Beth Fand Incollingo

In patients with non–small cell lung cancer (NSCLC) harboring a 

 G12C mutation, an aberration without any FDA approved treatment options, a study showed that the investigation agent, sotorasib (AMG510) achieved encouraging antitumor activity.

Findings from the study were presented during the 2020 European Society of Medical Oncology (ESMO) Virtual Congress and simultaneously published in the 

The investigational drug sotorasib (AMG510) demonstrated promising antitumor activity in patients with non-small cell lung cancer (NSCLC) that harbor the 

 p.G12C mutation, an aberration for which no targeted treatment has yet been approved, according to findings presented at the 2020 ESMO Virtual Congress and published simultaneously in the 

In a subgroup of the multicenter, open-label, phase I CodeBreaK100 trial that included 59 heavily pretreated patients with 

 p.G12C-positive NSCLC, researchers found that 32.2% experienced a confirmed objective response and 88.1% experienced disease control. The drug also had a favorable safety profile, David S. Hong, MD, deputy chair of investigational cancer therapeutics at The University of Texas MD Anderson Cancer Center, said. Hong, the study’s lead author, shared the data in an oral presentation at the congress.

 p.G12C mutation occurs in 13% of NSCLCs, 3% to 5% of colorectal cancers, and 1% to 3% of other cancers, Hong noted. Sotorasib, he said, is a first-in-class small molecule that selectively and irreversibly targets 

CodeBreaK100 included 129 patients: 59 with NSCLC, 42 with colorectal cancer, and 28 with any of 11 other solid tumor types. Hong’s presentation at ESMO focused on the patients with NSCLC.

Within the NSCLC subgroup, each of 4 cohorts received a different dose of the daily oral medication: 180 mg (n=3), 360 mg (n=16), 720 mg (n=6), and 960 mg (n=34). Although tumor reduction was seen across all dose levels, 960 mg was determined to be tolerable and the most effective, and thus was studied in the trial’s expansion phase.

The study’s primary endpoint was safety, with secondary endpoints including objective response rate (ORR), duration of response (DOR), disease control rate (DCR) and progression-free survival (PFS). At a median follow-up of 11.7 months, 14 patients were still receiving treatment. Most of the 45 patients who discontinued the drug did so due to disease progression.

Study participants were a median 68 years of age (range: 49-83), 59.3% female and 89.8% current or former smokers. All had previously received platinum-based chemotherapy, and most had taken PD-1 or PD-L1 immunotherapy prior. In all but 2 cases, the patients had ECOG performance scores of 0 or 1. Although eligibility criteria disqualified patients with brain metastases, 18 developed the condition, and Hong shared a case study demonstrating that one of them experienced central nervous system response to sotorasib.

At the first of a series of scans conducted every six weeks, researchers observed tumor shrinkage of any magnitude in 42 patients (71.2%), Hong reported. In the 34 patients who took the 960 mg dose, he said, the confirmed ORR was 35.3%, or 12 patients (95% CI, 19.8-53.5), the median duration of response was 10.9 months, with 10 of 19 responders still in response as of the data cutoff of June 1, 2020. The DCR was 91.2% (95% CI, 76.3-98.1); the median duration of stable disease was 4.0 months.

There were no complete responses. The rate of stable disease was 55.9% in both the 960 mg cohort (n=19) and across the whole study population (n=33). The median time to response was 1.4 months.

The median PFS for all patients with NSCLC in the study was 6.3 months (0.0+ to 14.9 months).

There were no dose-limiting toxicities, nor were there any treatment-related deaths. Grade 3 or 4 treatment-related adverse events (AEs) occurred in 18.6% of patients. This included a single grade 4 event, increased alanine transaminase (ALT). The most common grade 3 AEs were increased ALT in 6 patients and diarrhea and increased aspartate aminotransferase (AST) in 3 patients each. The most frequent AEs of any grade were diarrhea in 15 patients and increased ALT and AST in 12 patients each.

