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PER® Chemotherapy Foundation Symposium (CFS)

The treatment landscape of relapsed/ refractory multiple myeloma (RRMM) has undergone rapid changes over the past 2 decades, with over a dozen drug approvals by the FDA. Between December 2019 and September 2020, 4 new drugs received approval: the oral selective inhibitor of nuclear export selinexor (Xpovio), the anti-CD38 monoclonal antibody isatuximab-irfc (Sarclisa), the subcutaneous formulation of daratumumab (Darzalex Faspro), and the anti-BCMA antibody-drug conjugate belantamab mafodotin-blmf (Blenrep) (

). With multiple drug options available within 7 classes of antimyeloma agents in various combinations, therapeutic sequencing in RRMM has become increasingly complex. Moreover, it has been shown that response rates and duration of response diminish with each successive line of therapy,

 making the early use of efficacious regimens to achieve and sustain remissions critical.

Timeline. Drug Approvals in Multiple Myeloma, June 2019 to September 2020

Numerous randomized studies of novel agents added to an immunomodulatory drug (IMiD) or proteasome inhibitor (PI) backbone in RRMM have shown improvement in outcomes compared with doublet controls. However, cross-trial comparisons are limited by differences in patient populations and study designs, and it is important to not simply compare outcomes such as overall response rate (ORR), progression-free survival (PFS), and overall survival (OS) among trials but to also appreciate the relative benefit from the novel agent over the control arm via the HR. Additionally, clinicians must take into account factors such as frailty and comorbidities, symptom burden and disease biology, as well as toxicities and patient response to prior therapies, when making therapeutic decisions. Recent reviews summarizing current treatment paradigms in RRMM have been published,

 from which a basic framework for choosing therapies in early and late relapses can be drawn using data from major phase 3 randomized IMiD- and PI-backbone studies in RRMM.

Investigators have conducted multiple large phase 3 randomized studies of lenalidomide (Revlimid)– and bortezomib (Velcade)–backbone regimens in RRMM. These agents in combination have demonstrated a consistent PFS benefit when triplet regimens are used compared with doublet control across studies.

Specifically, investigators examined lenalidomide and dexamethasone (Rd) alone versus Rd in combination with a third agent, including carfilzomib (Kyprolis) in ASPIRE (NCT01080391), 

ixazomib (Ninlaro) in TOURMALINE-MM1 (NCT01564537), elotuzumab (Empliciti) in ELOQUENT-2 (NCT01239797), and daratumumab (Darzalex) in POLLUX (NCT02076009).

Further, studies using the backbone regimen of bortezomib and dexamethasone (Vd) versus Vd and a third agent included carfilzomib in ENDEAVOR (NCT01568866), panobinostat in PANORAMA-1 (NCT01023308), elotuzumab in a phase 2 study (NCT01478048), daratumumab in CASTOR (NCT02136134), and most recently, pomalidomide (Pomalyst) in OPTIMISMM (NCT01734928), venetoclax (Venclexta) in BELLINI (NCT02755597), and selinexor in BOSTON (NCT03110562).

In many of these studies, patients were not heavily pretreated, having received a median of 1 to 2 lines of prior therapy. Of the Rd- and Vd-backbone studies, data from the daratumumab combination studies—POLLUX and CASTOR—have shown the lowest PFS HRs (0.43 and 0.31, respectively). Notably, patients with translocation t(11;14) in the BELLINI study had a remarkable PFS HR of 0.10, which might be considered the first example of personalized medicine in MM.

Initial results of the ongoing phase 3 BOSTON study evaluating selinexor in combination with Vd (SVd) versus Vd in RRMM have also shown a PFS benefit (13.9 vs 9.5 months, HR, 0.70) with SVd compared with Vd.

 Whereas most novel therapies to date have resulted in an improvement in PFS for high-risk patients but have not shown the ability to overcome high-risk status,

 it is notable that patients enrolled in the BOSTON study with 17p deletion had a PFS HR of 0.38, suggesting a possible benefit of this combination in patients with high-risk disease.

