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 to reference the same entity: the study and management of nonmalignant disorders of the blood. It is a discipline unto itself, distinct from its sister field, malignant hematology. The scope of practice can be broad and includes thrombotic and hemorrhagic disorders, transfusion medicine, hemoglobin disorders including sickle cell disease and thalassemia, anemia, thrombocytopenia, leukocytosis, leukopenia, and disorders of iron metabolism.

In many health care systems, classical hematologists function as stewards of cost-intensive, specialty-related medications that are often complex and require content knowledge, experience, and clinical expertise for appropriate management.

 Others find roles as systems-based hematologists, defined as a specialty-trained physician, employed by a hospital medical center or a health system, who optimizes individual patient care as well as the overall system of health care delivery for patients with blood disorders.

 Duties of these professionals can include implementing health care initiatives for the management of thrombosis or bleeding, working in conjunction with anticoagulation oversight clinics, and standardizing management of therapeutic phlebotomy.

To characterize the future of the workforce for this diverse field, results of an American Society of Hematology (ASH) survey of practicing hematologists projected that nearly 25% of hematologists specializing in nonmalignant disorders would reach retirement age by 2018.

 This was expected to have a profound impact on creating a workplace shortage.

 The study results cited several influences, including the age of the workforce

 and decreasing rates of graduate selection of nonmalignant hematology as a primary area of focus.

 Other influences included salary discrepancies between nonmalignant hematology and malignant hematology/oncology, lack of mentorship, and uncertainty regarding nonmalignant hematology job opportunities in nonacademic settings.

 Physicians practicing in adult nonmalignant hematology disorders are now seeing the results of this decreasing specialist collective in clinical care and research.

Educational programs have historically been tasked with attempts to address the shrinking pool of classical hematologists. Prior research showed that only 20% of hematology/oncology fellowship graduates pursued an academic career with a clinical research focus, and only 8% pursued an academic career as a clinicianeducator.

 Of the 20%, less than 6% selected careers in nonmalignant hematology.

 A great demand exists for well-trained physicians.

 Furthermore, literature suggests that soon a large patient volume with hematologic care needs will be without a sufficient number of specialists.

These challenges may require complex solutions (

). One initiative is an expansion of easily accessible nonmalignant hematology training and educational resources for both trainees and practicing hematologists/oncologists. Many colleagues have not experienced the opportunity to train with a dedicated mentor in this specialty, as fellowship programs can vary significantly in their faculty experience with nonmalignant hematology. In fact, many programs have few available dedicated hematologists on staff for teaching and clinical care.

 Guidance and widely disseminated education can enhance practitioner comfort in the management of hematologic conditions when programs do not have an available content area expert.

Figure. Areas of Opportunity to Expand Training in Nonmalignant Hematology Disorders

Additional focus should be given to the enlistment and training from colleagues to surmount this disparity. Offering training sessions or workshops in the management of high-yield, common topics led by experienced hematology teachers for their colleagues in internal medicine, family practice, and primary care could provide a foundation for initial management of hematologic issues, improved comfort with the subject matter, and an enhanced understanding of the indications for specialist referral. Topics of interest include management of iron-deficiency anemia, simple and complex thromboses, anticoagulation oversight, bleeding evaluations, thrombotic microangiopathy presentation and identification, and the initial evaluation of cytopenias. These examples represent common scenarios with significant intersection with classical hematology.

Residency training programs may also find the opportunity to incorporate nonmalignant hematology focus into their curricula. Not only would this serve to improve proficiency and prepare trainees for the reality of their practice, but it would also be a step toward eliminating the gap in care that will be left by a workplace shortage.

A clear and prominent need also exists to train more classical hematologists to increase consultant availability across subspecialties. ASH has undertaken this issue in prior years through the creation of its Recruitment and Retention Working Group, a study collaborative with The George Washington University Fitzhugh Mullan Institute for Health Workforce Equity, and it has raised awareness through publication and educational initiatives.

 In October 2020, ASH announced that it will provide “institutional funding to develop 10 new innovative hematology-focused fellowship tracks within existing adult hematologyoncology training programs.”

 The training provided in the educational platform must lead to eligibility for American Board of Internal Medicine hematology certification. The goal of the program is to generate enough recruitment and training to add at least 50 academic hematologists in the coming years, with a focus on training hematologists in nonmalignant disorders.

 More information will follow when the request for proposals becomes available on February 15, 2021. Additional information is available at https://bit.ly/37Gmyic.

Well-informed hematologists/oncologists can also play a critical role in reshaping the trajectory of these gaps through raising awareness, participating in professional societies and continuing medical education, teaching students and trainees, and recruiting colleagues to extend these efforts. The nurture and retention of nonmalignant hematology content expertise is a critical aspect of health care that merits protection. 

Wallace PJ, Connell NT, Abkowitz JL. The role of hematologists in a changing United States health care system. 

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Gormley C. Innovative education, training strategies needed to address shortage of benign hematologists.

. November 22, 2017. Accessed December 8, 2020. https:// www.healio.com/news/hematology-oncology/20171116/ innovative-education-training-strategies-needed-to-address-shortage-of-benign-hematologists

Marshall AL, Jenkins S, Mikhael J, Gitlin SD. Determinants of hematology-oncology trainees’ postfellowship career pathways with a focus on nonmalignant hematology. 

 2018;2(4):361-369. doi:10.1182/bloodadvances.2017013722 

Lawrence L. Adapting to changes in practice-based hematology. ASH Clinical News. May 15, 2015. Accessed December 8, 2020. https://www.ashclinicalnews.org/spotlight/adapting-to-changes-in-practice-based-hematology/ 

Sharma D, Wallace N, Levinsohn EA, et al. Trends and factors affecting the US adult hematology workforce: a mixed methods study. 

. 2019;3(22):3550-3561. doi:10.1182/bloodadvances.2019000307 

Todd RF III, Gitlin SD, Burns LJ; Committee on Training Programs. Subspecialty training in hematology and oncology, 2003: results of a survey of training program directors conducted by the American Society of Hematology. 