“Sotorasib demonstrates clinical activity in NSCLC across a range of 

 p.G12C mutant allele frequencies, PD-L1 expression levels, tumor mutational burden plasma levels, and co-mutational profiles,” Hong noted, with no particular mutation associated with a heightened response.

He added that “additional CodeBreaK trials evaluating sotorasib as a monotherapy or in combination with other anticancer agents are currently underway.”

Specifically, he said, it’s likely that sotorasib can be combined with checkpoint inhibitor immunotherapy because it “can have an immunogenic effect on the tumor microenvironment, so in combination will likely be synergistic.”

“This drug is overall relatively well tolerated and works across different dose levels,” he concluded, so “I’m confident we’ll be able to find a therapeutic window.”

Hong DS, Fakih MG, Strickler JH, et al. KRASG12C inhibition with sotorasib in advanced solid tumors. Presented at: 2020 ESMO Virtual Congress; September 19-21, 2020; Virtual. Abstract 1257O.

Articles

In patients with non–small cell lung cancer harboring a KRAS G12C mutation, an aberration without any FDA approved treatment options, a study showed that the investigation agent, sotorasib achieved encouraging antitumor activity.









Sotorasib Shows Early Activity in Advanced Non–Small Cell Lung Cancer

Selinexor (Xpovio) in combination with bortezomib (Velcade) and dexamethasone resulted in improvements in responses and outcomes compared with bortezomib and dexamethasone alone in patients with relapsed or refractory multiple myeloma, according to findings from the phase 3 BOSTON trial. Additionally, the triplet regimen showed a reduction in the frequency of peripheral neuropathy events.

Results of the global study were presented May 29 during the virtual scientific program of the American Society of Clinical Oncology (ASCO) 2020 Annual Meeting.

A first-in-class oral drug that reactivates tumor suppressor proteins, selinexor was approved in 2019 in combination with the steroid dexamethasone for heavily pretreated patients with relapsed or refractory myeloma that did not respond to at least 2 proteasome inhibitors, 2 immunomodulatory agents, and an anti-CD38 monoclonal antibody. Selinexor targets the protein XPO1 (exportin 1), which is overexpressed in myeloma.

The investigators embarked on the BOSTON study because twice-weekly administration of the subcutaneous proteasome inhibitor bortezomib as part of combination therapy is effective but can’t be used for extended periods as it sparks peripheral neuropathy in 50% to 60% of patients. Previous research testing selinexor in combination with bortezomib and dexamethasone demonstrated anti-myeloma activity in patients whose cancers were sensitive to proteasome inhibition, the authors noted.

In the BOSTON study, patients received either the selinexor triplet regimen or a doublet of bortezomib and dexamethasone.

The study enrolled 402 adults with ECOG status scores of 0-2 who had previously taken 1 to 3 treatments for myeloma but had never been exposed to a selective inhibitor of nuclear export. Of those, 207 took 1.3 mg/m

 of bortezomib and 20 mg of dexamethasone twice weekly, while 195 took that combination plus 100 mg of selinexor once weekly. In the selinexor arm, researchers lowered the bortezomib dose by 40% and the dexamethasone dose by 25% at 24 weeks.

The median age of participants was 67, with 59.6% older than 65 years, and 57.1% male. Baseline characteristics were balanced across the 2 arms.

When randomized, patients were stratified by the number of prior regimens used and Revised International Staging System stage III (18.5%) vs stages I or II. If participants taking the doublet experienced progressive disease, they were allowed to cross over to either the drug triplet or, if they were intolerant to bortezomib, to selinexor plus dexamethasone.

The primary endpoint of the study was progression-free survival (PFS) and secondary endpoints included objective response rate (ORR), overall survival (OS), duration of response, and peripheral neuropathy rates and outcomes.