Importantly, with long-term follow-up, data have shown that a PFS benefit can translate to an OS benefit in some studies. Of the Rd-backbone studies, an OS or PFS2 benefit has been reported in 3 studies. In ASPIRE, the median OS was 40.4 months versus 48.3 months in the Rd versus carfilzomib plus Rd arms, respectively (HR, 0.79).

 The median OS for patients enrolled in ELOQUENT-2 was 39.6 months with Rd compared with 48.3 months with elotuzumab plus Rd (HR, 0.78).

 In POLLUX, the median PFS2 favored the combination of daratumumab plus Rd versus Rd alone (53.3 vs 31.6 months, respectively; HR, 0.54).

Similarly, in the Vd-backbone studies, data from ENDEAVOR demonstrated an improvement in OS, with a median OS of 47.8 months for carfilzomib and Vd and 38.8 months for Vd (HR, 0.76). The most recent analysis of CASTOR showed that daratumumab plus Vd (DVd) significantly prolonged PFS2 compared with Vd alone (34.6 vs 20.7 months; HR 0.47), with a trend toward improved 3-year OS rates.

When considering the above, it is important to appreciate that OS outcomes across studies can be confounded by differing access to drugs at time of progression. Of note, although the BELLINI study demonstrated improved PFS with the addition of venetoclax to Vd overall, a nearly 2-fold-higher risk of death was observed in the venetoclax arm (HR, 1.47). The increase in deaths was due mainly to treatment-emergent infections. Further, in a subgroup analysis, 3 groups of patients did not benefit from the addition of venetoclax to Vd: patients without t(11;14), those with high-risk cytogenetics, and those with low expression of BCL-2.

Selecting an evidence-based regimen based on refractoriness to the backbone control arm is of critical importance. When considering the above Rd- and Vd-backbone studies, in lenalidomide- and bortezomib-sensitive patients, using daratumumab combination regimens in early relapses is efficacious and likely to attain a greater PFS benefit, as suggested by the PFS HR data. However, many of the Rd-backbone studies in RRMM have excluded lenalidomide-refractory patients. As seen in the Vd-backbone studies OPTIMISMM, CASTOR, and ENDEAVOR, the median PFS of lenalidomide-refractory patients is inferior to that of the total study population. 

For lenalidomide-refractory patients, specifically, the median PFS for each trial was 9.5 versus 5.6 months (pomalidomide and Vd [PVd] vs Vd), 9.3 versus 4.4 months (DVd vs Vd), and 8.6 versus 6.6 months (carfilzomib and dexamethasone [Kd] vs Vd), respectively. In comparison, the median PFS for the total study populations was 11.2 versus 7.1 months (PVd vs Vd), 16.7 versus 7.1 months in (DVd vs Vd), and 18.7 versus 9.4 months (Kd vs Vd).

Thus, the use of second-generation IMiDs and PIs in patients who are refractory to lenalidomide or bortezomib at relapse becomes necessary. Moreover, as daratumumab moves to the front-line setting, the use of second-generation IMiDs and PIs should be considered in patients who may be refractory to daratumumab and lenalidomide or bortezomib at the time of first relapse.

In subsequent relapses, early use of a second-generation IMiD- and PI-based triplet regimen should be considered based on recent data from major randomized studies. The IMiD-based pomalidomide and dexamethasone (Pd) combination studies include ELOQUENT-3 (NCT02654132), investigating Pd alone or in combination with elotuzumab (EPd), and ICARIA-MM (NCT02990338) examining isatuximab and Pd (Isa-Pd) versus Pd alone. The PI-based Kd studies include CANDOR (NCT03158688) comparing daratumumab plus Kd (KdD) versus Kd alone, and IKEMA (NCT03275285), Isa-Kd vs Kd).

