Months of deferred screenings or delayed treatments due to coronavirus disease 2019 (COVID-19) could reverse the US streak in improved cancer mortality that has lasted more than 25 years, said Norman E. “Ned” Sharpless, MD, director of the National Cancer Institute (NCI), during the American Society of Clinical Oncology (ASCO) 2020 Annual Meeting, presented in a virtual format due to the pandemic.

Sharpless, who served briefly as acting FDA commissioner in 2019, opened the virtual session on “Cancer and COVID-19” with a sober assessment of COVID-19’s effects on both clinical care and cancer research.

His talk preceded presentations on some of the earliest findings about the effects of COVID-19 on cancer: It appears that patients treated with chemotherapy for lung or thoracic cancer shortly before being diagnosed with COVID-19 face a higher risk of death, and so do patients with cancer who take the combination of hydroxychloroquine (HCQ) and azithromycin.

The separate data sets help shape an emerging picture of what patients with cancer face under COVID-19: They are more likely to be older or have underlying health problems, which are known to make the virus more deadly.

And, as explained by Jeremy L. Warner, MD, MS, an associate professor of medicine at Vanderbilt University Medical Center, patients may be immunosuppressed, from the treatment or the disease itself, and have more frequent contact with the health care system than people without cancer.

The decision to preserve hospital and clinical capacity was “necessary and important” as COVID-19 peaked this spring, Sharpless said, “But all this deferred care—it’s going to have costs for patients with cancer,” he noted. “It may mean more cancer suff ering outcomes for our patients. What we don’t know yet is the scale of these bad outcomes.”

Each year, Sharpless said, NCI works with the American Cancer Society and others to publish an annual report on the state of cancer, and the declining mortality rates have become an annual “shot in the arm” for cancer researchers. “My fear is that diminished cancer care will produce a negative impact on these cancer statistics of relevance to the public health. And we expect to see these trends play out over several years,” he said. “We cannot escape this reality.”

Research is taking a hit, too, as patient accruals in NCI trials have fallen off pace, and Sharpless said he had heard similar reports about industry-sponsored trials. What has fi lled the gap somewhat, he said, are aggressive efforts to start trials to understand COVID-19’s eff ect on patients with cancer. He highlighted 2 groups presenting results during the ASCO meeting, as well as registries set up by ASCO and the American Society of Hematology.

On May 21, 2020, NCI launched the COVID-19 in Cancer Patients Study

that will enroll 2000 patients with cancer who are diagnosed with COVID-19. “We aim to conduct the study at more than 1000 sites,” Sharpless said. “We need to know as much about the impact of COVID-19 on cancer patients in Montana as we do

He asked, rhetorically, “What have you learned about the impact of the virus on patients across racial and ethnic groups?” Sharpless pointed out that the NCI effort “is not a registry” but a trial approved by an institutional review board; investigators will seek patient consent to collect samples, analyze biomarkers, and develop germline sequencing of patients.

Patients who participate will be required to have regular health care visits, during which the facility will collect blood samples and copies of routine imaging scans for up to 2 years. “It’s important to note that participation in this study will not require additional visits to the hospital or other facilities,” Sharpless said. “Much of the data will be collected electronically and some of the tests will be part of the patient’s routine care.”

Prior smoking history or lung damage are among the characteristics that put patients with thoracic cancer at particular risk from COVID-19, according to insights gleaned from 400 patients’ records in the Thoracic cancERs international coVid 19 cOLlaboraTion (TERAVOLT) registry.

tumors, mesothelioma, carcinoid tumors, and thymic neoplasms.

According to the researchers, use of chemotherapy within 3 months of a COVID-19 diagnosis turned out to have a particularly strong association with early death: a 64% increased risk of dying from the virus. The effect of chemotherapy was seen whether or not patients also had other therapies, such asœimmunotherapy,œwhich showed up as a potential risk factor in an earlier study.

Of the 400 patients, 144 died: 79.4% (n = 112) from COVID-19, 10.6% (n = 15) from cancer, and the rest from other causes. Treatments with anticoagulants and corticosteroids were also linked to increased death risk, adding to existing concerns about the use of corticosteroids for patients with chronic disease. More data will be needed to draw any fi rm conclusions about the use of anticoagulants.

Lead author Leora Horn, MD, MSc, commented on the speed with which the research eff ort has taken shape. “In less than a week, we had a study enrolling patients,” said Horn, who is the Ingram Associate Professor of Cancer Research and the director of the thoracic oncology program at Vanderbilt University Medical Center. “We have seen clinical trials being funded, approved, and enrolling patients within weeks, when it can often take months or years to get approval for a trial.”

Cancer patients with COVID-19 who were treated with both HCQ and azithromycin were 3 times more likely to die during the 30 days after they were diagnosed with COVID-19, according to fi ndings4 presented by Warner, lead author of the study from the COVID-19 and Cancer Consortium, which launched its registry March 15.

Warner cautioned that the association is of “uncertain validity” and may stem from residual confounding. “For example,” he said, “patients receiving this combination were more likely to have severe disease or more likely to be hospitalized.”

The researchers also reported that neither drug was associated with an added mortality risk when taken alone.

After some statistical adjustments, the researchers found that patients with worsening cancer were 5 times more likely to have died within 30 days of their COVID-19 diagnosis than patients in remission or with no evidence of disease.

Of the 928 people with cancer and COVID-19 who were included in the study, 121 (13%) died within 30 days of their COVID-19 diagnosis, according to fi ndings that Warner presented. The written abstract, submitted earlier to meet ASCO deadlines, had slightly diff erent numbers: 1108 cases and 106 deaths, or 10.4% of the total cases. 