Researchers found that the triplet significantly prolonged PFS compared with the doublet by a median 13.93 months versus 9.46 months (HR, 0.70; 

 = .0075). PFS was improved in all subgroups, including in patients with 17p deletions and those who had previously taken the immunomodulatory (IMiD) drug lenalidomide.

“As lenalidomide is often used in the frontline setting and with daratumumab, having an IMiD-free option in the relapsed setting with a novel mode of action is an important finding from the BOSTON trial,” said the study’s lead author, Meletios A. Dimopoulos, of the National and Kapodistrian University of Athens School of Medicine in Greece.

The triplet was associated with a significantly higher ORR overall (76.4% vs 62.3%; 

 = .0012) and in all subgroups. Median OS was not reached in the selinexor group compared with 25 months in the doublet group (HR, 0.84; 95% CI, 0.57-12.3; 

 = .19).

Patients experienced a response sooner with the triplet than the doublet (1.1 months vs 1.4 months) and the median duration of response was longer with the selinexor combination (20.3 months vs 12.9 months). The time until next therapy was a median 16.1 months in the selinexor group compared with 10.8 months in the bortezomib/dexamethasone alone group (HR, 0.66; 95% CI, 0.50-0.86; 

 = .0012).

More patients in the doublet arm than the triplet arm discontinued treatment due to disease progression (52% vs 34%). Of the patients in the selinexor and doublet groups, respectively, a total of 47 vs 62 of the patients died during the follow-up period.

Using the European Organisation for Research and Treatment of Cancer’s questionnaire QLQ-CIPN20, the researchers found clinically important differences in motor, autonomic, and sensory scales. Peripheral neuropathy rates of grade 2 or higher were significantly lower with the selinexor combination compared with bortezomib plus dexamethasone alone (21.0% vs 34.3%; 

The most frequent treatment-related adverse events of grade 3 or higher for the triplet versus the doublet was thrombocytopenia (39.5% vs 17.2%), fatigue (13.3% vs 1.0%), and nausea (7.7% vs 0%). The discontinuation rate due to adverse events was 17% in the triplet arm and 11% in the doublet arm.

Dimopoulos concluded that the selinexor regimen is effective, convenient, and IMiD-free, requiring approximately 40% fewer clinic visits while conferring a reduced rate of peripheral neuropathy.

“Overall, this data indicates that the once-weekly regimen of selinexor plus bortezomib and dexamethasone could be a new standard of care and a most convenient triplet therapy … in patients with multiple myeloma,” he concluded.

Dimopoulos MA, Delimpasi S, Simonova M, et al. Weekly selinexor, bortezomib and dexamethasone versus twice weekly bortezomib and dexamethasone in patients with multiple myeloma after 1-3 prior therapies: initial results of the phase III BOSTON study. Presented at: 2020 ASCO Virtual Scientific Program; May 29, 2020. Abstract 8501.

<< View more of Targeted Oncology's coverage from the 2020 ASCO Virtual Annual Meeting

Selinexor in combination with bortezomib and dexamethasone resulted in improvements in responses and outcomes compared with bortezomib and dexamethasone alone in patients with relapsed or refractory multiple myeloma, according to findings from the phase 3 BOSTON trial from the 2020 ASCO Virtual Scientific Program.

Improved Responses Achieved for R/R Multiple Myeloma With Selinexor Combo

Measuring circulating tumor DNA (ctDNA) in patients with advanced mantle cell lymphoma (MCL) may be a viable way to predict how well they will respond to specific therapies, according to study findings reported at the 2018 ASH Annual Meeting.

Watching the rise or fall of ctDNA very early in treatment can be a good way to determine whether therapies are working or should be changed, said lead author, Rahul Lakhotia, MD, from the Center for Cancer Research at the National Cancer Institute in Bethesda, Maryland. This is useful because, while therapies are chosen based on physician expertise, results are uncertain as the disease exhibits &ldquo;striking clinical variability&rdquo; from patient to patient.