A significant PFS benefit with the triplet regimen versus doublet control has been seen in both the randomized phase 2 ELOQUENT-3 and phase 3 ICARIA-MM studies, in which the patient populations were heavily pretreated, and the majority were lenalidomide refractory. The median PFS in ELOQUENT-3 was 10.3 versus 4.7 months with EPd vs Pd, respectively (HR, 0.34), and 11.5 months versus 6.5 months with Isa-Pd vs Pd in ICARIA-MM (HR, 0.60). Additionally, early data have shown an improvement in OS in both studies, with a 68% 18-month OS rate versus 49% for EPd versus Pd, respectively (HR, 0.54), and 72% versus 63% for Isa-Pd vs Pd, respectively.

Based on these trials, the addition of elotuzumab or isatuximab to a Pd backbone therapy offers considerable benefit in patients with heavily pretreated RRMM. Pd is also being studied in combination with daratumumab in RRMM in the ongoing phase 3 APOLLO study (NCT03180736). Daratumumab in combination with Pd previously received FDA approval based on data from the phase 1 EQUULEUS study (NCT01998971) study of approximately 100 patients.

Two major phase 3 Kd-backbone studies, CANDOR and IKEMA, have similarly shown a significant PFS benefit in heavily pretreated MM patient populations. In CANDOR, the median PFS was not reached with KdD compared with 15.8 months for Kd alone (HR, 0.63). The median PFS in IKEMA was not reached with the triplet regimen of Isa-Kd versus 19.2 months for Kd alone (HR, 0.53). Although OS data are not yet mature, PFS HRs favor the triplet combinations across clinically important subgroups including lenalidomide-exposed and lenalidomide-refractory patients. Notably, numerous clinical trials of carfilzomib to date, CANDOR and IKEMA, are the first to use Kd at a dose of 56mg/m

Based on the trials above, for patients who are refractory to lenalidomide and bortezomib at relapse, clinicians should highly consider subsequent therapy with a CD38 monoclonal antibody in combination with Pd or Kd. Additionally, they should base their choice of the IMiD or PI backbone on patient character

istics including age, cardiovascular risk, and cytopenias. For example, a CD38 monoclonal antibody in combination with a Pd backbone would be an ideal choice in patients without cytopenias, those with a cardiac history, elderly patients (> 70 years), and those who desire to minimize parenteral therapies. A CD38 monoclonal antibody in combination with a Kd backbone may be a more optimal treatment selection for patients with cytopenias, a thrombotic history, and those who have t(4;14).

Patients who have become refractory to existing therapies have a very poor prognosis, in particular those who are penta refractory (or refractory to a CD38 monoclonal antibody plus 2 IMiDs plus 2 PIs) and those who are triple refractory and quad refractory (refractory to a CD38 monoclonal antibody plus 1 or 2 IMiDs plus 1 PI, or a CD38 monoclonal antibody plus 1 IMiD plus 1 or 2 PIs).

 The development of novel agents for the treatment of such patients is a critical need.

The novel agent selinexor, a first-in-class selective inhibitor of nuclear export, has been approved in combination with dexamethasone in RRMM.

 Selinexor is further being studied in combination with several other MM backbone therapies, including in combination with Rd and Pd as well as daratumumab and dexamethasone (Dd) and Kd in the ongoing multiarm phase 1/2 STOMP study (NCT02343042). Early results of selinexor in combination with Rd and Pd arms of the STOMP trial have shown promising activity.

 Moreover, initial results of selinexor in combination with Dd have demonstrated activity in patients with IMiD- and PI-refractory MM.

Belantamab mafodotin, a first-in-class anti-BCMA antibody-drug conjugate, is another novel agent under clinical development for MM. It recently received accelerated approval from the FDA based on the promising preliminary results of the ongoing phase 2, randomized DREAMM-2 trial (NCT03525678) as monotherapy for adult patients with RRMM who have received at least 4 prior therapies including an anti-CD38 monoclonal antibody, a PI, and an IMiD.

 From the safety data available to date, an important toxicity observed with belantamab mafodotin is keratopathy. Thus, a Risk Evaluation and Mitigation Strategy program is required to manage the risks of ocular toxicity with the administration of belantamab mafodotin. The agent is also being studied in combination with IMiD and PI backbones including Rd and Vd in the DREAMM-6 trial (NCT03544281).