In their analysis of the cases and deaths, the researchers found that factors associated with a 30-day mortality risk including worsening, progressing, or active cancer; older age; male sex; and being a former smoker.

Only 3 of the 121 deaths that Warner discussed in his video presentation were of people with no comorbidities. Of the 466 who were hospitalized, 106 died.

1. NCI COVID-19 in Cancer Patients Study (NCCAPS). National Cancer Institute. May 21, 2020. Accessed May 30, 2020. https://www.cancer.

gov/research/keyinitiatives/covid19/coronavirusresearchinitiatives/nccaps

2. Horn L, Whisenant JG, Torri V, et al. Thoracic Cancers International COVID19 Collaboration (TERAVOLT): impact of type of cancer therapy and COVID therapy on survival. J Clin Oncol. 2020;38(18 suppl; abstr LBA111). doi:10.1200/JCO.2020.38.18_suppl.LBA111

3. Dai M, Liu D, Liu M, et al. Patients with cancer appear more vulnerable to SARSCoV2: a multicenter study during the COVID19 outbreak.’Cancer Discov. 2020;10(6):783791. doi:10.1158/21598290.CD200422

4. Warner JL, Rubinstein S, Grivas P, et al. Clinical impact of COVID19 on patients with cancer: data from the COVID19 and Cancer Consortium (CCC19). J Clin Oncol. 2020;38(18 suppl; abstr LBA110). doi:10.1200/JCO.2020.38.18_suppl.LBA110

Articles

Evidence-Based Oncology

The talk by Ned Sharpless, MD, director of the National Cancer Institute, preceded presentations on some of the earliest findings about the effects of COVID-19 on cancer: It appears that patients treated with chemotherapy for lung or thoracic cancer shortly before being diagnosed with COVID-19 face a higher risk of death, and so do patients with cancer who take the combination of hydroxychloroquine (HCQ) and azithromycin.

COVID-19 and Cancer: NCI's Sharpless Says COVID-19 Could Halt Streak of US Cancer Mortality Gains

Virtual for the first time ever, the annual meeting of the American Society of Clinical Oncology (ASCO) kicked off its sessions with an address from outgoing president Howard A. “Skip” Burris III, MD, who will next assume the position of chair of ASCO’s Board of Directors.

“Our patients are the reasons we do what we do. They are the reason we do the work. It’s been a joy for me to have such a diverse job,” said Burris, who is also president of clinical operations, chief medical offi cer, and executive director of drug development at Sarah Cannon Research Institute. Additionally, he is a member of the board of directors of’Conquer Cancer: The ASCO Foundation. Burris, a 1981 graduate of the United States Military Academy at West Point who served with the Army Corps of Engineers, chose the 2-pronged theme for his yearlong presidential term to be “Unite and Conquer: Accelerating Progress Together.”

“Uniting and conquering” and “accelerating progress” are goals that can be addressed, and accomplished, through a multidisciplinary team approach to cancer care, believes Burris. He views this approach as essential to every patient’s spectrum of care, with the patient squarely at the center. The approach pairs well with

the ASCO mission, which is conquering cancer through the latest research and education, as well as promoting the importance of quality patient care. Burris returned to the mission time and again, sharing highlights from the past year while noting how far the fi eld of oncology still has to go to improve the quality of cancer care through education, research, and advocacy—principles that underlie ASCO’s mission.

“We’ve had advancements, but we need to go faster,” Burris pointed out, stressing the importance of advancing therapies for better patient outcomes by addressing obstacles to patients’ care. “Access to care, access to clinical trials, and access to information are really key.”

Burris highlighted’ASCO CancerLinQ, an initiative that is aggregating big data from clinicians across the country, analyzing the findings. The entire cancer community will have access to CancerLinQ. Burris also described ASCO’s push to transform care delivery, and in doing so he broached an issue that continues to trouble many: patients’ inability to access care because of fi nancial reasons. ASCO is helping to address this barrier to health care through its’Patient-Centered Oncology Payment Program, an alternative payment model meant to ensure access to high-quality and high-value care.

Last fall, Burris noted, ASCO volunteers held more than 160 meetings, advocating to Congress on behalf of the Bipartisan Clinical Treatment Act, which would require Medicaid to cover the routine costs that come with being in a clinical trial, including doctor visits and lab studies. The act is meant to open up access of patients, especially underrepresented minorities, to potential treatment advances. It would be a victory for ASCO and for patients with cancer, Burris stressed.

Burris noted how his 30-plus years as a clinical researcher, clinical oncologist, leader of people—there are more than 1000 now at Sarah Cannon&mdash;military experience, and dual passions of cancer drug development and phase 1 clinical trials have opened his eyes to so much high-quality work that is going on both in the United States and around the world. It’s given him a great sense of faith and confi dence in the future of the field to see so many people pulling together to try to improve cancer care.

“We are strongest together. We are united in our mission to reduce the global burden of cancer,” Burris said. “We need all of you serving on our committees and task forces, connecting and collaborating, to solve the complex problems of cancer care. Together we are a powerhouse.”

“We’ve had advancements, but we need to go faster,” said ASCO President Howard A. "Skip" Burris III, MD, as he stressed the importance of advancing therapies for better patient outcomes by addressing obstacles to patients’ care. “Access to care, access to clinical trials, and access to information are really key.”

Access to Care: Burris Says United With Our Patients, We Accelerate Progress Together

Pembrolizumab as First-Line Treatment Doubles PFS in Certain Patients With Colorectal Cancer

Using Biomarkers to connect the right patients with the right treatment at the right time is the mantra for deciding when to use immunotherapy in cancer care. Results presented virtually at the American Society of Clinical Oncology (ASCO) 2020 Annual Meeting proved that point for certain patients with metastatic colorectal cancer (mCRC).

