In the phase 2 trial EMPOWER-CSCC-1 (NCT02760498), up to 3 years of follow-up showed continued response rates, and a clinically meaningful survival and duration of response (DOR) for cemiplimab-rwlc (Libtayo) in patients with advanced cutaneous squamous cell carcinoma (CSCC).

A poster session at the 2020 American Society of Clinical Oncology Virtual Scientific Program presented by Danny Rischin, MD, highlighted the important aspects of these data, including an overall response rate (ORR) of 46.1%, complete response (CR) rate of 16.1%, and a median time to CR of 11.2 months in 89 responders. The DOR had not yet been reached at the time of data cutoff.

"The data demonstrated deepening clinical responses with cemiplimab over time. Furthermore, duration of response and overall survival [OS] are considerably longer with cemiplimab than what has previously been recorded with other agents," said Rischin, director of the Division of Cancer Medicine and head of the Department of Medical Oncology at the Peter MacCallum Cancer Centre in Victoria, Australia.

This open-label, non-randomized, multicenter, international study included 3 groups of patients with advanced CSCC. Group 1 contained patients with metastatic disease and group 2 had patients with locally advanced disease; in both groups, patients received 3 mg/kg of cemiplimab every 2 weeks. In group 3, patients with metastatic disease received 350 mg every 3 weeks. The median duration of follow-up was 15.7 months for all 3 groups.

Group 1, 2, and 3 had primary data and follow-up at about 1 year, and group 1 had follow-up again at about 2 years. Of 193 patients total, group 1 had 59 patients, group 2 had 78, and group 3 had 56.

In group 1, there was a CR rate of 6.8% at primary analysis, 16.9% at 1 year, and 20.3% at 2 years. Group 2 had a CR rate of 12.8% in the primary analysis and at 1-year follow up. Group 3 had a 5.4% CR rate at primary analysis and 16.1% rate at 1 year.

The ORR per independent central review was 50.8%, 44.9%, and 42.9% for groups 1, 2, and 3, respectively. For patients who had not received prior anticancer systemic therapy (n = 128), the ORR was 48.4%; for those who did receive prior anticancer systemic therapy (n = 65), it was 41.5%.

For this study, median DOR had not been reached (range, 1.9-34.3 months), nor had the OS. At 24 months, the Kaplan-Meier estimated probability of OS was 73.3% (95% CI, 66.1%-79.2%). There was an estimated proportion of 69.4% of patients with ongoing response at 24 months (95% CI, 55.6%-79.6%).

The estimated median progression-free survival for all patients was 18.4 months (95% CI, 10.3-24.3). The Kaplan-Meier estimated progression-free survival rate was 44.2% at 24 months (95% CI, 36.1%-52.1%).

Overall, there was a 2-month observed time to response in 46.1% of patients, 2 to 4 months for 32.6%, 4 to 6 months for 9.0%, and 6 months or more for 12.4%.

In terms of treatment-emergent adverse events (TEAEs) in the total population, 99.5% of patients experienced at least one any-grade TEAE, regardless of attribution. The most common any-grade TEAEs overall were fatigue at 34.7%, diarrhea at 27.5%, and nausea at 23.8%. There were no new TEAEs leading to death.

Grade 3 or more TEAEs regardless of attribution occurred in 48.7% of patients. The most common were hypertension at 4.7% and anemia and cellulitis at 4.1% each. Treatment-related AEs were reported in 17% of patients, with pneumonitis at 2.6% and autoimmune hepatitis at 1.6% being the most common.

At baseline, patients had a median age of 72 (range, 38-96) and 83.4% were male. All patients had an ECOG performance status of 0 (44.6%) or 1 (55.4%). Cemiplimab was a first-line therapy in 66.3% of the patients.

There was a median duration of exposure to cemiplimab of 51.1 weeks (range, 2.0-109.3) and the median number of doses of cemiplimab administered was 18 (range, 1-48).

The original data of cemiplimab monotherapy, a high-affinity, highly potent human immunoglobulin G4 monoclonal antibody to the PD-1 receptor, had a median follow-up of 9.4 months. This was the basis for the FDA approval in patients with metastatic or locally advanced CSCC.

 The regimen achieved clinically meaningful activity in these patients and its safety profile was consistent with other anti-PD-L1 inhibitors.

Rischin D, Khushalani NI, Schmults CD, et al. Phase II study of cemiplimab in patients (pts) with advanced cutaneous squamous cell carcinoma (CSCC): longer follow-up. 