. 2004;103(12):4384-4388. doi:10.1182/blood-2003-11-3986 

Horn L, Koehler E, Gilbert J, Johnson DH, et al. Factors associated with the career choices of hematology and medical oncology fellows trained at academic institutions in the United States. 

 2011;29(29):3932-3938. doi:10.1200/ JCO.2011.35.8663 

Hill QA, Hill A, Allard S, Murphy MF. Towards better blood transfusion—recruitment and training. 

. 2009;19(1):2-5. doi:10.1111/j.1365-3148.2008.00901.x

Sinsky CA, Dugdale DC. Medicare payment for cognitive vs procedural care: minding the gap. 

. 2013;17(18):1733-1737. doi:10.1001/jamainternmed.2013.9257 

Hematology-focused fellowship training program. American Society of Hematology. Accessed December 8, 2020. https://www.hematology.org/education/educators/ resources-for-training-program-directors/hematology-focused-fellowship-training-program

Articles

Partner Perspective

The scope of adult nonmalignant hematology can be broad and includes thrombotic and hemorrhagic disorders, transfusion medicine, hemoglobin disorders including sickle cell disease and thalassemia, anemia, thrombocytopenia, leukocytosis, leukopenia, and disorders of iron metabolism. 

Adult Nonmalignant Hematology Is an Endangered Field That Merits Protection

The current standard of care for patients with non–small cell lung cancer (NSCLC) does not include therapies targeting HER2, a mutation that occurs in up to 4% of cases. However, data from recent studies of antibody-drug conjugates (ADCs) directed at HER2 activity are generating excitement about the potential utility of ADCs in this space. Specifically, efficacy data from phase 2 trials have described HER2 gene mutations as an emerging biomarker to identify therapies for patients with metastatic disease (TABLE

Ado-trastuzumab emtansine (T-DM1; Kadcyla) broke the historical trend of low response rates to HER2-directed therapies in lung cancer with data from a phase 2 basket trial (NCT02675829), which examined the ADC in a cohort of patients with advanced HER2-mutant lung adenocarcinoma. The objective response rate (ORR) among 18 patients with HER2 mutations was 44% (95% CI, 22%-69%), all partial and confirmed responses. The median progression-free survival (PFS) for all patients in the cohort was 5 months (95% CI, 3-9), whereas the median PFS for responders was 6 months (95% CI, 4–not reached).

Data from DESTINY-Lung01 (NCT03505710), a phase 2 trial involving the ADC fam-trastuzumab deruxtecan-nxki (Enhertu), further solidified the potential role of these agents in patients with HER2-mutant disease. An interim analysis presented at the 2020 American Society of Clinical Oncology Virtual Scientific Program (2020 ASCO) showed an ORR of 61.9% (95% CI, 45.6%-76.4%) in 42 patients with unresectable/metastatic nonsquamous NSCLC treated with trastuzumab deruxtecan.

 Further, the median PFS was 14 months (95% CI, 6.4-14.0), and median overall survival was not reached (95% CI, 11.8–not reached).

“Antibody-drug conjugates are showing promising data in breast cancer, and some of that efficacy has been observed in data in lung cancer,” said Hossein Borghaei, DO, MS, during an OncLive® Lung Cancer Talk video program. Borghaei was joined by Balazs Halmos, MD, MS; Jarushka Naidoo, MBBCh; and Joshua M. Bauml, MD, in reviewing the latest data that pave a path forward for the role of HER2-targeted agents for patients with metastatic lung cancer.

The methods for establishing the most effective biomarker for HER2-targeted therapies were a key focus in the discussion. Whereas HER2 positivity has been defined by immunohistochemistry (IHC) protein expression (IHC 3+ or IHC 2+) for breast cancer therapy, emerging data in NSCLC are identifying responses in patients with HER2 activating mutations through molecular analysis of tissue samples.1,2 Borghaei estimated the rate of HER2 mutations in NSCLC at 2% to 4% and HER2 overexpression by IHC testing at up to 30%.

: Trastuzumab deruxtecan seems to be garnering a lot of attention, primarily because it has received breakthrough therapy designation from the FDA in NSCLC, and it’s already approved in breast [and gastric] cancers.

At the 2020 ASCO meeting, data were presented from a phase 2 study that investigated the utility of the compound in patients with NSCLC and a HER2 mutation. Keep in mind this is not the IHC overexpression that we were talking about; this is strictly the HER2-mutated NSCLC. Patients who participated in this study had received prior chemotherapy, and the majority had received chemotherapy plus immunotherapy.

The patient population was very similar to that of other NSCLC studies that we’ve seen in this setting. Interestingly, based on a 42-patient data set, a response rate of nearly 62% was reported, which is pretty eye-catching. The median duration of response was not reached at the time of the initial presentation. It looks like a very active, very interesting compound.

There is a specific toxicity that I think we should discuss. With this compound you do have to worry about interstitial lung disease or pneumonitis because it can happen, and learning how to mitigate some of that is important to clearing the established safety of the compound and, of course, making sure that patients are identified if they have that.

The median PFS was around 14 months, which was pretty interesting for a patient population that’s already been treated. So it does appear that we’re making some progress. ADCs, at least with this particular compound, seem to be very promising, and subsequent studies are needed to establish their role.

Based on these efficacy data, do we move this agent to the front line? Or is this compound strictly for patients who’ve had chemoimmunotherapy? I think subsequent studies are going to [evaluate] the importance of establishing a role for these kinds of compounds.

: This is a very interesting situation because in contrast with RET inhibitors, for instance, these drugs—both T-DM1 and trastuzumab deruxtecan—are already approved by the FDA in other indications such as breast cancer; you can access them.

So if you have a patient who comes in with a HER2 exon 20 mutation, what are you doing now? If you have access to a clinical trial, I’m sure that’s what you’re selecting for your patient.