The interim analysis of the phase 3 KEYNOTE-177 trial, presented during ASCO’s plenary session on May 31, showed that using pembrolizumab as a first-line therapy in mCRC patients with specific genetic mutations—microsatellite instability high/mismatch repair defi cient (MSI-H/dMMR) tumors&mdash;doubled progression-free survival (PFS) compared with chemotherapy (16.5 vs 8.2 months).

FDA approval for pembrolizumab in this setting came less than a month later, on June 29, 2020, as 

Lead study author Thierry André, MD, professor of medical oncology, the Sorbonne Université and Hôpital Saint Antoine in Paris, said during the plenary session that the results would change clinical practice. “No medical treatment has shown such an improvement,” he noted.

“Pembrolizumab works in nonrandomized studies in this group of patients with advanced disease,” André said. “This randomized study demonstrates a huge benefi t in fi rst-line [treatment] with pembrolizumab and should be the new standard of care.”

Michael Overman, MD, of the University of Texas MD Anderson Cancer Center, a discussant for KEYNOTE-177, agreed. “These results should change clinical practice,” he said, noting that the type of tumors being treated in the study are particularly good candidates for immunotherapy. Going forward, Overman said, “It is critical that we test all colorectal cancer patients for mismatch repair or microsatellite status.”

The only caveat, Overman explained, might involve patients for whom near-term survival is the highest priority, because results show that the benefit of immunotherapy over chemotherapy does not start to appear until about the 6-month mark. About 5% of mCRC patients’ tumors are MSI-H/dMMR, and these patients do not fare as well with conventional chemotherapy.

Pembrolizumab’s effectiveness when this mutation is present is well recognized, and it led to FDA’s first tissue-agnostic approval in 2017.

“These data represent another step forward for biomarker-driven studies,” André said. 

The data cutoff for the interim analysis was February 19,¨2020; at that time, the study included 307 mCRC patients with MSI-H/dMMR. Patients were randomized to receive first-line pembrolizumab for up to 2 years, or the investigator’s choice of 6¨diff erent standard chemotherapy regimens. Primary end points were PFS and overall survival (OS), while secondary end points included objective response rate (ORR) and safety.

An independent data monitoring committee had¨previously found statistically signifi cant and clinically meaningful improvement, and it called for the trial to continue without changes to the second co-primary end point of OS.

Patients in the chemotherapy group who progressed were allowed to cross over into the pembrolizumab group.

At 12 months, PFS was 55.3% with pembrolizumab vs 37.3% with chemotherapy; at 24 months, PFS was 48.3% with pembrolizumab vs 18.6% with chemotherapy.

The ORR, a measure of how much patients’ tumors shrank, was also better for the patients treated with pembrolizumab: 43.8% compared with 33.1% for chemotherapy. The data also show:

• 11% of the pembrolizumab patients had a complete response, meaning no detectable cancer, compared with 3.9% treated with chemotherapy

• 32.7% of the pembrolizumab patients had a partial response, compared with 29.2% in the chemotherapy group

• 30.9% taking pembrolizumab had stable disease, compared with 42.2% in the chemotherapy group.

• 83% in the pembrolizumab group had responses lasting longer than 2 years, compared with 35% in the chemotherapy group.

Severe events, grade 3 or above, were less common among patients in the pembrolizumab group: 22%, compared with 66% in the chemotherapy group. The most common toxicities in the immunotherapy group were colitis and hepatitis, while the most frequent chemotherapy-related toxicities were diarrhea, neutropenia, fatigue, nausea, stomatitis, alopecia, and neurotoxicity. Merck funded the study.

1. André T, Shiu K-K, Kim TW, et al. Pembrolizumab versus chemotherapy for microsatellite instability-high/mismatch repair deficient metastatic colorectal cancer: the phase 3, KEYNOTE-177 study. J Clin Oncol. 2020;38(18 suppl; abstr LBA4). doi:10.1200/JCO.2020.38.18_suppl.LBA4

2. Caffrey M. Pembrolizumab approved for first-line treatment of patients with colorectal cance and key mutations. The American Journal of Managed Care® website. www.ajmc.com/newsroom/pembrolizumab-approved-for-firstline-treatment-of-patients-with-colorectal-cancer-and-key-mutations. Published and accessed June 29, 2020.

3. FDA grants accelerated approval to pembrolizumab for first tissue/site agnostic indication. FDA. May 23, 2017. Updated May 30, 2017. Accessed June 6, 2020. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-pembrolizumab-first-tissuesite-agnostic-indication

4. Merck announces KEYTRUDA (pembrolizumab) significantly improved progression-free survival as first-line treatment for advanced microsatellite instability high (MSI-H) or mismatch repair deficient (dMMR) colorectal cancer. News release. Merck; April 2, 2020. Accessed June 6, 2020. https://investors.merck.com/news/press-release-details/2020/Merck-Announces-KEYTRUDA-pembrolizumab-Significantly-Improved-Progression-Free-Survival-as-First-Line-Treatment-for-Advanced-Microsatellite-Instability-High-MSI-H-or-Mismatch-Repair-Deficient-dMMR-Colorectal-Cancer/default.aspx

Osimertinib After NSCLC Surgery Keeps Cancer at Bay for Patients With Key Mutation

Osimertinib, already the first choice to treat patients with advanced EGFR-mutated non—small cell lung cancer (NSCLC), should become the treatment of choice for patients with this mutation who are treated after surgery for early-stage, localized disease, according to the lead investigator who outlined results virtually at the American Society of Clinical Oncology Annual Meeting.