. 2020;38(suppl 15):10018. doi:10.1200/JCO.2020.38.15_suppl.10018

FDA approves cemiplimab-rwlc for metastatic or locally advanced cutaneous squamous cell carcinoma. FDA. Updated January 18, 2019. Accessed May 30, 2020. https://bit.ly/36KDJhv

Articles

In the phase 2 trial EMPOWER-CSCC-1, up to 3 years of follow-up showed continued response rates, and a clinically meaningful survival and duration of response for cemiplimab-rwlc in patients with advanced cutaneous squamous cell carcinoma.

Longer Follow-Up for Cemiplimab Confirms Superior Efficacy Over Other Regimens for CSCC

An ongoing study of CC-92480 in combination with dexamethasone demonstrated favorable activity and safety data in patients with heavily pretreated relapsed or refractory multiple myeloma (RRMM), according to a presentation from the 2020 American Society of Clinical Oncology (ASCO) Virtual Scientific Program.

In the phase 1 multicenter, dose-escalation trial (NCT03374085), there was an overall response rate (ORR) of 21.1%—with 1 complete response (CR), 6 very good partial responses (VGPRs), 9 PRs, and 4 minimal responses (MRs)&mdash;observed among the overall patient population. The efficacy of the combination was dependent on the dose level and schedule the patients were on.

 “CC-92480 as a novel CELMoD [cereblon E3 ligase modulator] agent, has promising activity preclinically, and this has been successfully translated to the clinic with a manageable safety profile in patients with heavily pretreated RRMM,” Paul G. Richardson, MD, the clinical program leader and director of clinical research at the Jerome Lipper Multiple Myeloma Center at Dana-Farber Cancer Institute, said in his presentation.

CC-92480 was administered in either a continuous or an intensive dosing schedule. In the continuous schedule cohorts, treatment started at 0.1 mg daily and escalated up to the maximum tolerated dose (MTD) of 1.0 mg per day administered for 10 out of 14 days (10/14) in a 28-day cycle after 2 dose-limiting toxicities (DLTs) were observed. The patients receiving the 10/14-day schedule had deep Aiolos degradation but needed a longer continuous break to recover their neutrophil counts. Based on this, the investigators switched to a 21/28-day schedule and decided this was the best schedule for the MTD of 1.0 mg.

For the intensive schedule, patients received 0.2 mg escalated up to 0.8 mg twice a day, administered 3 out of 14 days twice a month, which was then adapted to 1.6 mg to 2.0 mg once daily for 7/14 days twice a month. The 3-day schedule was associated with deep Aiolos degradation, but patients needed more time on treatment to prevent the rebound of serum myeloma paraproteins.

Although the investigators were able to dose escalate up to 2.0 mg daily, the 1.0 mg dose for the 21/28-day continuous schedule was determined to be the recommended phase 2 dose after several DLTs were observed.

Ages of the 76 total patients ranged from 44 to 78 years old, with the median being 66 years old. The ECOG performance status of these patients ranged from 0 to 2, with a majority of patients having a status of 1 (63.2%). They had stage I to III disease by the International Staging System at baseline, with 44.7% patients at stage II and 22.4% at stage III. In this trial, 36.8% of patients had extramedullary plasmacytoma. The time from initial diagnosis was 7.2 years (range, 0.9-23).

The median number of prior regimens for patients in this study was 6 (range, 2-13). These therapies included proteasome inhibitor (PI) therapy in 100% of patients, lenalidomide in 97.4%, pomalidomide in 92.1%, anti-CD38 antibodies in 75.0%, and autologous stem cell transplantation in 76.3%. There were 73.7% of patients who were lenalidomide-refractory, 78.9% who were pomalidomide-refractory, and another 73.7% who were PI-refractory.

“Those who were truly refractory to monoclonal antibody therapy was 70%, and thus in aggregate in terms of triple-class refractory disease. In fact, 50% of the patients constituted this exquisitely vulnerable population,” Richardson said.

The primary end points of this trial were to find the MTD, the recommended phase 2 dose, safety, tolerability and pharmacokinetics of this combination for patients with RRMM. Patients eligible to be on the study were those who had progression on or within 60 days of their last MM therapy, resistance or intolerance to, or not candidates for the therapies currently available in this setting. The main secondary end point was to assess preliminary efficacy.

The ORR was 40% in patients treated with a 10/14-day continuous dosing schedule and 54.5% with a 21/28-day continuous schedule. There was 1 CR, 1 VGPR, 2 PRs, and 1 MR in the 21/28-day group; 7 of the 11 patients on this schedule were triple class-refractory.