But if you don’t enroll on a trial and that patient comes to your door, Dr. Naidoo, what are you doing?

: I present both options [T-DM1 and trastuzumab deruxtecan] to the patient, and I print it out on paper and go through it with them. Now, usually their eyes glaze over a little bit, I have to admit, and at the end they might say, “What would you do if you were me?” But I feel better showing them what the 2 options are and saying I don’t clearly know which one may be better for you, but I will balance my decision, taking their comorbidities into account as well as various other things. I think that is the fairest way to approach it.

I have a lot more clinical experience with T-DM1. I’ve given it to patients with NSCLC with HER2 aberrations for several years, and in a past life, when I treated patients with breast cancer, I had certainly given T-DM1.

I think there is a certain level of clinical familiarity that providers are probably going to have that may sway them in the direction of T-DM1. However, when we have a very exciting agent with a very impressive response rate, and when the phase 2 data that supported the use of T-DM1 do not look as impressive as those for trastuzumab deruxtecan, I think that that may change over time.

: When you’re using T-DM1 or trastuzumab deruxtecan, are you using them after chemoimmunotherapy? Are you using them in the first line? How are you approaching that?

: Again, it’s a similar approach to a RET inhibitor. I’m a believer that oncogenic drivers are driving the growth of the cancer. If a patient is stable and can wait for the results of testing, I would prefer to give it in the first line.

: Interesting. Dr Halmos, where are you using these agents right now?

: I think we need to learn a little bit more in this setting. I don’t think I’m fully comfortable using them in the first line yet, especially, for example, in HER2-mutated disease because of the bad pneumonitis. There’s that risk—how is it going to play out?

It’s such a complex molecule, and as a result, there’s a lot of nuance. I think I would love to learn a little more about it before replacing a fairly effective treatment up front for most of our patients with metastatic lung cancer, and that is chemotherapy.

I would sequence them more in the secondline setting, but I am very eager to learn more about these compounds, including TKIs [tyrosine kinase inhibitors] that are moving along in the HER2 field, as well.

: What I like about ADCs is that if we can establish that by detecting the HER2 overexpression using IHC, we can actually show clinical utility.

If an ADC works the way it’s promised— the antibody moiety binds to HER2, as long as it’s overexpressed—and is internalized and goes to the target, it could potentially have a lot more utility. Unless there are specific mutations that prevent internalization, or if the cancer cell is inherently resistant to the protection of chemotherapy that’s being used as a toxic payload, the clinical utility of the agent can be expanded a little.

I think these are important topics to explore in the future studies. In fact, the study that we’re running will test this particular compound [trastuzumab deruxtecan] in both patients with a HER2 mutation and those with HER2 overexpression. We should be able to generate some data in these settings to see where the clinical utility really lies [NCT04042701].

: What’s fascinating about these agents is that these ADCs are gigantic molecules; they are huge. So it is not expected that they’re going to penetrate the CNS [central nervous system]; it is not expected they are going to be getting into the cells.

But what’s remarkable, in a paper about T-DM1, Li et al did an enormously elegant analysis where they looked at what factors lead to response.1 Investigators performed IHC, FISH [fluorescence in situ hybridization], mass spectroscopy, and mutation analysis, and the only thing associated with response was mutation, which shouldn’t be the case.

It should not make any sense given how these drugs work, and yet that is exactly what we see. I wonder with trastuzumab deruxtecan—which has a much higher response rate, a much longer durable response—whether we’re still going to see that same thing. But what I took away from the toxicity profile of trastuzumab deruxtecan is that it looks a lot like chemotherapy. Although it is a targeted agent, the adverse effect profile looks similar to that of a platinum doublet.

: But that’s not unprecedented. We’ve seen other ADCs that have similar profiles because the toxic payload is basically cytotoxic as you get into it. Now, I’ve seen the data for patients with a HER2 mutation, and in terms of predicting responsiveness, I’m also a little puzzled to the extent that I’m trying to communicate with the investigators about how to best explain a drug that’s supposed to bind to a specific target.

Why is it that in a patient with a HER2 mutation, it actually does seem to be working better? I don’t think there is any clear evidence at this point, at least not an explanation that I have seen, that’s satisfactory. I’ve seen the same data, and yes, I do question them. It’s an ADC; the simple mechanism is supposed to be the antibody binds the target, it’s internalized, the toxin is released, and you get your activity. But unfortunately, the patients experience some adverse effects because the drug does get out into the systemic circulation.

: Let me mention that this highlights how much we don’t know about HER2 expression and HER2 amplification in lung cancer. It’s one thing for a subset of patients who have a mutation that is oncogenic, actionable, and important for the cancer to survive to have that identified pathway. But for those who have HER2 overexpression, resistance may emerge within weeks or as selection of subclones that don’t express it. So any long-term mutation to the compound is simply not realistic.

: I think on that, as well, the mutation matters. Similarly, the paper you referenced, as well as other work, has shown that patients with exon 20 YVMA insertions appear to have poorer responses. So obviously having a familiarity with exactly what you’re treating is the first step.

: Maybe the HER2 mutation predicts the binding specificity, or it somehow affects weak or stronger binding, depending on the kind of mutation. Maybe it has something to do with that, and again, as was pointed out, we simply don’t understand much of it. Clinical development is a lot faster than the science.

Usually we have a little more science than clinical development, and here the drugs are working, we’re trying to use [them], but we don’t understand what exactly is going on from a science point of view.

Li BT, Shen R, Buonocore D, et al. Ado-trastuzumab emtansine for patients with HER2-mutant lung cancers: results from a phase II basket trial. 

. 2018;36(24):2532-2537. Published correction appears in 

. 2019;37(4):362. doi:10.1200/ JCO.2018.77.9777

Smit EF, Nakagawa K, Nagasaka M, et al. Trastuzumab deruxtecan (T-DXd; DS-8201) in patients with HER2-mutated metastatic non-small cell lung cancer (NSCLC): interim results of DESTINY-Lung01. 