A remarkable 90% of the patients with stage II or stage IIIA NSCLC who received the targeted therapy osimertinib after surgery were alive after 2 years without cancer recurring, compared with 44% of those patients who received placebo, according to fi ndings presented during the May 31, 2020, plenary session. In patients at these stages, the risk of death or recurrence was reduced by 83%. Median disease-free survival (DFS) for osimertinib was not reached (NR) while for placebo, it was

20.4 months (HR, 0.17; 95% CI, 0.12-0.23; 

The full study, called ADAURA, was unblinded in April after the overwhelming effi cacy became evident.

 AstraZeneca, maker of osimertinib (Tagrisso), a third-generation 

 tyrosine kinase inhibitor, sponsored the study.

Roy S. Herbst, MD, PhD, the lead study author and chief of medical oncology at Yale Cancer Center and Smilow Cancer Hospital, called the trial a “home run” and said the results clearly pointed to giving osimertinib to patients earlier in course of treatment.

”Collectively, these data support the use of osimertinib as an appropriate treatment in the long-term adjuvant setting,” Herbst said, with safety and tolerability being important considerations. “Looking ahead, future considerations for ADAURA include investigation of local versus distant recurrence; sites of disease recurrence, including incidence of [central nervous system] metastases; subsequent therapy; and quality of life.”

with disease ranging from stage IB to IIIA, treatment with osimertinib reduced the risk of death or recurrence by 79% compared with placebo. Overall, DFS at the 2-year mark was 89% with osimertinib vs 53% for placebo.

Of note, Herbst pointed to data showing that patients who had adjuvant chemotherapy alongside osimertinib fared about the same as those who did not. Among patients who received chemotherapy, the median DFS for osimertinib was NR, compared with 22.1 months for those on placebo (HR, 0.18; 95% CI, 0.11-0.29).

Among those without chemotherapy, median DFS for osimertinib was NR, compared with 33.1 months for placebo (HR, 0.23; 95% CI, 0.13-0.38).

Data for overall survival are not yet mature, and both Herbstand a discussant, David Spigel, MD, chief scientific officer of the Sarah Cannon Research Institute, acknowledged that this might be challenging to evaluate going forward, now that the trial has been unblinded.

Other questions remain, including what happens after 3 years, when patients would be scheduled to stop taking the daily 80-mg tablets. Still, Spigel said if asked the question he hears in the clinic—which treatment would he give a family member?&mdash;he would choose osimertinib.

The results have important implications for managed care. Currently, patients with stage IB to stage III NSCLC who have surgery to remove the tumor typically have chemotherapy, but Herbst said rates of recurrence are high: Cancer returns in about half of patients with stage IB disease, and rates are higher at later stages.

In addition, the ability to more eff ectively treat patients with early-stage 

-mutated NSCLC tumors raises new questions about the need to screen more patients for lung cancer—and catch more cancers at earlier stages. Spigel said it is unclear at this point whether osimertinib is eliminating disease or “simply controlling and deferring disease that cannot be eradicated.” But the safety and tolerability of the targeted therapy are important, given a planned 3-year treatment course. And, he said, the results were consistent across subgroups.

Adrian Kilcoyne, MD, MBA, MPH, AstraZeneca’s vice president for US Medical Affairs and Health Economics Outcomes Research in Oncology, said the results should be paradigm shifting. “What we’ve been able to demonstrate is compelling,” Kilcoyne said. Any time a study is stopped early the results are important, but ADAURA “is important in a number of ways.”

“One, it’s telling us that if you hit [the disease] early, you can have very compelling results in lung cancer,” Kilcoyne said. “Second, in some of these patients, while they all had surgery, not all of them had adjuvant chemotherapy—half didn’t&mdash;and regardless of that, you’re seeing a signifi cant benefit. “It may drive people to want to identify disease earlier, which is&bsp;really important, too.”

When asked if the results might reopen discussion about current US Preventive Services Task Force guidelines on who should be screened or lung cancer,

 Kilcoyne said, “You’ve asked the million dollar question.”

Current guidelines are based on a mix of factors that include a person’s age, smoking history, and how long ago they quit smoking. Some study results suggest that the guidelines do not cast a wide enough net, but a CDC study found earlier this year that even under the current standards, very few people eligible for screening are tested.

”We’re at a point where we just can’t just focus on smoking,” Kilcoyne expressed. “ I think we should look at screening in a far more broad way. It’s not just screening patients who would have been smoking, how many pack years, age, etc.…How we screen is going to be incredibly important. We need to embrace newer

technology” that takes a personalized medicine approach.

1. Herbst RS, Tsuboi M, John T, et al. Osimertinib as adjuvant therapy in patients (pts) with stage IB-IIIA EGFR mutation positive (EGFRm) NSCLC after complete tumor resection: ADAURA. J Clin Oncol. 2020;38(18 suppl; abstr LBA5). doi:10.1200/JCO.2020.38.18_suppl.LBA5

2. Tagrisso phase III ADAURA trial will be unblinded early after overwhelming efficacy in the adjuvant treatment of patients with EGFR-mutated lung cancer. News release. AstraZeneca; April 10, 2020. Accessed June 6, 2020. https://www.astrazeneca.com/media-centre/press-releases/

2020/tagrisso-phase-iii-adaura-trial-will-be-unblinded-early-after-overwhelmingefficacy-in-the-adjuvant-treatment-of-patients-with-egfr-mutated-lung-cancer.html

3. Richards TB, Soman A, Thomas CC, et al. Screening for lung cancer—10 states, 2017. MMWR Morb Mortal Wkly Rep. 2020;69(8):201-206. doi:10.15585/mmwr.mm6908a1

4. Francis Crick Institute. New lung cancer trial will use personalized monitoring to help predict relapse. Technology Networks. May 26, 2020. Accessed June 6, 2020. https://www.technologynetworks.com/tn/news/new-lung-cancer-trial-will-use-personalizedmonitoring-to-help-predict-relapse-335275

Zanubrutinib Pulls Away From Ibrutinib in Update, Shows Durable Responses in WM Patients Lacking Key Mutation

Zanubrutinib, the Bruton tyrosine kinase (BTK) inhibitor approved by the FDA to treat mantle cell lymphoma, showed a clear advantage over its competitor in new data presented virtually on May 29, 2020, during the American Society of Clinical Oncology (ASCO) 2020 Annual Meeting.

