DNP, RN, senior director of client services at Carevive Systems, Inc; Madelyn Trupkin Herzfeld, cofounder and vice chair of Carevive; and Bruno Lempernesse, chief executive officer of Carevive.

“A mainstay of quality cancer care is symptom management. It’s core to what we do because cancer is so symptomatic, and our treatments are highly symptomatic as well,” Basch said. “And early in my career, I began to observe that, unfortunately, we often miss symptoms that patients may be experiencing that emerge later on. We realized that really, they were presenting themselves much earlier—but they evaded our notice.”

This realization led him and his research group to conduct early studies on whether utilizing PROs and clinician reporting simultaneously would reveal gaps in reported symptoms. They found significant differences between the incidence of symptoms reported by patients vs clinicians, with symptoms underreported by clinicians compared with PROs. “This is a missed opportunity to catch symptoms early to intervene and to improve the patient experience and potentially avoid downstream complications,” Basch said.

Basch highlighted electronic PRO (ePRO) systems as one way to implement patient reporting and symptom management. Patients self-report symptoms with the system, whether through a web interface, smartphone, or an automated telephone questionnaire. He noted that a traditional telephone system is most accessible to patients, especially in community practices and rural areas. The system can automatically reply with information on how to self-manage the symptoms while conveying the information to providers and electronic health records.

Providing multiple interface options for patients and preset reminders for them to input their surveys are 2 key best practices to help ensure adherence on the patient’s end, Basch said.

One randomized controlled trial from Basch’s research group found that compared to standard care, patients utilizing ePRO were 7% less likely to visit the emergency department.1Median survival was also 5.2 months longer among patients in the self-reporting arm of the study. “In this study and in other studies, patients have been able to stay on chemotherapylonger when using this kind of ePRO intervention,” Basch added. Better quality of life and functionality were also seen in those patients.

Basch noted that patients have generally reported satisfaction with ePRO systems and so have nurses. He cautioned that these systems do increase up-front work for nurses but will save work down the line if fewer patients have hospital visits. Therefore, workflow accommodation should be planned, and clinics must be prepared before beginning to utilize ePRO systems.

Introducing patients to ePRO systems can be quick, Still explained during her presentation. In the case of Carevive PROmpt, for example, a physician could introduce the concept to patients before a patient navigator explains the system to the patient in more depth. By the next week, patients should be comfortable completing weekly surveys from home.

Based on survey answers, the system responds with a self-management plan that includes evidence-based methods to manage their symptoms. Regarding provider notifications, practitioners can set the threshold to avoid being bogged down with alerts.

Herzfeld discussed reimbursement, high-lighting reimbursement codes that were createdspecifically to address the boom in telehealth during the pandemic. Some examples she provided were codes for e-visits, which are set up by providers to address situations for which a clinic visit is not necessary; codes for virtual check-ins initiated by the patient; the Principal Care Management code, which is for compre-hensive care management for a single, high-risk disease lasting more than 3 months; and reimbursement for remote monitoring with an FDA-approved device such as a fitness tracker.

RSM may be included as a required enhanced patient service in the upcoming Oncology Care First Model, which is expected to begin in July 2022, Herzfeld pointed out. For physicians who plan on participating, it would be a good idea to become accustomed to utilizing ePROs beforehand, she said.

Finally, Lempernesse touched on the importance of patient experience data, which include disease symptoms, impact on quality of life, experience with treatments, input on the outcomes most important to patients, and the relative importance of any given issue to each patient. Use of ePROs provides a full picture of the patient experience, he said.

“So if we look at the implications for the future of cancer care with these data, what do we see? Well, today [there are] already several applications and benefits to using this kind of data in cancer care,” Lempernesse said. “These data empower patients as an active stakeholder, with more engagement in their treatment and disease. From the clinician standpoint, the use of data and patient-reported outcomes improves patient-provider communication, informs treatment and symptom pathways, increases vigilance and real-time actions with alerts, and finally, supports personalized care.”

1. Basch E, Deal AM, Dueck AC, at al. Overall survival results of a tri-al assessing patient-reported outcomes for symptom monitoring during routine cancer treatment. 

. 2017;318(2):197-198. doi:10.1001/jama.2017.7156

Both cancer and its treatments are highly symptomatic, making it difficult at times for clinicians to closely monitor every symptom a patient experiences outside the office walls. 

Integrating Remote Symptom Management With ePROs in Cancer Care

As was the theme of many of the presentations during the 2019 NCCN Annual Conference, changes to the guidelines in colorectal cancer (CRC) focused on expanded biomarker testing to guide treatment.

Work is needed in this area to fill the knowledge gaps in metastatic CRC, which has a 5-year survival rate of just 11%, said Wells A. Messersmith, MD, co-director of the developmental therapeutics program at the University of Colorado Cancer Center.