Among patients treated with the continuous dosing schedules, DLTs were reported in 3 out of 11 patients treated at 1.0 mg in the 21/28-day cohort and 2 out of 10 patients treated at 1.0 mg in the 10/14-day cohort. Grade 4 DLTs in the 21/28 group were neutropenia and sepsis; grade 4 DLTs in the 10/14 group were neutropenia and febrile neutropenia. In the intensive schedule cohorts, 2 patients treated with 2.0 mg once daily of CC-92480 for 7/14 days experienced a total of 4 DLTs, including grade 4 neutropenia, grade 4 thrombocytopenia, grade 3 increased alanine aminotransferase, and grade 2 pneumonitis.

The most frequent treatment-emergent adverse events (TEAEs) of any grade included neutropenia in 73.7% of all 76 patients, infections in 71%, anemia in 55.3%, thrombocytopenia in 43.4%, and fatigue in 38.2%. DLTs in the different cohorts were mostly due to neutropenia. The most frequent grade 3 toxicities were infections at 32.9% and neutropenia at 30.3%, and grade 4 toxicities were neutropenia at 34.2% and thrombocytopenia at 9.2%.

Dose reduction of CC-92480 occurred in 22.4% of patients, and there were no discontinuations due to TRAEs.

“For a relapsed/refractory population, this is fairly typical,” Richardson said. “In terms of AEs of interest, there was little in the way of peripheral sensory neuropathy, just 5%; and importantly, there was only one case of deep vein thrombosis.”

At the time of the data cutoff, there were 25 patients, or 32.9%, still on therapy. Progressive disease caused 51.3% of patients to discontinue treatment. There were 5 deaths during this study, but none were due to CC-92480.

CC-92480, a potent CELMoD agent, was designed for rapid and maximal degradation of target proteins, such as Aiolos and Ikaros. The basis for this study was the drug’s “impressive” immune-stimulatory and antimyeloma activity in preclinical models, as well as its potent antiproliferative and tumoricidal activity in MM cell lines, including in patients who are resistant to lenalidomide and pomalidomide. It also had synergy with the standard-of-care therapies for these patients, such as dexamethasone, PIs, and monoclonal antibodies.

Richardson PG, Vangsted AJ, Ramasamy K, et al. First-in-human phase I study of the novel CELMoD agent CC-92480 combined with dexamethasone (DEX) in patients (pts) with relapsed/refractory multiple myeloma (RRMM). 

. 2020;38(suppl 15):8500. doi:10.1200/JCO.2020.38.15_suppl.8500

An ongoing study of CC-92480 in combination with dexamethasone demonstrated favorable activity and safety data in patients with heavily pretreated relapsed or refractory multiple myeloma.

CC-92480 Shows Encouraging Efficacy in First-in-Human Study for R/R Multiple Myeloma

A high body mass index (BMI) at baseline may be independently associated with improved survival outcomes in patients with non—small cell lung cancer (NSCLC) who receive immune checkpoint inhibitor therapy, according to study results published recently in 

The findings add to the growing evidence of an “obesity paradox” in patients with cancer in which a high BMI is linked to an increased incidence of some malignancies but may offer protection from others, investigators noted.

“This is an interesting outcome, and it raises the potential to investigate further with other cancers and other anticancer drugs,” lead investigator Ganessan Kichenadasse, MBBS, FRACP, a medical oncology researcher at the Flinders Centre for Innovation in Cancer in Adelaide, Australia, said in a statement.

 “We need to do further studies into the possible link between BMI and related inflammation, which might help [us] to understand the mechanisms behind paradoxical response to this form of cancer treatment.”

Kichenadasse and colleagues noted that findings in other studies have suggested that high BMI correlates with improved survival rates in patients with advanced cancers and melanoma.

“Previous studies have explored a concept called an ‘obesity paradox’ where obesity is associated with increased risks for developing certain cancers and, counterintuitively, may protect and give greater survival benef its in certain individuals,” Kichenadasse said. “Our study provides new evidence to support the hypothesis that high BMI and obesity may be associated with response to immunotherapy.”

To examine the relationship between body weight and outcomes, investigators analyzed patient-level data from 4 clinical trials in which participants with NSCLC were treated with atezolizumab (Tecentriq), a PD-L1 inhibitor, or docetaxel. The post hoc analysis comprised data from 1434 patients who received atezolizumab and 890 treated with docetaxel during the OAK (NCT02008227), POPLAR (NCT01903993), BIRCH (NCT02031458), and FIR (NCT01846416) trials.

Among the evaluable patients, 49% were normal weight, 34% were overweight, and 7% were obese. BMI, calculated by weight in kilograms divided by height in meters squared, was categorized by the World Health Organization criteria: underweight (<18.5 kg/m

). If the patient’s height or weight information for the calculation of BMI was missing, or if they fell into the underweight category, they were excluded from the analysis.