The BTK inhibitor also produced meaningful and durable responses in certain patients with Waldenström macroglobulinemia (WM), even though they lacked a key mutation that has signaled successful treatment, according to updated results of the ASPEN trial.

 mutations are present in 95% of patients with WM, a rare form of lymphoma,‘and BTK inhibitors have been effective in treating WM patients who have them. Prior research showed poorer response rates and shorter progression-free survival (PFS) among those who lack the mutations. Complicating matters is the fact that diagnosing mutations in WM can be tricky.

Results from ASPEN released in December 2019, and updated at ASCO,

 compared zanubrutinib with ibrutinib in WM patients with the 

 mutation. Early reactions were mixed. Some analysts noted that the ASPEN trial missed the goal of doubling ibrutinib’s rate of complete or very good partial responses, but

others pointed to the fact that data showed zanubrutinib numerically outperformed ibrutinib, with 28.9% of relapsed or refractory patients achieving this mark, compared with 19.8% for ibrutinib. Results for all patients, including those starting treatment, were comparable—28.4% vs 19.2%.

In an interview, lead investigator Constantine Tam, MBBS, MD, a clinical hematologist and professor at the Peter MacCallum Cancer Centre in Victoria, Australia, noted there were “some imbalances” in the randomization; more patients in the zanubrutinib arm were older than 75 years and more were anemic.

ASPEN did more follow-up in January, accruing another 5 months of data. “This is important,” Tam said during the interview. “The longer you take the drug, the better your responses become.” So, while the study technically did not meet its end point, Tam said the lines separating zanubrutinib and ibrutinib have diverged since the first results were announced.‘Data presented online May 29, 2020, showed the following

Featuring findings from the KEYNOTE-177, ARAURA, ASPEN, and CITYSCAPE trials, and new results from MURANO. 

ASCO 2020: Clinical Updates

Bispecific antibodies received plenty of attention at last year’s meeting of the American Society of Hematology, and the momentum continued in late May during the virtual annual meeting of the American Society Society of Clinical Oncology (ASCO). As the name suggests, these therapies are manufactured proteins that can bind to 2 separate antigens at the same time, bringing extra power to the fight against cancer.

During ASCO, Janssen presented results from the CHRYSALIS study on amivantimab,

 a bispecific antibody being developed to treat non—small cell lung cancer (NSCLC). The pharma giant, along with its parent company, Johnson & Johnson (J&J), had previously received a breakthrough therapy designation in December for teclistamab, another bispecific antibody indicated for potential treatment of multiple myeloma.

Mark Wildgust, PhD, vice president of Global Medical Affairs/Oncology at Janssen, who leads a team of scientists and physicians developing new, targeted therapies for oncologic and hematologic conditions, expounded on the similarities and differences of these 2 novel dual-targeted therapies with 

Wildgust explained that intervening earlier in the premalignant setting is a primary goal. To that end, Janssen has 6 bispecific antibodies in development—all first-in-class therapies. He also touched upon medication aff ordability, noting that availability and regulatory approval are moot points if a drug is not accessible, because although it is proven safe and eff ective, patients can’t benefi t from a treatment if they can’t get it.

This interview has been edited slightly for clarity.

: Two bispecific antibodies in development, amivantamab for NSCLC and teclistamab for multiple myeloma, have some similarities, but one is being developed for a solid tumor and the other for hematologic cancer. Can you discuss the similarities and differences?

Both are built on the same duobody platform, which is what we call it. Bispecifics are essentially monoclonal antibodies that bind to 2 different targets—that’s why we call them bispecific. The method by which we make them is the same, but they are actually quite distinctly different.

Let’s take teclistamab. We actually create 2 individual antibodies: 1 targets CD3 and 1 targets BCMA. We then break those apart and glue them back together so that they can basically target CD3 and BCMA. So, that’s teclistamab.

Now, the same process is used for making amivantamab as well: 1 [antibody] targets 

 and 1 targets c-MET. We break these 2 antibodies apart and glue them back together and create that single bispecific. So, the similarities kind of end there. Then we get into the diff erences. Teclistamab binds to BCMA. BCMA is essentially an antigen target that’s almost ubiquitously expressed on myeloma cells. Then you have CD3. Why CD3? CD3 is essentially picking up T cells, which express CD3. The BCMA-CD3 teclistamab is really what we would call a T-cell redirector. It essentially picks up the T cell on the monoclonal antibody and then it binds to the BCMA antigen that’s expressed on the myeloma cells. And so, you’re essentially bringing the T cell to the cancer cell to kill it. So, that’s how teclistamab works. Amivantamab, though, targets 

 and c-Met, so it’s not redirecting T cells. With amivantamab you’re targeting 2 distinct antigen targets. And then there’s a variety of immune-type mechanisms by which binding of 

 or binding of c-Met separately kills the cancer cell. Why should you target 

When you think about NSCLC, there are those cases that are driven by driver mutations and those that are not. Those that are driven by driver mutations are things like 

 is quite distinct as a driver mutation. Lots of different compounds are out there for EGFR-expressing NSCLC, like gefitinib and erlotinib [Tarceva] and osimertinib. But we’ve learned over the last 10-plus years that in many 

 lung cancers, one primary mechanism of resistance is through c-Met.

 and c-Met is that potentially, you can target both the driver of the cancer and the resistance mutation, too.