Melflufen, an aminopeptidase with an alkylating payload, has shown clinical activity in patients with heavily pretreated RRMM and triple-class refractory disease and has been granted priority review by the FDA.

In conclusion, the major trials of combination therapies in RRMM to date have shown superior efficacy of the triplet regimens over double controls. An important factor in selecting subsequent therapy is a patient’s sensitivity to lenalidomide and bortezomib, as well as daratumumab, at time of relapse.

Daratumumab-based combinations in early relapses likely confer a greater benefit in PFS. For patients who are refractory to lenalidomide and bortezomib at relapse, clinicians should consider subsequent therapy with a CD38 monoclonal antibody in combination with a second-generation IMiD and PI. The should also continuously access clinical trial options should be continuously assessed throughout the disease course.

Results of the aforementioned ongoing clinical trials of novel agents as well as others in clinical development for RRMM—such as anti-BCMA antibody-drug conjugates, bispecific T-cell engagers, chimeric antigen receptor T-cell therapies, and the next-generation cereblon E3 ligase modulator iberdomide (CC-220)—will undoubtedly further change the treatment landscape.

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The treatment landscape of relapsed/ refractory multiple myeloma has undergone  rapid changes over the past 2 decades, with over a dozen drug approvals by the FDA. 

Navigating the Increasing Complexity of Therapeutic Sequencing for Relapsed/Refractory Multiple Myeloma

A strong cognizance of germline testing is becoming increasingly important in the field of oncology, across an array of tumor types, according to Mark E. Robson, MD, who also emphasized the critical role of genetic professionals in terms of interpreting assay results during the 

“Importantly, germline predisposition is more common than we once believed, and it can't always be identified through traditional criteria. In fact, about 50% of women with 

-mutated triple-negative breast or ovarian cancers do not appear to have a family history that would have triggered testing before they were diagnosed themselves,” Robson explained. “This must be kept in mind. This is particularly the case now that PARP inhibitors have become such an integral part of the care pathway for patients with these diseases. This is now expanding, with the evidence that PARP inhibitors are active in prostate and pancreatic cancers, and they may be beneficial in other tumor types and other genes, as well.”

, Robson, who is the chief of Breast Medicine Service at Memorial Sloan Kettering Cancer Center, discusses the critical importance of germline testing and genetic counselors in the field of oncology.

: What are some of the limitations with germline testing? What research efforts are needed to address these challenges?

 Understanding of the germline landscape in patients who have cancer is becoming increasingly important. One of the challenges is establishing a distinction between testing for therapeutic decision making, which should be quite broad, and testing for the purposes of risk assessment in unaffected individuals, which perhaps could be narrower.

The reason that the distinction is important is because the way that providers should go about obtaining consent, is different. People who need the information for treatment decision making, may need a different level of decision making for assistance. This is the same for men if they’re trying to establish their own personal risk level. So, the traditional counseling models that are focused on risk assessments remain highly appropriate for that setting; however, it might not be efficient enough to test people for therapeutic decision making.

Furthermore, interpreting test results remains difficult and, in some ways, it's becoming more difficult as more genes are incorporated into multi-gene panel testing.

It’s very important, on the back end, to ensure that the input from informed genetics professionals is being interpreted and acted upon correctly. Unfortunately, this is not always happening. People are defaulting to how they would manage a [patient with a] 

 mutation, even if the individual has another alteration.

Could you further expand on these reports and how they are evaluated?

The report is just like any other laboratory report, it tells us whether there is a finding. However, moving from the finding to an action requires education. The provider has to understand what the appropriate recommendations are. If they're not entirely clear about what the recommendations are, they need to ensure that there’s access to more specialized information and they should refer the patient to a genetic counseling group.

How do liquid and tissue biopsies compare?