Many of the patients who were obese, compared with those who were not obese, were white, male, previous smokers, had a neutrophil-to-lymphocyte ratio <3, and lower C-reactive protein concentrations. Overall, the median age was 64 years (range, 57-70) and 62% were men.

Patients who were considered normal weight, overweight, and obese had significant differences in overall survival (OS) when treated with atezolizumab (

 <.001). Patients who were obese and overweight had an improved OS (HR, 0.64; 95% CI, 0.51-0.81 and HR, 0.81; 95% CI, 0.68-0.95; respectively), compared with patients who had a normal BMI.

Additionally, there was a significant difference between PD-L1—positive and PD-L1–negative tumors (

 value for interaction = .02).Patients considered overweight or obese had a larger survival advantage associated with PD-L1—positive tumors (overweight: HR, 0.73; 95% CI, 0.58-0.91 vs obese: HR, 0.48; 95% CI, 0.34-0.66) when compared with PD-L1–negative tumors.

Patients who were obese and had high PD-L1 expression (≥50% of tumor cells or ≥10% of tumor-infiltrating immune cells) had an OS HR of 0.36 (95% CI, 0.21-0.62) and for patients who were overweight, the HR was 0.69 (95% CI, 0.48-0.98).

Of note, those in the obese and overweight BMI groups of these trials did not have a statistically significant progression-free survival (PFS) when analyzed separately (overweight: HR, 0.89; 95% CI, 0.78-1.01 vs obese: HR, 0.86; 95% CI, 0.73-1.01; 

 = .09) but demonstrated an improved PFS together over patients with a normal BMI (HR, 0.88; 95% CI, 0.780.99; 

Similar to OS, those with high PD-L1 expression had the best PFS HR (obese: HR, 0.68; 95% CI, 0.49-0.94; overweight: HR, 0.72; 95% CI, 0.56-0.92) of the patients with PD-L1—positive tumors.

The incidence of treatment-related adverse events did not differ significantly between the BMI groups, with all-grade events at 65% for the normal BMI group, 64% for overweight BMI, and 65% for those in the obese BMI group (

 = .92). Grade 3 through 5 events were 12%, 14%, and 12%, respectively (

In patients treated with docetaxel in the OAK and POPLAR trials, no significant associates were observed between BMI and OS and PFS, and the OS for PD-L1—positive and –negative tumors did not significantly differ between the groups.

OAK, a phase III trial, and POPLAR, a phase II trial, randomized patients with advanced disease who failed prior platinum therapy to 1200 mg of atezolizumab or 75 mg/m2 of docetaxel administered intravenously every 3 weeks. BIRCH and FIR were both phase II trials of patients with PD-L1—positive tumors who were receiving atezolizumab as first line or later lines of treatment. PD-L1 positivity was defined as PD-L1 expression on ≥5% of the tumor or tumor-infiltrating cells based on the Ventana SP142 immunohistochemistry assay.

Investigators emphasized that the results are exploratory and need to be confirmed by future clinical trials. They also pointed out the limitation of BMI as a measurement of obesity because it is unable to differentiate fat from lean muscle mass and cannot be used to diagnose sarcopenia. BMI is also not reflective of body fat distribution.

Kichenadasse G, Miners JO, Mangoni AA, Rowland A, Hopkins AM, Sorich, MJ. Association between body mass index and overall survival with immune checkpoint inhibitor therapy for advanced non—small cell lung cancer [published online December 26, 2019]. 

High BMI may improve cancer survival [news release]. EurekAlert! website. eurekalert.org/pub_releases/2019-12/fu-hbm122219.php. Published December 26, 2019. Accessed January 31, 2020.

A high body mass index at baseline may be independently associated with improved survival outcomes in patients with non–small cell lung cancer who receive immune checkpoint inhibitor therapy.

High BMI Linked to Better Immunotherapy Outcomes in NSCLC

The second-generation TKIs dasatinib (Sprycel), nilotinib (Tasigna), and bosutinib (Bosulif), along with the emerging potential for TKI discontinuation, have transformed the treatment paradigm for chronic myeloid leukemia (CML), said Jorge Cortes, MD.

Researchers are now seeking to enhance patient responses through combinations, such as a regimen combining the BCL-2 inhibitor venetoclax (Venclexta) with a second-generation TKI.

, Cortes, deputy chair of the Department of Leukemia in the Division of Cancer Medicine at The University of Texas MD Anderson Cancer Center, discussed frontline advances, discontinuation, and remaining challenges in the CML paradigm.