/c-Met that’s unique as well. The different kinase inhibitors I just mentioned—like osimertinib and gefi tinib and Tarceva&mdash;target 

 from an intracellular perspective, and amivantamab targets it in an extracellular manner.

When you think about lung cancer and exon 20 insertion, why don’t the classical 

 inhibitors work in that space? They don’t work because they don’t have the ability to bind within the conformational pocket. By targeting the receptor from an extracellular perspective, you don’t have that issue. We know that about 10% of 

 lung cancers are of the exon 20 insertion type. They currently have no standard of care. By targeting 

 extracellularly, we can target that and potentially address something where current 

So, similarities, but quite a few more differences.

Are these therapies meant to be curative? 

 That’s a good question. Let’s take multiple myeloma for a second, a highly complex, heterogeneous disease. Once patients become refractory, we know that their overall survival is quite poor. I think in the refractory setting it’s very unlikely that we will give patients cure, but what we’re really trying to do is achieve really deep, durable responses, for as many patients as possible, with the idea that if we can get deep, durable responses, we can give them a meaningful amount of time.

In the relapse setting, I think that it’s about harnessing the immune system, harnessing those T cells to be able to try to target those cancer cells. As we learn more about teclistamab, I think the question will be, how can we use it to build curative-type regimens? One of our focuses at J&J and Janssen is to develop individual molecules or compounds, but at the same time, we’re very much interested in building curative regimens. So, I think for teclistamab in its current setting, unfortunately, I don’t think there is the potential for cure, mostly because of the disease complexity and heterogeneous nature. I think that teclistamab has the potential to be part of a regimen for cure in the earliest setting, and that’s certainly something that we will explore.

Now, in terms of amivantamab, there are a couple of places to think about it. The first is where we just got the breakthrough designation, for patients with the exon 20 insertion. A patient with lung cancer who has an 

 exon 20 insertion unfortunately has a survival of probably about a year and a half. Their outcomes are very poor.

I don’t think it’s really about cure, but more about trying to build regimens right now that can give patients more time. For patients with exon 20 insertion, for patients who have progressed after initial therapy—that’s where the breakthrough designation is for amivantamab. Once a patient has had initial therapy and progresses with exon 20, their median life expectancy is probably less than a year. What we’re trying to do now is give them more time. That’s the goal.

Ultimately, we would love to get to cure, and that’s part of our overall initiative. We actually have an ongoing lung cancer initiative across J&J; we brought the 3 different parts of the company together to look at how we can intervene earlier in the premalignant setting and premalignant stage. That’s the place

where we can think, potentially, about cure for some of these patients, and that’s part of our overall approach in terms of disease intervention.

: Especially for lung cancer, because it’s so often diagnosed in such a late stage that by the time it’s caught, it has metastasized.

Unfortunately, most patients are caught at stage IV because it’s relatively asymptomatic. Most patients might have a cough. It may seem like they have something that seems quite benign, so unfortunately, most patients get caught late. More than 1.8 million patients die a year from lung cancer worldwide,3 and the median life expectancy for a patient with newly diagnosed stage IV lung cancer is less than 2 years.

You saw some of the quite exciting data that came out at ASCO on one of the other compounds, looking at a checkpoint inhibitor in chemotherapy, and we’re heralding the outcomes of that. But we’re talking about moving survival by a couple of months. Median survival is still less than 2˜years, right? For 

-driven disease, the outcomes are a little bit better, but still, the outcomes are very poor. We’ve got a long way to go to help patients with lung cancer....

You asked me about cure. We’re trying to give patients more time by advancing new, innovative therapies. You talked about teclistamab and amivantamab; we have 6 different bispecifics in the clinic. All of them are brand-new, first-in-class therapies, and we’re hopeful that these can help advance care for patients.

 For teclistamab, what biologic process underlies the effectiveness for patients with hematologic malignancies who have not responded to prior therapies or have relapsed disease?

We know that the T cells in patients with multiple myeloma are still very active. So even in the patient who has been multiply treated or is refractory, we’re trying to harness the killing [power] of those T cells and redirect them to be able to kill the cancer cells. And because we know that BCMA is so widely expressed, we can target the antigen, that BCMA, and redirect the T cell there.

Then the question is going to be, are those responses durable? When you look at the teclistamab data, in particular—and we’re still in that dose-finding and dose-escalation phase with teclistamab, but also already at the 270 mcg/kg dose&mdash;we’re seeing two-thirds of patients responding. If we look broadly across the patients there, we’re seeing patients who are having not only responses, but durable responses. So, 16 of 21 patients in that trial&mdash;with time, we will report the data&mdash;still haven’t progressed.

When you talk about biological processes that underlie the effectiveness, I think the key question is, what causes resistance? Is it the T cell becoming exhausted? And if that’s the case, can we use checkpoint inhibitors to overcome that? Or is it the immunosuppressive eff ect of the bone marrow niche? Or is it loss of the receptor target? Did BCMA go away? Did the target go away?

We’re going to learn more about that in terms of patients who progress, and then from there, we can start to identify how we can better optimize care for these patients, using these T-cell—oriented or T-cell–redirecting types of compounds.

Is teclistamab being studied in patients who have relapsed on chimeric antigen receptor (CAR) T-cell therapy?

: Not yet, because we’re still in that dose-finding/dose-escalation phase, trying to understand what the right dose is. I think it is an outstanding clinical question. Could you target a patient who’s had a CAR T with a bispecific? I think there are 2 parts of that question. 

The fi rst is, do they have the same antigen target? If you think about a BCMA CAR T and a BCMA bispecifi c, there’s a question of, is that the right thing to do? Because we don’t know why patients might have progressed on the BCMA-targeted therapy. Maybe it wasn’t the loss of that BCMA antigen, and if that’s the case, then targeting it with another BCMA targeting agent probably doesn’t make sense. But if it’s actually something diff erent, then there may still be potential to do that.