. 2020;38(suppl 15):9504. doi:10.1200/ JCO.2020.38.15_suppl.9504

NCCN. Clinical Practice Guidelines in Oncology. Non-small cell lung cancer, version 1.2021. Accessed December 4, 2020. https://www. nccn.org/professionals/physician_gls/pdf/nscl.pdf

Borghaei H, Besse B, Bardia A, et al. Trastuzumab deruxtecan (T-DXd; DS-8201) in combination with pembrolizumab in patients with advanced/metastatic breast or non-small cell lung cancer (NSCLC): a phase Ib, multicenter, study. 

. 2020;38(suppl 15):TPS1100. doi:10.1200/JCO.2020.38.15_suppl.TPS1100

The current standard of care for patients with non–small cell lung cancer does not include therapies targeting  HER2, a mutation that occurs in up to 4% of cases. However, data from recent studies of antibody-drug conjugates directed at HER2 activity are generating excitement about the potential utility of ADCs in this space.  

HER2-Directed Antibody-Drug Conjugates May Carve Out a Place in NSCLC Landscape

The approval of belantamab mafodotin-blmf (Blenrep) for patients with refractory multiple myeloma marks the first therapy directed at B-cell maturation antigen (BCMA), a target of robust research interest, to reach clinical practice. The FDA granted an accelerated approval for the agent on August 5, 2020, for adults with relapsed or refractory multiple myeloma who have received at least 4 prior therapies, including an anti-CD38 monoclonal antibody, a proteasome inhibitor, and an immunomodulatory agent.

The decision was based on findings from the ongoing phase 2 DREAMM-2 study (NCT03525678), which tested 2 dosing levels of belantamab mafodotin in patients who were heavily pretreated. The approval stemmed from an overall response rate (ORR) of 31% (97.5% CI, 21%-43%) among 97 patients who received the recommended dose of 2.5 mg/kg administered intravenously once every 3 weeks. Responses persisted for 6 months or longer in 73% of responders.

After 13 months of follow-up, responses rates were similar regardless of the number of prior lines of therapy that participants had received, according to findings from a post hoc analysis presented at the virtual 62nd American Society of Hematology Annual Meeting and Exposition in December 2020 (ASH 2020). For those who had received 3 to 6 lines of prior therapy, the ORR was 34% with a median duration of response of 11.0 months (95% CI, 4.2-not reached [NR]), and the median overall survival was 13.7 months (95% CI, 9.1-NR). For patients who had 7 or more previous treatments, the ORR was 30% with a median response duration of 13.1 months (95% CI, 4.0-NR), and median overall survival of 13.4 months (95% CI, 8.7-NR).

Belantamab mafodotin, which is an antibody-drug conjugate, “represents a useful treatment option for relapsed/refractory multiple myeloma, including patients with a high burden of prior treatment for whom prognosis is otherwise poor,” Sagar Lonial, MD, the lead investigator in the DREAMM-2 study, said in presenting the updated data at ASH 2020. Such patients, Lonial said, typically experience a decrease in the depth of response and shorter remissions as they undergo successive lines of therapy.

Lonial, a 2020 Giants of Cancer Care® award winner, is chief medical officer at Winship Cancer Institute of Emory University in Atlanta, Georgia. He also is professor and chair of the Department of Hematology and Medical Oncology and the Anne and Bernard Gray Family Chair in Cancer, both at Emory University School of Medicine. In an interview with OncologyLive®, Lonial discussed key facets of belantamab mafodotin and potential next steps.

Some investigators have said that successful targeting of BCMA would be a transformative development for multiple myeloma therapy. Would you agree?

Yes. I think the advantage that BCMA has over, for instance, CD38, or even SLAMF7 is that the target is expressed much more exclusively on plasma cells, so the off-target impact is going to be less. Signaling through BCMA is 1 of the reasons multiple myeloma cells proliferate and are drug resistant. Blocking BCMA not only targets the tumor cell, but it also may help to overcome drug resistance.

Please describe the patient population for this drug.

The FDA approval is for patients who are triple-class refractory, so [the patient ideally would be] resistant to proteasome inhibitors, immunomodulatory drugs, and anti-CD38 antibodies. For me, it would be a patient who has had 3 prior lines of therapy and still has a reasonable performance status to get any treatment at all. My go-to in that situation, if not a clinical trial, would be belantamab mafodotin.

Belantamab mafodotin was approved with a boxed warning about the risk of ocular toxicity. Could you discuss this adverse event?

The ocular toxicity is somewhat unique for myeloma drugs. It is more of an exam finding by an ophthalmologist or an optometrist; it does not always result in significant symptoms. In fact, only in 18% to 20% of the time [does it actually result] in change in visual acuity.

I think the take-home messages are that [the agent] is a really good option for triple-class refractory myeloma and, importantly, partnering with an eye care professional is part of the process. It’s something we should get used to doing in order to figure out how to maximize the benefit from belantamab.

The best way to treat [an ocular effect] is to hold the drug and let the patient recover from the toxicity. What I think is important and different from many other drugs, though, is that the half-life of belantamab mafodotin is long enough that even if you have to hold a dose or 2 for 3 weeks, or oftentimes 6 weeks, most patients still maintain or improve their response. So, it’s not as though if you don’t stay on schedule you’re going to be in trouble.

Are there immunogenic qualities to belantamab mafodotin?

Yes, it does induce immunogenic cell death. As such, it’s being tested right now in partnership with for instance, pembrolizumab [Keytruda; DREAMM-4; (NCT03848845)] to see whether that immunogenic cell death in combination with a checkpoint inhibitor may activate an innate T-cell response separate from the effect directly of the development.

What are some unanswered questions about this drug?

I think the question is going to be, how do you partner [BCMA-targeting agents] with other drugs? Those trials are being done now, combining it with pomalidomide [Pomalyst], with bortezomib [Velcade], with lenalidomide [Revlimid]. How you sequence [the drugs] is another question that’s coming up. If you’ve had 1 [anti-BCMA drug], can you respond to another?