&ldquo;Mantle cell lymphoma is an incurable disease that can be aggressive, requiring multiple treatments, or (slower-growing and) not needing immediate therapy,&rdquo; he said, adding that &ldquo;treatments are usually not adjusted based on depth of response.&rdquo;

Another advantage to testing tumor DNA is that this strategy is able to detect relapse earlier than CT scans can, Lakhotia explained.

In particular, determining at certain points during treatment whether patients have minimal residual disease (MRD) is an important predictor of patient health outcomes, the study found.

Lakhotia and his colleagues used a genomic sequencing assay that measures ctDNA; the assay relies on tumor samples collected at baseline to recognize circulating tumor cells.

The researchers applied the tests during a clinical trial that tested whether adding bortezomib (Velcade) as a maintenance drug after chemotherapy improved health outcomes in patients with previously untreated MCL.

Patients were initially given one round of bortezomib, with their ctDNA tested before and after that treatment. Then, the patients were given induction therapy with 6 cycles of rituximab (Rituxan), EPOCH (etoposide, prednisone, vincristine, cyclophosphamide and doxorubicin) and bortezomib. Their ctDNA was checked after every cycle.

Finally, the patients were divided into 2 groups: one that took bortezomib alone and another that was observed. The patients&rsquo; ctDNA was checked every 3 to 6 months for 5 years, and annually after that.

Patients also underwent CT scans every 4 months for two years, every 6 months during years 2 through 4, and then annually.

The trial included 53 patients, the majority of them men with stage 4 disease whose median age was 59. Most patients did not have a high MCL International Prognostic Index (MIPI) score or blastoid disease type, both of which are associated with poorer health outcomes. The patients were treated between September 2005 and January 2016.

After a median follow-up of 9.9 years, the median progression-free survival (PFS) of patients across both study arms was 29.3 months and their 5-year overall survival (OS) was 78.2 percent. When the 2 arms were compared, it was found that taking bortezomib after induction therapy had not increased PFS: Those who took the drug had a median PFS of 27.3 months, compared with 33.5 months for those who did not take it. However, there was a small group of patients whose PFS lasted years past the median without the need for consolidation therapy or stem cell transplant, suggesting that they were particularly sensitive to this treatment, Lakhotia pointed out.

Pathologists were able to detect circulating tumor cells in 50 of 52 patients (96%) eligible for analysis, Lakhotia reported, and baseline levels of circulating DNA correlated with patients&rsquo; metabolic tumor volume.

The researchers observed a reduction in circulating tumor DNA as patients moved through treatment.

Before they started treatment, 94% of evaluable patients had detectable tumor DNA in their blood. After 2 cycles of bortezomib followed by chemotherapy, about half (54%) had detectable cancer cells. Following completion of the chemotherapy induction, about 20 percent had detectable tumor DNA in their blood.

Imaging tests identified 3 nonresponders, 3 partial responders and 44 complete responders. Yet, 5 of the complete responders, who by definition should have been free of disease, were found to have circulating tumor DNA evident in their blood. This means that &ldquo;traditional response criteria may not be sufficient in this disease,&rdquo; Lakhotia said

When measuring PFS from study enrollment until disease progression, the researchers found that patients who were free of any circulating tumor DNA after induction fared better. Those with no detectable circulating tumor cells at that juncture had a median PFS of 31.5 months, compared with 17.9 months for those who did have circulating tumor DNA. The same held true for OS: Those with detectable tumor DNA in their blood after induction had a median OS of 47.2 months, compared with a number not yet reached for those with no detectable tumor DNA at that time point.

In addition, there were earlier moments in the course of treatment when circulating tumor DNA measurements were found to predict health outcomes.

After the first 2 cycles of induction therapy, median PFS was 21.4 months in those with detectable tumor DNA compared with 32.4 months in those with none; this was associated with a trend toward superior median OS. After just the first cycle of induction therapy, the difference between the groups was even more clear: The median PFS in those with detectable tumor DNA was 20.7 months, versus 76.4 in patients with no measurable tumor DNA; this was also associated with a trend toward superior four-year OS.