Now, if you have a CAR T and a bispecific that target diff erent antigens, I think that’s an entirely diff erent question, and I think the answer is, yes, you probably could use them one after another. That’s because you’re really then talking about a different target versus anything else.

 Does amivantamab, which targets activating and resistant 

 and MET mutations and amplifications in NSCLC, have potential in other solid tumor cancers?

 is expressed in other cancers as well, and so is MET. And so, as part of our development plan, we will look at other cancers where EGFR and MET are potential drivers. I think the biggest unmet need is in NSCLC. As I mentioned earlier, patients with exon 20—expressing and 

-expressing lung cancer don’t respond to traditional 

-targeting agents. The outcomes for those patients are particularly poor. But dual targeting of 

 and MET is particularly interesting because we know MET is a resistance pathway for 

. But discretely, there are other cancers that are MET driven, 

 driven, and we will absolutely be thinking about exploring those other tumor types, looking at amivantamab.

 In results for amivantamab presented at ASCO, the overall median progression-free survival (PFS) of 8.3 and 8.6 months, clinical benefi t rates of 67% and 72%, and their ranges, were comparable between all patients and those who received previous platinum-based chemotherapy, respectively. How much of a survival advantage is amivantamab really providing?

CHRYSALIS is a single-arm exploratory cohort study. The idea was that we wanted to take the recommended phase 2 dose and then explore that in a cohort of patients who are exon 20. We’re not comparing it with something else, so I can’t tell you if it did improve survival. But the median survival is less than 12 months for a patient with exon 20 insertion who has progressed after prior therapy, so we know the outcomes for these patients are poor.

The PFS data that we reported were about 8.5 months, but those data are still actually quite immature. There’s a lot of censoring there, because the follow-up is quite short. We still need to learn more about the PFS for those patients. But to see a PFS of between 8 and 9 months in this group of patients, when the median survival is 12 months, is very promising. It seems like [amivantamab] is providing real benefi t, because the median PFS for these patients would normally be a couple of months. The data look exciting and promising.

I think that’s why the FDA gave us a breakthrough designation for this therapy. One, because there are no currently approved therapies out there. And second, because there’s a high unmet medical need. Again, the data look very, very promising, and better than anything else out there at this point.

 Do bispecific antibodies have other advantages?

 When we talked about amivantamab, we talked about targeting a receptor in a different way. That’s an advantage. But when you think about teclistamab, you have to think about it in terms of what other types of therapies are out there. You almost have to think about teclistamab as a bispecific and a CAR T.

And, fi rst of all, when we think about teclistamab and the CAR T, what are some of the differences?

First of all, we don’t see grade 3 or grade 4 cytokine release syndrome for teclistamab, and I think that’s particularly important. We see very low rates of neurotoxicity. But one of the things about CAR T cells is that you have to collect the patient’s T cells through apheresis, send them away, and have [the product] manufactured and come back. So, if a patient has a very aggressive myeloma, you can’t wait for the number of days it takes for that T cell to be sent off, to make a CAR T, and come back. Among of the benefi ts of the bispecific is that it’s on the shelf; it’s available straightaway for that patient who walks through the door.

It seems like teclistamab has a very good safety profile, which means it looks like a good option for patients in that regard. It doesn’t have the grade 3, grade 4, rates of neutropenia, anemia, and thrombocytopenia that you might see with CAR T therapy. I think there are advantages of them versus other similar targeting types of agents, like CAR Ts, which I think is good as well.

But the other advantage of a bispecific, particularly one like teclistamab, is that it’s taking those T cells that we know are active and redirecting them against the cancer. The advantage of something like amivantamab is that it’s dual-targeting. The potential to target both pathways is important, particularly as we know

that c-MET is a resistance escape pathway for 

This is a good example of how you start to think about, how do I use my tools? How do I use the different types of tools to target the cancer and to try to provide meaningful responses and benefit for patients?

While these therapies are still very early in the study phase, are there general financial models that Janssen or J&J is discussing with payers to ensure that this treatment can reach patients?

: I think at the end of the day, not necessarily with these specifi cally, our overall goal is to make our medicines accessible and aff ordable for patients of our health care systems. That’s the key. While we strive to develop innovative therapies that are transformative, the only medicines that really deliver value are those that patients can access. We work really hard with different health care systems around the world, and different governments and different stakeholders, to try to make our medicines available through coverage, through reimbursement. And as part of our development process, we engage with diff erent payers to try to understand how we can bring these medicines to patients, looking at different ways in which we can negotiate price or different agreement methods so that we can provide access.

At the end of the day, if you have a drug that’s available, but not accessible, then the regulatory approval really doesn’t count for anything, whether it’s safe or effective, because unless that patient can get it, they can’t receive the benefi t. So we take that very seriously. And whenever we develop medicines, we’re not only thinking about regulatory approval, we’re also thinking about making sure that we can provide access. And that means access through payers as well.

1. Study of JNJ-61186372, a human bispecific EGFR and cMet antibody, in participants with advanced non-small cell lung cancer (CHRYSALIS).

ClinicalTrials.gov. Updated June 2, 2020. Accessed June 8, 2020. https://clinicaltrials.gov/ct2/show/NCT02609776

During ASCO, Janssen presented results from the CHRYSALIS study on amivantimab, a bispecific antibody being developed to treat non–small cell lung cancer (NSCLC). The pharma giant, along with its parent company, Johnson & Johnson (J&J), had previously received a breakthrough therapy designation in December for teclistamab, another bispecific antibody indicated for potential treatment of multiple myeloma.