Germline testing is usually conducted by using blood and normal cells that are circulating in the blood; however, oftentimes, saliva could also be used. When you start talking about tissue or liquid biopsies, it’s true that germline abnormalities can be reflected in those samples. However, in theory, they could also just be abnormalities that arose in the tumor itself.

There are patients who have mutations, such as 

 which are only present in tumors and not in the blood. As such, if you're using circulating tumor DNA from the tumor or blood as a way of identifying mutations in these genes, then you must reflect on the blood test to evaluate whether it’s inherited and potentially shareable with other members of the family.

How could we augment the utility of germline testing in this space?

We need to develop 2 different pathways. We need to develop a clear-cut pathway for providing individuals with the information they need to essentially ask or agree to germline testing in the setting of therapeutic decision making. It’s particularly important for them to understand that these results do potentially have family implications and, therefore, they need to be prepared to share that information with family members.

Efficient pathways are critical, especially when providing information to people who do not have cancer and are seeking risk assessment. We must leverage new technologies such as telehealth and centralized testing.

Moreover, we need to have satisfactory follow-up pathways established for individuals who are undergoing therapeutic decision making, along with those who are undergoing a risk assessment test, without the involvement of a genetic counselor. I believe that there's a number of places where those handoffs are not as robust as they could be.

As we continue to discover more actionable alterations, do you see the field of oncology broadening multi-gene panels or creating more tumor-specific assays?

It’s probably going to be broad because it’s more efficient that way. The incremental cost of adding additional genes onto a multi-gene panel is relatively limited. There are technological limits to what one can do but, pragmatically, making tumor-specific decisions is just going to become increasingly challenging.

If you're doing this in the germline setting, it becomes complicated because you have several different kinds of information that you can get from a tumor agnostic panel. Some of that is not relevant at all. For instance, if you conduct a broad multi-gene panel, you may find an alteration in a gene that causes Lynch syndrome in someone who has breast cancer, which is probably not a Lynch syndrome-associated cancer. While you're looking for a therapeutic target, you’re also simultaneously screening the population, which is complicated.

People have to understand that, even with the different types of information that flows out of a multi-gene panel, it doesn't necessarily mean that they need to choose.

Is there anything that you would like to add?

Genetics professionals continue to play a critical role in variant interpretation [and in making] recommendations for non-therapy–related actions, such as screening and prevention-related actions. With cascade testing, we could maximize the benefits for the family as a whole. The models that do not fully incorporate genetics professionals into this process are unwise and are certainly not taking full advantage of the information that can be provided.

Mark E. Robson, MD, discusses how a strong cognizance of germline testing is becoming increasingly important in the field of oncology, across an array of tumor types. 







Need for Germline Testing Becomes Increasingly Pronounced in Oncology

Maurie Markman, MD, physician and president of Medicine and Science at Cancer Treatment Centers of America, and the editor-in-chief of our flagship publication, 

, discusses the utility of PARP inhibitors in ovarian cancer.

The field of ovarian cancer has continuously improved due to the number of clinical trials done and advancements made in the space, says Markman. Patients who have a documented 

 mutation, either germline or somatic, and have achieved a partial or complete response to primary chemotherapy can receive benefit from PARP inhibitors, says Markman. The benefit of PARP 

 is impressive, according to Markman. Hazard ratios observed with these agents are around 0.30, which equates to a 70% reduction in the risk of progression, explains Markman.

That benefit has not been observed in solid tumor oncology for 30 to 50 years, and 

 not in ovarian cancer, says Markman. That is a population-based outcome and results have showed that PARP inhibitors have led to a doubling or more in terms of time to progression compared with placebo, adds Markman. Some trials have follow-up between 3 to 6 years and the curves between placebo and PARP inhibitors remain very separated. 

 mutation receive PARP inhibitors, unless there is a contrary indication, such as a patient without insurance, says Markman. Even then, there are programs have that have been developed to assist patients, concludes Markman.

Maurie Markman, MD, discusses the utility of PARP inhibitors in ovarian cancer.