CRC has 4 consensus subtypes, known as CMS1, CMS2, CMS3, and CMS4, with varying lengths of overall survival (OS), said Messersmith.

He explained that while there are 13 FDA-approved drugs for CRC, until recently only 4 were biomarker-driven. The 2019 update adds treatment based on

The cost of expensive combination therapy is driving the quest for better biomarkers, Messersmith explained, citing data from his university&rsquo;s pharmacy that showed 24 to 30 months of combination therapy in metastatic  CRC exceeded $300,000 by 2013. At the same time, OS has increased incrementally. Spending more for better biomarker studies makes more sense than spending billions on therapies that don&rsquo;t work or could be harmful, he said.

With that, he reviewed studies and key updates for 2019:

an additional option was added for unresectable stage IV mCRC: mFOLFOXIRI plus the EGFR inhibitor panitumumab (Vectibix) for

wild-type metastatic CRC were randomized in a 2:1 ratio to mFOLFOXIRI plus panitumumab (n = 63) or mFOLFOXIRI alone (n = 33). The objective response rate (ORR) with the addition of panitumumab was 85.7% compared with 54.5% with mFOLFOXIRI alone.

Although microsatellite instability (MSI) and mismatch repair (MMR) is usually not inherited, this does not rule out Lynch syndrome, which is seen in 1% of cancers with

Germline testing is indicated if there is a strong family history.

The latest guidelines also include additional explanation of MMR immunohistochemistry testing for the 4 genes known to be mutated in Lynch:

New frontline immunotherapy treatment options listed in the NCCN guidelines for advanced or metastatic CRC are nivolumab (Opdivo) or pembrolizumab (Keytruda), or a combination of nivolumab and ipilimumab (Yervoy), both in dMMR and MSI-H only. These recommendations are category 2B and are intended for patients who are not appropriate candidates for cytotoxic combination regimens. These same immunotherapy options are also listed in the guidelines as second- and third-line recommendations for dMMR/MSI-H patients.

Larotrectinib (Vitrakvi) is now a second-line treatment option

gene fusion positive, based on a pivotal 2018 paper published in the

The pivotal analysis was also the basis of the FDA&rsquo;s November 2018 approval of larotrectinib for the treatment of adult and pediatric patients with solid tumors that have an

gene fusion without a known acquired resistance mutation, are metastatic or where surgical resection is likely to result in severe morbidity, and have no satisfactory alternative treatments or that have progressed following treatment. The pivotal trial included 4 patients with CRC, 1 of whom achieved an objective response.

Combination therapies added to the guidelines as second-line options are: (1) dabrafenib (Tafinlar;

), plus cetuximab or panitumumab (EGFR mAb), (2) encorafenib (Braftovi; BRAF) plus binimetinib (Mektovi; MEK) plus cetuximab or panitumumab (EGFR mAb).

The regimen of encorafenib/binimetinib and an EGFR inhibitor is supported by findings from the safety lead-in phase of the phase III BEACON trial. In 30 patients with

V600E-mutant metastatic CRC, the estimated median progression-free survival with encorafenib/binimetinib plus cetuximab was 8.0 months and the estimated median OS was 15.3 months with a median duration of follow-up of 18.2 months.

The ORR was 48% by local assessment, with 3 patients achieving a complete response.

Messersmith WA. NCCN Guidelines Updates: Management of Metastatic Colorectal Cancer Presented at: 2019 NCCN Annual Conference; March 21-23, 2019; Orlando, FL.

Lenz HJ, Ou FS, Venook AP, et al. Impact of consensus molecular subtyping (CMS) on overall survival (OS) and progression free survival (PFS) in patients with metastatic colorectal cancer (mCRC): analysis of CALGB/SWOG 80405 (Alliance).

. 2017;35(15 suppl):3511 DOI: 10.1200/JCO.2017.35.15_suppl.3511.

Drilon A, Lactsch TW, Kummar S, et al. Efficacy of lacrotrectinib in TRK fusionpositive cancers in adults and children.

. 2018;378:731-739. DOI: 10.1056/NEJMoa1714448.

Kopetz S, Grothey A, Yaeger R, et al. Updated results of the BEACON CRC safety lead-in: Encorafenib (ENCO) + binimetinib (BINI) + cetuximab (CETUX) for BRAFV600E-mutant metastatic colorectal cancer (mCRC). Presented at: 2019 Gastrointestinal Cancers Symposium; January 17-19; San Francisco, CA. Abstract 688.

Wells A. Messersmith, MD, reviews key updates to the NCCN guidelines for the treatment of colorectal cancer.

Mary Caffrey | Authors

Articles

After PD-1 Inhibitor Indications Are Withdrawn in SCLC, What Now?

Clinical Pathways Expanded to Include Data Collection, EHR Management at Geisinger

Integrating Remote Symptom Management With ePROs in Cancer Care

New NCCN CRC Guidelines Include Updates in Testing, Treatment Options