: What new frontline therapies have come out recently and how are they improving?

: The most recent change was the approval of bosutinib, another second-generation [TKI], as frontline therapy. Now we have 3 second-generation TKIs for frontline and imatinib. So, 4 approved [TKIs] for frontline therapy. I think the bulk of the data, if you put all the second-generation data together, they all look consistent with that benefit compared to imatinib. There are some differences which are difficult to reconcile considering that these are similar but not identical studies from one drug to the other, but I do think that it is fair to say that these have become standard.

One of the important things that is emerging now is, for dasatinib in particular, the use of lower doses. It's no surprise that the initial results that have emerged from our institution are positive when we consider that with both nilotinib and bosutinib, the dose that we use for frontline is lower than the dose that we use for salvage, so sure enough, that's proving to be the same with dasatinib.

I think that a lot of the focus now is to see if we should do some interventions early on to try to optimize the number of patients who get to the deepest molecular responses and that would, at some point, be eligible for treatment discontinuation. There are studies adding ruxolitinib [Jakafi] and adding interferon and other agents. Perhaps one of the most exciting ones is adding venetoclax [Venclexta] with some good preclinical data, but there's not enough data yet clinically to assess, but they will come soon.

What are the benefits of using second-generation TKIs over first-generation?

There are randomized studies, there's several of them now, and then some sequencing studies independent from the initial studies. They all have confirmed that we have a faster response [with second-generation TKIs]. We get a deeper response. We have fewer transformations and it is more and more important that over time we get more patients with the deepest molecular responses, the MR

These events, or the frequency of these responses, is not inconsequential. For example, from the ENESTnd study, which has some of the longest follow-up. We know that, for example, 5 years you get to over 50% of patients with an MR

, whereas with imatinib only about 30% of patients. It's a 20 percentage point difference, which is important. The sustained MR

 goes from 40% to 45% versus 20% with imatinib, so I think that those are the things you need to keep in mind. It doesn't improve survival, or it hasn't so far. I think that if we had enough patients and enough follow-up, we would probably see a small benefit, significant but small. But I think we're beyond that now. We've established that other endpoints are important and I think that’s the type of consideration that you, at the very least, have to discuss with the patient—what you're getting with one drug versus the other.

What are some challenges that are still unmet in the CML space?

I think that I mentioned briefly the challenge of these 2 or 3 occlusive events and these are events that happen with all these drugs, particularly the second- and the third-generation drugs. More with ponatinib [Iclusig] perhaps, but it also happens with nilotinib and dasatinib. Maybe a little bit less with bosutinib and certainly much less with imatinib. It's a challenge because it has to do with the comorbidities that patients have, but a lot of our patients have comorbidities. Some are diabetic, some have hypertension, some smoke. We need to learn more about how to manage these patients so that we give them the benefit of the drugs to try to minimize the risks, because we don't understand the mechanism and we cannot prevent it. I think that's still a big challenge.

The other one that's big is the treatment discontinuation. It's become a reality, no question, and it's a big thing for the patients, but unfortunately today it benefits only about 20% to 25% of the patients because not everybody gets to have the criteria of sustained deep molecular responses, which in my opinion has to be a sustained MR

 for at least 2 years, and ideally 5. And then, of those patients who meet the criteria, about half of them will relapse. So, it is great, but it is not a reality for most patients, so how can we improve [that rate]? How can we make more patients eligible and how can we decrease the relapse rate? Either one of those 2 would help us improve the overall impact of this approach, but ideally, we would like to address both. Some combination studies may help us with that hopefully, but we'll have to wait for some data because right now we do have some leads pre-clinically, some early data in the clinic, but nothing definitive yet. I think that's an important challenge for the future.

What do you see coming in the future for CML treatment?

I think that the future is still bright for CML. I think that there are some interesting new drugs coming along. Asciminib seems to be a very potent, active drug that'll be very helpful. I think it is important that we haven't addressed much in more advanced stages, blast phase, etc. I think it is important that we continue treating our patients in the best possible way, meaning good monitoring, good management, and that we can continue addressing those unmet needs with clinical trials.

Jorge Cortes, MD, discusses frontline advances, discontinuation, and remaining challenges in the chronic myeloid leukemia paradigm.

Dylann Cohn-Emery

Articles

Longer Follow-Up for Cemiplimab Confirms Superior Efficacy Over Other Regimens for CSCC

CC-92480 Shows Encouraging Efficacy in First-in-Human Study for R/R Multiple Myeloma

High BMI Linked to Better Immunotherapy Outcomes in NSCLC

CML Paradigm Transforms With New Treatments, Potential for TKI Discontinuation