That’s a question we’ve not been able to answer because most of the trials have excluded prior exposure to BCMA. But now they’re including cohorts of prior BCMA therapy. So I think we’ll get an answer to that question in the next year.

FDA granted accelerated approval to belantamab mafodotin-blmf for multiple myeloma. FDA. Updated August 6, 2020. Accessed December 13, 2020. https://bit.ly/2J4MdIO

Lonial S, Lee HC, Badros AZ, et al. DREAMM-2: single-agent belantamab mafodotin (Belamaf) in patients with relapsed/refractory multiple myeloma (RRMM)–1-year outcomes by prior therapies. Presented at: 2020 ASH Annual Meeting; December 5-8, 2020. Abstract 1417. https://ash.confex.com/ash/2020/ webprogram/Paper137693.html

Sagar Lonial, MD, discussed key facets of belantamab mafodotin and potential next steps.

First BCMA-Targeting Therapy Debuts in Multiple Myeloma

During this past decade, we have witnessed substantial achievements in the treatment of patients with advanced malignant disease. Although these benefits do not pertain to all cancers and “cure” remains a relatively uncommon event, oncologists have an increasing number of molecularly targeted and immunotherapeutic strategies to employ based on objectively meaningful clinical trial outcomes.

Unfortunately, despite the acceleration in regulatory approval of effective strategies, we continue to see reports in the peer-reviewed literature lamenting the lack of robust overall survival (OS) benefits documented in phase 3 randomized trials. For example, a recent report examined FDA approval of anticancer therapeutics between 2000 and 2016 and concluded that despite the fact that these agents caused “substantial tumor responses,” they were “associated with...prolonging median overall survival by only 2.4 months.”

Even in settings in which progression-free survival (PFS) has been accepted as a valid end point for regulatory approval, such as antineoplastic therapy for advanced ovarian cancer, some continue to inquire whether this outcome can serve as a reliable surrogate for OS.

 This discussion fails to acknowledge the increasing relevance of the chronic disease nature of many cancers and the potentially substantial impact of multiple therapeutic options once an individual patient ceases treatment on a given clinical trial.

Several examples emphasize this critical point. Findings from 2 second-line ovarian cancer chemotherapy trials conducted for regulatory purposes and initiated 8 years apart (1999 and 2007) had the same eligibility (and ineligibility) criteria and included an identical carboplatin/gemcitabine chemotherapy treatment arm.

Although cross-trial comparisons must always be conducted with caution, it is notable that these studies were carefully monitored (as required by regulatory agencies) and resulted in essentially the same median PFS outcomes (median 8.6 and 8.4 months, respectively).3,4 Although similar outcomes would have been anticipated for similar or identical treatment regimens, OS findings observed for these 2 study populations were strikingly different. For the carboplatin/gemcitabine trial regimen initiated in 1999, the median OS was 18.0 months,

 whereas it was almost twice as long—35.2 months—for the same regimen employed in a study started 8 years later.

Although a definitive reason for why survival was so much longer in the later study is not possible to discern, the most likely is the availability of an increasing number of potentially beneficial therapeutic agents employed either on or off label following removal of research participants from the phase 3 trial.

A second excellent example of the increasing utility of later lines of therapy and their impact on an OS end point in a phase 3 randomized trial is provided by data involving therapy for metastatic melanoma. In an analysis of 9 randomized trials that employed a dacarbazine control arm with no crossover to the experimental regimen, there was a very strong correlation between PFS and OS (correlation coefficient, 0.96). However, when trials were included that permitted crossover from dacarbazine to the effective experimental regimen, the correlation coefficient between PFS and OS decreased to 0.55.

And in a more recent report of 5-year outcomes observed in patients with wild-type 

 advanced melanoma treated with nivolumab (Opdivo) versus a control arm of dacarbazine, investigators found strikingly improved 5-year PFS for patients treated with the checkpoint inhibitor (28% vs 3%). This translated into improved 5-year OS for the nivolumab-treated population (39% vs 17%). The overall response rate was, not surprisingly, also superior in the nivolumab study arm (42% vs 14%).

However, the 5-year OS rate of patients initially treated with dacarbazine in this study but who subsequently received additional therapy, including nivolumab, was 38%, essentially no different from that of the group who received the checkpoint inhibitor as primary treatment. This outcome occurred despite the substantially inferior PFS observed with dacarbazine during the trial.

Of course, the appropriate conclusion here is not that nivolumab failed to improve OS despite its influence on time to disease progression, but rather that despite the objectively poor primary trial outcome (PFS) associated with the almost inactive chemotherapeutic (dacarbazine), effective therapy delivered after completion of the study regimen was able to have an impressively favorable influence on individual participants’ ultimate survival.

Ladanie A, Schmitt AM, Speich B, et al. Clinical trial evidence supporting US Food and Drug Administration approval of novel cancer therapies between 2000 and 2016. 

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Pfisterer J, Plante M, Vergote I, et al; AGO-OVAR; NCIC CTG; EORTC GCG. Gemcitabine plus carboplatin compared with carboplatin in patients with platinum-sensitive recurrent ovarian cancer: an intergroup trial of the AGO-OVAR, the NCIC CTG, and the EORTC GCG. 

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Aghajanian C, Blank SV, Goff BA, et al. OCEANS: a randomized, double-blind, placebo-controlled phase III trial of chemotherapy with or without bevacizumab in patients with platinum-sensitive recurrent epithelial ovarian, primary peritoneal, or fallopian tube cancer. 

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Flaherty KT, Henning M, Lee SJ, et al. Surrogate endpoints for overall survival in metastatic melanoma: a meta-analysis of randomized controlled trials. 

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Robert C, Long GV, Brady B, et al. Five-year outcomes with nivolumab in patients with wild-type BRAF advanced melanoma. 