The difference could even be seen after the initial round of bortezomib, the researchers found. Patients with tumor DNA in their blood exceeding 35 cell equivalents/ml had a median PFS of 22 months, versus 34 months for those with tumor DNA below that level. This was an early indication of sensitivity to therapy, Lakhotia said.

The results of the study confirmed data from previous research showing that a post-therapy status of no MRD predicts a better health outcome, and that sequential MRD assessments can be used to guide therapy, Lakhotia said.

Measuring circulating tumor DNA in the blood of patients with advanced MCL may be a viable way to predict how well they will respond to specific therapies, according to study findings reported at the 2018 ASH Annual Meeting.

Utilizing Circulating Tumor DNA as a Predictor of Treatment Response in MCL

The oncology community has lost a pioneer in the integration of humanity into cancer care.

Jimmie C. Holland, MD, known as the mother of psychosocial oncology, died on Christmas Eve at age 89. The mother and grandmother, who was married to noted oncologist James F. Holland, MD, succumbed to cardiovascular disease at their home in Scarsdale, New York, according to

For her countless contributions to supportive care, she had been named an

Holland, who worked until the end of her life in the field she was largely responsible for founding, had served, since 1989, as the Wayne E. Chapman Chair in Psychiatric Oncology at Memorial Sloan Kettering Cancer Center (MSKCC), in New York. At that institution in 1977, she founded the nation&rsquo;s first full-time psychiatric program in an oncology center, and since then had continued to treat patients and conduct research there. In 2013, she told

Holland had also helped her field evolve by launching 2 professional societies. The International Psycho-Oncology Society got off the ground in 1984, and in 1992 Holland co-founded its journal,

. She launched the American Psychosocial Oncology Society in 1986.

Her only nod to her age was her interest in working with people of her generation. She worked within MSKCC&rsquo;s 65+ program to help older patients get through their cancer treatment, and conducted research focused on psychotherapy for elderly patients with cancer.

In part due to her work with that program, Holland, with Mindy Greenstein, PhD co-authored a 2014 book titled

Lighter as We Go: Virtues, Character Strengths, and Aging

. Among the inspirations for the book was Holland&rsquo;s Vintage Readers&rsquo; Book Program, which she had started as part of the 65+ program in 2011. Its members, older cancer patients, were reading the Harvard Classics and gathering monthly to discuss them. Holland also co-wrote

The Human Side of Cancer: Living With Hope, Coping With Uncertainty

, which was published in 2000, as well as the first textbook on psycho-oncology,

Despite her focus on an older population, Holland also gave her attention to the younger members of her field. She supervised fellows in psychology and psychiatry, trained them in the psychological care of patients with cancer and provided them with the history of the evolution of psychosocial oncology.

Holland wanted her students to understand that &ldquo;you have to treat the whole person, not just the tumor,&rdquo; she told

. &ldquo;To do that, you must have a good sense of your own vulnerability, because they need to sense that you are someone who&rsquo;s there with them, that you&rsquo;ll go through the illness with them. Patients are very keenly aware of whether a doctor is concerned for them. The bottom line is, as Francis Peabody said, &lsquo;The secret of caring for the patient is caring for the patient.&rsquo;&rdquo;

Holland had grown up an only child on a cotton farm in Texas, where, she said, &ldquo;girls get boys&rsquo; names and boys get girls&rsquo; names.&rdquo; She was 1 of just 3 women in her class at the Baylor University School of Medicine, in Houston.

Her interest in the way patients dealt with illness developed during her medical training, leading to her specialty in psychiatry, which she studied as a resident and research fellow at the Malcolm Bliss Mental Health Center and Washington University School of Medicine, both in St. Louis, and then during a residency and fellowship at Massachusetts General Hospital in Boston.