Dr. Markman on the Benefit of PARP Inhibitors in Ovarian Cancer

James B. Yu, MD, MHS, professor of Therapeutic Radiology at Yale School of Medicine, and associate chief medical officer for Radiation Oncology, and medical director Smilow Radiation Oncology, at Smilow Cancer Hospital, discusses the utility of radiation in men with prostate cancer.

Two groups of data support the use of radiation in metastatic prostate cancer, says Yu. The first concerns the efficacy of radiation when a patient already has metastatic disease. The phase 3 STAMPEDE study, which included patients with a low metastatic burden who benefitted from treatment with radiosurgery or radiation therapy, helped to answer this question, according to Yu. 

That was a revelation for the field because if the cancer is spreading, the question now has to do with the utility of local treatment when the primary concern is dealing with the metastatic disease, says Yu; theoretically, this might be helpful because it prevents future metastatic disease from the primary tumor. In general, this also decreases disease burden, which will prove beneficial for patients with metastatic disease.

The second batch of evidence pertains to metastatic disease that is recurrent or metastatic disease where the primary tumor has already been treated, adds Yu. Results from multiple studies have demonstrated that if all sites of metastatic disease are treated with focused radiation, the prostate-specific antigen levels can be better controlled, the hormonal therapy could be decreased, or, if a patient is on life-long hormonal therapy, future metastatic disease could potentially be decreased, concludes Yu.

James B. Yu, MD, MHS, discusses the utility of radiation in men with prostate cancer.

Dr. Yu on the Role of Radiation in Prostate Cancer

The National Cancer Institute (NCI) has made several efforts to combat the coronavirus disease 2019 (COVID-19) pandemic, according to Norman E. “Ned” Sharpless, MD, such as investigating anticancer agents to treat the disease, increasing flexibility with regard to clinical trials, and conducting critical serology research to increase understanding and inform future approaches.

On November 3, 2020, the World Health Organization reported that more than 3.3 million new cases of COVID-19 had been reported worldwide in the past week alone.

 As of November 1, 2020, approximately 46 million cases, along with 1.2 million deaths had been reported worldwide. In the United States, the Centers for Disease Control and Prevention has reported around 9,463,782 cases since January 21, 2020; 629,390 if those cases were identified in the past week.

 (CCC19), investigators have been able to collect important data on adult patients with a history of or who currently have an invasive solid tumor or hematologic malignancy and have also been diagnosed with COVID-19.

Results from this effort have revealed some factors that are associated with increased 30-day all-cause mortality in patients with cancer and COVID-19, including increasing age, male sex, smoking status (former smoker vs never smoker), cancer status (present, stable, or responding, and present, progressive disease vs remission or no evidence of disease), treatment with hydroxychloroquine plus azithromycin versus treatment with neither, and 2 or more comorbidities requiring treatment.

 These efforts have also yielded factors that are not associated with mortality such as race and ethnicity, obesity, type of malignancy, type and recency of anticancer treatment, and recent surgery.

“As many of you are aware, the NCI has significant expertise…and a lot of external capabilities to do cutting-edge research in an emergency setting,” said Sharpless, director of the NCI, in a virtual presentation during the 

. “As such, I think it was natural when the pandemic really got going, that the NCI was asked to step in and help provide some scientific response.”

Disruptions to Care Projected to Impact Cancer Mortality in Next Decade

A modeling effort performed last spring and published in 

 utilized the NCI’s Cancer Intervention and Surveillance Monitoring Network (CISNET) to better understand cancer control interventions in terms of prevention, screening, and treatment and their impact on population trends in both incidence and mortality.

“We asked the CISNET investigators to consider what we thought at that time were quite significant disruptions to cancer care, [in terms of] screening, diagnosis, and delayed therapy,” said Sharpless. “We asked [them to make] what we thought were significant assumptions about disruption of care [so we can gain some insight on] what would happen to cancer mortality over the next decade.”