. 2020;38(33):3937-3946. doi:10.1200/JCO.20.00995

From the Editor

Although recent benefits do not pertain to all cancers and “cure” remains a relatively uncommon event, oncologists have an increasing number of molecularly targeted and immunotherapeutic strategies to employ based on objectively meaningful clinical trial outcomes.

PFS Deserves More Than Surrogate Status as a Clinical Trial End Point 

The development of additional molecularly targeted therapies and the search for enhanced immunotherapy regimens are expected to permeate the oncology landscape across a broad range of malignancies as 2021 unfolds, according to experts.

Those were among the key trends for the New Year that experts in breast, lung, genitourinary, and hematologic malignancies described in interviews with 

. Many of the expectations for the coming year grew out of the advances of 2020, in which new targeted therapies emerged for patient subsets across multiple tumor types and novel immunotherapies continued to expand.

These developments include FDA approvals for the first RET inhibitors, selpercatinib (Retevmo) and pralsetinib (Gavreto), in non–small cell lung cancer (NSCLC) and thyroid cancer settings, and a third chimeric antigen receptor (CAR) T-cell therapy for an oncology indication, brexucabtagene autoleucel (Tecartus), for mantle cell lymphoma.

Continuing progress in the optimal use of antibodies aimed at immune checkpoints is also anticipated. This year will mark a decade since the first checkpoint inhibitor, the anti–CTLA-4 antibody ipilimumab (Yervoy), gained FDA approval for patients with unresectable or metastatic melanoma. Since then, antibodies directed at the PD-1/PD-L1 pathway have dominated the field. Research findings that shed light on how best to use these agents in combinations, as well as new checkpoint therapies, are expected this year.

Novel therapeutic strategies that are likely to advance this year include expansion of uses for tyrosine kinase inhibitors, new combinations incorporating checkpoint immunotherapy, and progress in developing personalized cancer vaccines, according to Howard A. “Skip” Burris III, MD.

“Across all of oncology, there are several common buckets,” said Burris, chief medical officer and president of clinical operations at Sarah Cannon in Nashville, Tennessee, and a 2014 Giants of Cancer Care

 award winner in the Drug Development category. “There is a lot of promise across most of the disease entities from the research that’s been done.”

Molecularly targeted therapies continue to gain traction, some in multiple tumor types, Burris said, citing agents directed at 

 activity as examples. “We have seen that with pemigatinib [Pemazyre], the FGFR2 inhibitor, in cholangiocarcinoma, which will certainly play in some other areas. 

—the long, undruggable target—has seen the KRAS G12C inhibitors, and we’ve had the approval of the RET inhibitors in lung cancer and thyroid cancer. We are seeing that we no longer have undruggable targets, and we know that we can find driver mutations in small sets of patients; it’s certainly a place to go to pursue development,” he said.

In immunotherapy, clinical findings are starting to emerge for combination therapies involving PD-1/PD-L1 inhibitors, including some regimens that pair immune checkpoint agents, Burris noted. “We’re seeing that combinations with other antibodies, TIGIT and LAG3, are showing improved activity over what seemed to be a checkpoint inhibitor alone, as well as activity in patients who previously had a checkpoint inhibitor, and that’s playing out in tumors as diverse as lung cancer, colon cancer, and melanoma—so really, this is across the spectrum. There’s a lot of excitement there.”

Furthermore, Burris anticipates that CAR T-cell therapies, or other types of genetically modified treatments will move forward in clinical development, including in solid tumor trials. “We’ve got more than a dozen trials ongoing at Sarah Cannon, and patients are being matched to those studies. There’s a great deal of enthusiasm, and I’m optimistic that we’re going to see this class of immune effector cells begin to help more patients than just [those] who have hematologic malignancies.”

In breast cancer, antibody-drug conjugates (ADCs) such as fam-trastuzumab deruxtecan-nxki (Enhertu) and sacituzumab govitecan-hziy (Trodelvy), approved in refractory settings, may move into earlier lines of therapy. “Those trials are now moving into the frontline setting in HER2-positive patients, even including HER2-low patients, and of course, with sacituzumab govitecan in TNBC [triple negative breast cancer]. We’re doing what we need to do, which is having these drugs approved in late-line settings, seeing them overcome relapsed/refractory disease, and having a quick move into the frontline arena.”

On the heels of the December 2020 emergency use authorization of Pfizer-BioNTECH’s BNT162b2, the first vaccine for the prevention of coronavirus disease 2019 (COVID-19), the oncology community can expect to hear more about platforms for personalized cancer vaccines. BNT162b2, cleared for individuals 16 years and older, contains messenger RNA.

“Interestingly, I’ve heard from several of the scientists that the COVID-19 vaccine was pretty simple compared with what they’re working on for cancer vaccines,” Burris said. “We’re going to see the play of cancer vaccines coming in. There are already some personalized cancer vaccine trials ongoing, for example, in melanoma, plus or minus the immunotherapies—we’ll see that in several other disease settings.”

Debu Tripathy, MD, is looking forward to gaining deeper insights into immunotherapy, ADCs, oral formulations of chemotherapy, and AKT inhibitors in breast cancer. “2021 is going to be a refreshing year in many ways, with a lot of new data and advances for our patients with breast cancer,” said Tripathy, a professor and chairman of the Department of Breast Medical Oncology in the Division of Cancer Medicine at The University of Texas MD Anderson Cancer Center in Houston.

Although more data are needed, Tripathy emphasized that findings from the phase 3 CONTESSA trial (NCT03326674) could advance the arena of oral taxane therapy over intravenous options. The combination of tesetaxel, a novel oral taxane, plus a reduced dose of oral capecitabine demonstrated improved outcomes over capecitabine alone in patients with hormone receptor–positive, HER2-negative meta-static breast cancer previously treated with a taxane, according to findings presented at the 2020 San Antonio Breast Cancer Symposium. The tesetaxel regimen resulted in median progression-free survival (PFS) of 9.8 months (95% CI, 8.4-12.0) compared with 6.9 months (95% CI, 5.6-8.3) with capecitabine alone (HR, 0.716; 95% CI, 0.573-0.895; 

Unlike standard paclitaxel and docetaxel, tesetaxel can be orally administered because of its improved bioavailability and resistance to the P-glycoprotein efflux pump, which mediates gastric absorption and chemotherapy resistance.