Holland met her husband early in her career, and when they married, she moved to Buffalo, where he worked at the Roswell Park Cancer Institute.

From 1956 through 1973, Holland moved up the ladder to become associate clinical professor in the Department of Psychiatry at the State University of New York in Buffalo. During most of those same years, she held roles at a teaching hospital, moving up from attending psychiatrist to director of the Department of Psychiatry.

From 1972 to 1973, the family moved to the USSR for an academic year. While her husband consulted with the Russian Cancer Institute, Holland worked as a consultant to the Russian Psychiatric Research Institute on a Joint Schizophrenia Research Study. This was during the Cold War, but their work was part of a cultural exchange program between the 2 countries.

Back in the United States, Holland spent 4 years at the Albert Einstein College of Medicine and Montefiore Hospital, in the Bronx, New York, where she rose to the rank of associate professor.

Holland&rsquo;s husband was a pioneer in the treatment of pediatric acute lymphoblastic leukemia, and it was by learning about his work that she realized that consideration of psychosocial issues was largely missing from routine cancer care. She saw an opportunity to change that in the 1970s, when the stigma associated with cancer started to fade and patients were no longer being kept in the dark about their diagnoses.

At the time, her husband was chairman of the nation&rsquo;s first cooperative clinical trials group for cancer, and she encouraged him to add a committee for psychosocial issues. When he did, Holland joined the effort, helping to conduct the first clinical trials on quality of life in patients with cancer.

In 1977, she was hired at MSKCC to start building a Psychiatry Services group. One of the team&rsquo;s first tasks was to develop questionnaires designed to gauge patient distress. &ldquo;We began to use these tools in clinical trials. We showed that if we intervened with an antianxiety drug or talk therapy, we could reduce anxiety and make people less distressed,&rdquo; Holland said. &ldquo;Out of that has come our field of psychosocial oncology with its own evidence base.&rdquo;

Over the years, Holland was recognized for her pioneering leadership with numerous awards. These included the American Cancer Society&rsquo;s Medal of Honor for Clinical Research in 1994, a presidential commendation from the American Psychiatric Association in 2000 and the Adolf Meyer Award from the same organization in 2005. In 2007, she became a member of the Institute of Medicine, working on its Panel on Care of the Whole Patient. In 2015, Holland received the Pioneer Award at the Women of Influence Awards, given by the T.J. Martell Foundation, a music industry group that funds innovative, early-stage translational research aimed at finding treatments and cures for cancer.

​"Jimmie was a major force in our scientific research platform for the T.J. Martell Foundation," said its CEO, Laura Heatherly. &ldquo;She was a special leader, mentor and pioneer who helped many people. She will be sorely missed by us all.&rdquo;

In the later years of her career, Holland was gratified to witness a shift in cancer care toward patient-centered care, with physicians and other caregivers not just encouraged, but in some cases required by industry guidelines, to speak with patients about the effects of the disease on their lives.

The difference Holland made was meaningful not only to her field as a whole, but to her patients, students, and colleagues.

&ldquo;I, like so many of the generations she influenced, owe her my entire career,&rdquo; wrote Steven Passik, PhD, a clinical psychologist and former chief fellow in the Psychiatry Service at MSKCC. &ldquo;I am deeply saddened to hear of her passing, as I always fantasized that she would go on forever working her magicand, of course, she will, as we are all part of her massive legacy.&rdquo;

The oncology community has lost a pioneer in the integration of humanity into cancer care: Jimmie C. Holland, MD, known as the mother of psychosocial oncology.<br />
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Beth Fand Incollingo | Authors

Articles

Sotorasib Shows Early Activity in Advanced Non–Small Cell Lung Cancer

Improved Responses Achieved for R/R Multiple Myeloma With Selinexor Combo

Utilizing Circulating Tumor DNA as a Predictor of Treatment Response in MCL

Oncology Community Mourns Loss of Psychosocial Oncology Field Founder, Jimmie Holland