Investigators looked specifically at breast and colorectal cancers, as the CISNET models were advanced for these 2 tumors, according to Sharpless. When looking at the modeled cumulative excess deaths from these disease from 2020 to 2030, investigators projected that there would be an excess of 10,000 deaths, or a 1% increase in mortality over the next decade, said Sharpless. The same disruptions are believed to be at play in other malignancies, as well.

“We feel that the assumptions we made about the disruptions to care, were, if anything, conservative estimates and the disruptions that we're actually seeing in hospitals across the country are greater than what we had predicted back then in June,” said Sharpless. “This is something that we all have to bear in mind. We need to share some collective responsibility [to determine] how to preserve the cancer care enterprise during a pandemic and ensure that we're not exchanging one public health crisis for another.”

In light of the pandemic, data have indicated that there has been a decline in cancer screening and diagnosis, along with decreased or deferred care; these disruptions will likely have long-term implications for cancer mortality, stressed Sharpless. To combat this, the oncology community needs to come together to find safe, innovative ways to prioritize care for patients with cancer, he added.

“We don’t want our patients to be at risk for COVID-19, nor their caregivers; however, we need to get back to business,” said Sharpless.

The NCI has made several efforts in response to the pandemic. These efforts range from repurposing anticancer drugs to treat COVID-19, to the launch of the NCI COVID-19 in Cancer Patients Study (NCCAPS), to providing guidance and special procedures for clinical trials in the field of oncology, to conducting SARS-CoV-2 serology research, and offering flexibilities and opportunities for grantees.

Repurposing Cancer Drugs to Fight COVID-19

Patients who have severe infection with COVID-19 have a hyperinflammatory immune response that is indicative of macrophage activation. BTK is known to influence macrophage signaling and activation. Bearing this in mind, the selective BTK inhibitor acalabrutinib (Calquence) was evaluated off-label in 19 hospitalized patients with severe COVID-19 infection; of these patients, 11 required supplemental oxygen, while 8 were on mechanical ventilation. In 10 to 14 days of treatment, acalabrutinib led to an improvement in oxygenation in most patients; this benefit was observed within 1 to 3 days of treatment and with no toxicity was observed.

“Now, this agent is under exploration in 2 large randomized trials in Europe and the United States as a disease-modifying agent and for patients who may or may not get steroids depending on the clinical setting,” said Sharpless. “This is an example of the kind of scientific observation that comes out of the NCI; [this treatment] might make a difference for patients with [cancer and] COVID-19.”

In light of the pandemic, many laboratories had to close down, timelines for clinical trials were delayed, and several adjustments were required in order to continue the investigation of potentially life-saving drugs in patients who needed them most.

In recognition of the challenges posed by the pandemic with regard to clinical trials being performed in the United States, the NCI collaborated with the FDA to provide flexibility to their supported efforts. For example, patient care can now be transferred to different participating study sites. Also, local healthcare providers are able to provide study activities to encourage the continuity of care. Oral drugs may now be shipped from the NCI and trial sites directly to the study participant to decrease unnecessary risk. Moreover, remote informed consent via telephone has also become acceptable, in conjunction with a patient signature on a written document.

“We know that this has been a successful [effort]. Accrual on NCI therapeutic trials has largely returned to normal. Also, we have polled investigators and they really like some of these flexibilities,” said Sharples. “This is, perhaps, the silver lining of the pandemic. We've learned how to do trials in the modern era of Zoom chat and telehealth. We won’t forget those lessons. Many of these flexibilities will be good for clinical trials going forward and will affect how the NCI does business even after the pandemic is [over].”

NCCAPS Clinical Trial to Collect Longitudinal Data

NCCAPS is a natural history clinical trial of COVID-19 in patients with cancer. For the study, investigators are following patients and collecting relevant information over time to better understand how the virus and its symptoms develop and evolve.

 The objective of the trial is to help inform the future management of patients with cancer who are also diagnosed with COVID-19. The comprehensive dataset with collect information on cancers, treatments, symptoms, course, recovery, and comorbidities with longitudinal follow-up.

In the study, investigators will gather blood samples to estimate antibody response and genetic susceptibility. These samples will also be utilized for biomarker development. A total of 2000 patients are anticipated to be included in this trial.