 “Because it can be used as a stand-alone regimen, it may make adjuvant and metastatic therapy easier to tolerate,” said Tripathy, adding that the tesetaxel regimen does carry more neuropathy than capecitabine alone. “We could have oral regimens where people don’t even have to come to infusion centers.”

In targeted therapies, Tripathy expects the science to move forward on AKT inhibitors even though 1 agent in this class, ipatasertib, failed to show a significant improvement in PFS in combination with paclitaxel compared with placebo plus paclitaxel in patients with locally advanced, unresectable or metastatic TNBC with PIK3CA/AKT1/PTEN alterations in the IPATunity130 trial (NCT03337724). Investigator-assessed median PFS was 7.4 months (95% CI, 5.6-8.5) in the ipatasertib arm versus 6.1 months (95% CI, 5.5-9.0) with paclitaxel alone (HR, 1.02; 95% CI, 0.71-1.45; log-rank 

 = .9237). Nevertheless, the overall response rate (ORR) was 39% (95% CI, 31%-47%) with ipatasertib versus 35% (95% CI, 25%-46%) with paclitaxel alone.

“Unfortunately, the PFS was no different. Patients who had aberrations in this path-way did appear to have a benefit from the use of ipatasertib, so we look forward to more data,” Tripathy said.

Another AKT inhibitor, capivasertib, is currently being explored in the phase 3 CAPItello-290 study (NCT03997123) in combination with paclitaxel as a front-line treatment for patients with locally advanced or metastatic TNBC. In summary, Tripathy noted, there will be more data from this class of drugs.

For immunotherapy, a constantly evolving field, Tripathy predicted that nearly every medical meeting in 2021 will provide updates. Following the read-outs of the IMpassion031 (NCT03197935) and KEYNOTE-355 (NCT02819518) trials, which led to the approvals of atezolizumab (Tecentriq) plus nab-paclitaxel (Abraxane)

 and pembrolizumab (Keytruda) plus chemotherapy

 in patients with unresectable locally advanced or metastatic PD-L1–positive TNBC, more findings from immunotherapy studies in earlier stages of disease are expected.

“There are trials going on in [hormone receptor]–positive breast cancer in the neoadjuvant setting with pembrolizumab in patients with [stage] III breast cancer, so we’re going to be getting a lot of output from trials in the ones that are in the early-stage setting—which are very important for preventing a recurrence in the first place—if it can be given with good quality of life,” Tripathy said.

In the lung cancer field, 2021 will encompass a greater focus on adjuvant trials, additional novel molecular compounds for select patient subgroups, and a migration of circulating tumor DNA (ctDNA) analysis into a more minimal residual disease (MRD)–based setting, according to Balazs Halmos, MD, MS.

“2020, despite being a terrible year as a result of COVID-19, actually has been a good year for thoracic oncology,” said Halmos, a professor of clinical medicine at Albert Einstein College of Medicine and director of both the Multidisciplinary Thoracic Oncology Program and Clinical Cancer Genomics at Montefiore Medical Center, both in Bronx, New York. “As for next year, I think it will be hard to replicate what we’ve seen this year in terms of the great successes, but there are definitely a number of stories that will continue to unfold.”

The KRAS story, a molecular target long considered undruggable, is certainly an area where advances will continue, Halmos predicted. The agent that has attracted the most attention in this category so far is sotorasib (formerly AMG 510), a KRAS inhibitor being developed under a breakthrough therapy designation for patients with locally advanced or metastatic NSCLC with 

In the phase 2 CodeBreaK100 study (NCT03600883), sotorasib demonstrated an ORR of 32.2% (95% CI, 20.62%-45.64%) among previously treated patients with mutated NSCLC.

 Studies of other KRAS pathway inhibitors are under way, and Halmos said next steps will include combining these agents in the first-line setting with chemotherapy and/or immunotherapy. “There are some of the downstream inhibitors—for example, the SOX-inhibiting compounds—so there is great excitement in that field,” he said.

Other targets of interest that will gain more traction this year include therapies aimed at 

), as data sets continue to mature and results are reported. The challenge, Halmos said, will be to identify which patient subgroups are the best candidates to receive novel ADCs such as trastuzumab deruxtecan and patritumab deruxtecan (U3-1402), which have demonstrated antitumor activity in 

“ERBB2 is emerging as a real target now in lung cancer with these excellent antibody-drug conjugates that have shown success in breast, colon, and gastric cancers and likely will yield great benefits in 

–positive lung cancer patients, as well,” Halmos said.

In immunotherapy, Halmos is hoping for further advances in the adjuvant setting, both as monotherapy and in combination, for stage III disease. The phase 3 PACIFIC trial (NCT02125461), which led to the approval of the PD-L1 inhibitor durvalumab (Imfinzi) for patients with unresectable stage III NSCLC,

 initiated a new journey for checkpoint inhibitors as adjuvant therapy. “In PACIFIC, we’ve seen a major advance, but why not take another step forward?” Halmos said.

As for new molecules, tiragolumab, a monoclonal antibody directed at the TIGIT inhibitory immune checkpoint, is part of a new wave of developing strategies to leverage the immune system for anticancer therapy. These include vaccines that expand lymphocytes. “It can also be a more individualized approach; it’s almost like the CAR T-cell therapy approaches that are being investigated in some of these particular subsets,” Halmos said. “There is a lot of excitement there.”

Anticipation is also building with canakinumab (Ilaris), which is currently indicated for the treatment of a spectrum of autoinflammatory conditions, such as rheumatologic disorders. The agent demonstrated tolerability when used in combination with pembrolizumab and platinum-based doublet chemotherapy in the phase 2 CANOPY-1 trial (NCT03631199) in patients with advanced or metastatic NSCLC.