Janssen's Wildgust Breaks Down Bispecific Antibodies in Development for Non-Small Cell Lung Cancer and Multiple Myeloma

Genetic Testing Can Guide Treatment, but Access and Counseling Are Essential, Results Say

Advances in genetic testing increasingly connect cancer patients with treatments that work—and help them avoid those that won’t. But providers have a responsibility to make sure they are ordering the right tests and using the results correctly, said Erin Hofstatter, MD, associate professor adjunct and co-director of the Cancer Genetics and Prevention Program at Yale School of Medicine.

Getting the full picture means patients should have access to genetic counselors who can evaluate individual risk, Hofstatter said during the virtual session, “Cancer Risk, Genetics, and Prevention,” held May 30 during the¢American Society of Clinical Oncology (ASCO) 2020 Annual Meeting.

Hofstatter highlighted 4 studies that she said amplify the 3 components of using genetic testing in cancer treatment and prevention: (1) understanding the germline component of a tumor test, (2) broadening access to genetic counselors with video sessions, and (3) making sure risk assessment of each patient is accurate, so that patients do not have unnecessary surgeries.

. Tumor tests typically look for acquired mutations—somatic testing&mdash;to select targeted therapies. MSK-IMPACT evaluated the value, or clinical utility, of adding germline profi ling, for inherited mutations, for patients with advanced cancer, through next-generation sequencing.

 From a study population of 11,975 patients, investigators identified 2043 (17.1%) who had pathogenic or likely pathogenic germline variants, including 777 patients (6.5%) who had genes for which targeted therapies were available. Most of these were for BRCA mutations (n = 416) or for Lynch syndrome (n = 149). Of importance, Hofstatter said, is the share of patients with advanced disease who received a targeted therapy: The authors reported the share was 45.3% of 554 patients.

But Hofstatter noted that such findings are essentially a moving target. “If emerging genes of interest in homologous recombination repair are included, prevalence rose to 8.6%,” she said. “With the emergence of novel targeted treatments, it’s important to realize that the therapeutic actionability of germline variants is likely to increase signifi cantly over time,” Hofstatter noted. Increasingly, she said, the advanced setting is where germline testing will be indicated to select a cancer treatment. “It’s important to know your test. Remember that tumor sequencing is not a substitute for control. Hence of germline testing, and it should be considered separately to achieve the best results,” Hofstatter reminded.

 Despite broader availability of germline testing, uptake is poor. For instance, only about 2% of Lynch syndrome carriers have been identifi ed, Hofstatter said. Lack of knowledge, cost, inconvenience, and a shortage of genetic counselors—some payers require a counseling session before testing&mdash;have all been barriers.

Two studies presented during ASCO examined whether there was any disadvantage for patients if counselors met with them via telemedicine—a method that has taken off in recent months due to the coronavirus 2019 pandemic. The ProGen study, led by Huma Q. Rana, MD, of Dana-Farber Cancer Institute, was a randomized trial that compared the eff ectiveness of video visits with traditional genetic counseling among men diagnosed with prostate cancer.

—The study reported high uptake by both groups: 88% of the eligible men in the traditional counseling group agreed to be tested, compared with 93% of those eligible in the video group.

Testing completion rates were 99% in both groups who agreed to be tested, and according to initial survey results, patients in both groups were equally satisfied with the process. Over 2 years, 604 patients were tested and pathogenic variants were identified in 79 of them (13.2%).

However, Hofstatter noted that ProGen took place in a highly controlled setting. What, she wondered, would be the result in a study that reflected real-world conditions? For this answer, she turned to the MAGENTA study,

—which recruited many of its participants over social media. The study aimed to learn whether pre- and posttest genetic counseling is needed to best guide genetic testing for women at risk of hereditary breast and ovarian cancer.

All counseling took place online. Of 3822 patients randomized, 3111 were placed in a family-history cohort and 711 in a cascade cohort, where someone in the family was known to have a mutation. Among those completing genetic testing, 173 participants (7.2%) had a mutation in a breast or ovarian gene;

this included 114 patients (5.7%) in the family history cohort and 59 (14.2%) in the cascade cohort. Hofstatter explained the results, which focused on distress level among patients: It was lowest among those who had neither pre- nor posttest counseling. Overall, 318 participants (18%) had high levels of distress, and there was little difference whether their test was ultimately positive or negative.

Both studies, Hofstatter said, “demonstrate high uptake rates with pretest video education, and they truly represent new models of genetic counseling, breaking down barriers and improving accessibility to testing.

“And it would be very tempting,” Hofstatter continued, “to have our major take-home message being that pretest counseling is really [superfluous]—

that ‘Less is more,’ or at least that no counseling ‘is just as good.’ [Some could say,] ‘Let’s get rid of the counselors] altogether.’” However, “test completion 

or uptake of testing cannot be our only goal,” she said. “Truly, it’s what you do with the information from testing that counts. Certainly uptake, satisfaction,

Four studies were highlighted that amplified the 3 components of using genetic testing in cancer treatment and prevention: (1) understanding the germline component of a tumor test, (2) broadening access to genetic counselors with video sessions, and (3) making sure risk assessment of each patient is accurate, so that patients do not have unnecessary surgeries.

July 2020

COVID-19 and Cancer: NCI's Sharpless Says COVID-19 Could Halt Streak of US Cancer Mortality Gains

Access to Care: Burris Says United With Our Patients, We Accelerate Progress Together

ASCO 2020: Clinical Updates

Janssen's Wildgust Breaks Down Bispecific Antibodies in Development for Non-Small Cell Lung Cancer and Multiple Myeloma

ASCO 2020: Genetic Testing

ASCO 2020: Research Report

ASCO 2020: AJMCtv Interviews