“We launched this trial in about 6 weeks last spring and it is now open at nearly 1000 sites in the United States. It has begun fairly robust accrual for patients with a history of cancer and COVID-19 infection,” noted Sharpless. “We believe it will be very valuable to understand the

biomarkers that predict bad outcomes in patients with cancer, as well as to understand the longitudinal history of this disease, or the so-called long-haul COVID-19 conditions that we are now seeing in some patients.”

In October 2020, the NCI launched the Serological Sciences Network for COVID-19 (SeroNet), the goal of which was to increase the nation’s capacity for antibody testing and to assist the country’s research community to glean a better understanding of immune response to the virus.

“The NCI has a long history in serology research, and it has a fantastic lab that does serology research for human papillomavirus vaccine response; it was 1 of the standard study labs for the World Health Organization and other international agencies,” said Sharpless. “When the pandemic began, we repurposed that lab to become a SARS-CoV-2 coronavirus lab…[We wanted to] create a network to increase capacity for coronavirus testing and serology testing in the United States.”

This initiative is anticipated to engage over 25 academic, government, and private sector biomedical research institutions to evaluate immune response to the virus as a means for producing rapid testing and developing novel therapeutics and vaccines.

To assist this initiative, Congress authorized $306 million for the NCI to develop, validate, improve, and apply serological testing and associated technologies, according to the NCI.

Flexibilities to Support Grantees During the Crisis

In light of the COVID-19 pandemic, the NCI has also channeled efforts into providing certain flexibilities to grantees who experienced disruptions to their research efforts.

“This has been [a] hard [time] for trainees who need to move to the next stage of their training or [who need to] get a job,” noted Sharpless. “This has also been difficult for scientists whose labs have been closed or whose clinical research efforts have been put on pause. The NCI, along with the broader National Institutes of Health, has been trying to send the message to grantees that we are going to allow every possible flexibility during the pandemic so that research can get back to normal as quickly as possible.”

Some of the flexibilities offered by the NIH include extending deadlines for applications, permitting institutions to use NCI grant funds to maintain salaries and stipends, extending project timelines and reporting requirements, extending eligibility periods for early-stage investigators and trainees, and carryover for institutional training grants with previous approval.

2021: 50th Anniversary of the National Cancer Act of 1971

Outside of the COVID-19 pandemic, and with a goal to honor the 50th anniversary of the National Cancer Act of 1971, the NCI has announced that they seek to build a coalition of support for cancer research, which includes raising the payline to 15% by 2025.

“This is a commemoration of an important milestone. All the progress we've made in the past 5 decades has been wonderful and important, but we still have much yet to do,” concluded Sharpless. “The NCI would like to see this become a joined moment for the community to start talking about the National Cancer Act and what it means for cancer research in general. The entire cancer research and care community should discuss this; it’s an opportunity to make clear to the public and Congress what we've accomplished and where else we can go next.”

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Norman E. “Ned” Sharpless, MD, discusses the efforts that The National Cancer Institute has made to combat the coronavirus disease 2019 pandemic. 

PER® Chemotherapy Foundation Symposium (CFS) | Conference

Navigating the Increasing Complexity of Therapeutic Sequencing for Relapsed/Refractory Multiple Myeloma

Need for Germline Testing Becomes Increasingly Pronounced in Oncology

Dr. Markman on the Benefit of PARP Inhibitors in Ovarian Cancer

Dr. Yu on the Role of Radiation in Prostate Cancer

NCI Director Talks Response to COVID-19 Crisis, Focuses on Overcoming Disruptions in Cancer Care

Hudis Emphasizes Need for Cancer Research Funding During CFS® Keynote

Unlocking the Potential of Targeted Treatment Options for HCC

Dr. Weber on the Evolution of Melanoma Treatment

Immunotherapy in Gynecologic Cancers Shows Progress but Has a Long Way to Go

Dr. Jhaveri on Outlining First-Line Treatment in HER2+ Breast Cancer