In addition to therapeutic changes, Halmos is anticipating growing clinical utility for ctDNA assays. Given their convenience and ease, Halmos emphasized, practitioners should already be familiar with utilizing ctDNA testing to make individualized treatment decisions for patients with lung cancer. However, he is ready for the technology to move to the next level.

“I’m very eager to see ctDNA moving into the MRD platforms, where we can detect MRD after surgery or definitive chemoradiation and can use it to monitor immunotherapy responses. We’ve seen a lot of exciting technologies this year reflecting that, so that’s the next wave,” Halmos said.

Major developments that unfolded in late 2020 will shape practice and research for prostate, bladder, and kidney cancers going forward, said Neeraj Agarwal, MD. He is a professor of medicine and holds a Presidential endowed chair of cancer research at the University of Utah Huntsman Cancer Institute (HCI). He also serves as director of the Genitourinary Oncology Program and the Center of Investigational Therapeutics, and coleads the Experimental Therapeutic Program at the HCI.

Agarwal called the FDA approvals of the PARP inhibitors olaparib (Lynparza) and rucaparib (Rubraca) the biggest highlight in the treatment of patients with metastatic castration-resistant prostate cancer (mCRPC) in 2020. Rucaparib is indicated for men with a deleterious 

 mutation (germline and/or somatic) who have been treated with a novel androgen signaling– directed therapy and a taxane-based chemotherapy.

 Olaparib is approved for men with multiple deleterious or suspected deleterious germline or somatic homologous recombination repair gene mutations including 

 who have progressed following prior treatment with enzalutamide (Xtandi) or abiraterone acetate (Zytiga).

“We are going to see movement of PARP inhibitors to earlier lines of therapies with 3 trials going on in the first-line mCRPC setting, which will be declaring results in 2021 or 2022,” Agarwal said. These studies, all phase 3 trials, are TALAPRO-2 (NCT03395197), testing talazoparib (Talzenna) plus enzalutamide; MAGNITUDE (NCT03748641), evaluating niraparib (Zejula) plus abiraterone and prednisone; and PROpel (NCT03732820), exploring olaparib plus abiraterone (

In advanced bladder cancer, results from the JAVELIN Bladder 100 trial (NCT02603432) published in September established maintenance avelumab (Bavencio), as the standard of care. Maintenance avelumab plus best supportive care (BSC) induced a median overall survival of 21.4 months (95% CI, 18.9-26.1) compared with 14.3 months (95% CI, 12.917.9) for BSC alone (HR for death, 0.69; 95% CI, 0.56-0.86; 

= .001). At 1 year, 71.3% of patients in the experimental arm were alive versus 58.4% of those in the BSC arm. Patients in the trial had unresectable locally advanced or metastatic urothelial carcinoma without disease progression after 4 to 6 cycles of platinum-based chemotherapy.

The finding “undoubtedly places avelumab as the treatment of choice with category 1 evidence endorsed by all major guidelines,” Agarwal said. “I don’t think we have seen a similar magnitude of survival benefit with any treatment ever in the setting of metastatic bladder cancer.”

In 2021, Agarwal expects the ADCs enfortumab vedotin-ejfv (Padcev) and sacituzumab govitecan to be important developing agents. “We will see various combinations of these drugs coming up,” Agarwal said. “The phase 3 trial [EV-302; NCT04223856] has already started in the first-line setting, where enfortumab vedotin is being combined with pembrolizumab, and I think similar trials of sacituzumab are expected down the line,” he said. “This will mean that this highly well-tolerated chemotherapy delivering ADCs will be available to our patients who are newly diagnosed with metastatic bladder cancer in the very near future; I’m really hoping in the next few years at most.”

In metastatic renal cell carcinoma (RCC), Agarwal expects a new class of drugs, hypoxia-inducible factor-2α (HIF-2α) inhibitors, to become “a huge story.” In July 2020, the FDA granted breakthrough therapy designation to MK-6482 for the treatment of patients with von Hippel-Lindau (VHL) disease–associated RCC with nonmetastatic tumors less than 3 cm who do not require immediate surgery. The agency also granted the HIF-2α inhibitor orphan drug designation for patients with VHL disease.

Investigators are exploring the novel agent in a phase 3 trial (NCT04195750) in advanced clear cell RCC, a phase 2 trial (NCT03401788) in VHL-associated RCC, and a phase 1/2 dose-escalation and dose-expansion trial (NCT02974738) in advanced solid tumors, including advanced RCC.

Development of established agents will continue as well, Agarwal added. “We will be seeing the field of metastatic RCC rapidly evolving in 2021, with approval of cabozantinib [Cabometyx] with nivolumab [Opdivo], approval of pembrolizumab plus lenvatinib [Lenvima], and newer trials testing HIF-2α inhibitors in various combinations and, hopefully, approval of HIF-2α inhibitors for our patients.”

Cellular and targeted therapies continued to dominate the trends in the treatment of hematologic malignancies last year. Although practice-changing data did not shake up the treatment landscape dramatically in 2020, research presented at the 62nd American Society of Hematology (ASH) Annual Meeting and Exposition set the stage for where the field is headed in 2021, according to Lori A. Leslie, MD.

The development of additional molecularly targeted therapies and the search for enhanced immunotherapy regimens are expected to permeate the oncology landscape across a broad range of malignancies as 2021 unfolds.

Vol. 22/No. 01 | Oncology Live®

Adult Nonmalignant Hematology Is an Endangered Field That Merits Protection

HER2-Directed Antibody-Drug Conjugates May Carve Out a Place in NSCLC Landscape

First BCMA-Targeting Therapy Debuts in Multiple Myeloma

PFS Deserves More Than Surrogate Status as a Clinical Trial End Point

More Innovation Is on Tap for 2021: Five Experts Describe Key Trends

Momelotinib Trial Seeks to Address Myelofibrosis Symptoms