According to data presented during the 2021 Virtual American Association for Cancer Research Annual Meeting, patients with non‒small cell lung cancer (NSCLC) with undetectable circulating tumor (ctDNA) 

ex14) following treatment with savolitinib are more likely to have positive progression-free and overall survival outcomes.

ex14 clearance upon savolitinib treatment was correlated with significantly longer progression-free survival [PFS] and overall survival [OS] compared with those who had detectable 

ex14,” said lead author Yongfeng Yu, MD, of the Shanghai Chest Hospital, Shanghai Jiao Tong University in Shanghai, China.

He cautioned the sample size was small and confirmation of the finding with a larger sample size was needed.

The median PFS for patients treated with savolitinib who had undetectable 

ex14 (n = 14) was 30.3 months (95% CI, 6.8-NC) with a hazard ratio (HR) of 0.72 (95% CI, 0.28-1.87; 

 = .501). The median OS for these patients was 35.8 months (95% CI, 14-NC) with an HR of 0.89 (95% CI, 0.25-3.18; 

ex14 following treatment (n = 10), the median PFS was 5.5 months (95% CI, 0.66-5.6) with an HR of 4.94 (95 CI, 1.83-13.36; 

 = .002). The median OS for these patients was 8.7 months (95% CI, 0.8-10.6). HR was 7.06 (95% CI, 2.39-20.89; 

For patients treated with savolitinib who were non-evaluable for 

ex14 (n = 22), the median PFS was 4.1 months (95% CI, 4.0-6.9). HR was 3.45 (95% CI, 1.48-8.03; 

 = .006). The median OS for these patients was 10.6 months (95% CI, 4.8-12.0). HR was 5.88 (95% CI, 2.24-15.47; 

ex14 was undectable for 20 patients at baseline. The median PFS for those patients was 13.8 months (95% CI, 4.2-22.1) and the median OS was not calculable.

Investigators also studied concurrent gene alterations with METex14 and noted alterations with likely resistance to savolitinib including 

 tyrosine kinase inhibitor. The agent previously demonstrated clinical efficacy and a manageable safety profile in Chinese NSCLC patients with METex14 alterations in a phase 2 study (NCT02897479).

In the analysis presented at AACR, investigators studied ctDNA analysis of 

ex14 at baseline and clearance upon treatment using next generation sequencing, QIAamp Circulating Nucleic Acid Kit from Qiagen. They collected plasma samples pre-dose and at tumor assessment visits, until disease progression or end of treatment. Data cut-off was August 2020.

Sixty-six patients provided baseline plasma samples, of which 

ex14 ctDNA was detectable in 46 (70%) patients. Of these patients, investigators were able to evaluate 24 patients for clearance of 

ex14. Fourteen of those 24 achieved ctDNA clearance with a median time to clearance of 1.4 months of treatment.

In a previously published analysis of patients in this phase 2 study, savolitinib demonstrated promising anti-tumor activity and acceptable tolerability in 

 As of October 31, 2019, 593 patients were pre-screened/screened and 87 were identified as having 

ex14+; 70 of these patients were treated.

Sixty-one patients in this study were efficacy evaluable by independent review committee assessment. The objective response rate was 47.5% (95% CI, 34.6%-60.7%) with a disease control rate of 93.4% (95% CI, 84.1%-98.2%). The median duration of response has not been reached. The median PFS was 6.8 months (95% CI, 4.2-13.8) among all treated patients.

The most common (greater than or equal to 20%) treatment-related adverse events (TRAEs) were peripheral edema, nausea, increased AST/ALT, vomiting and hypoalbuminemia. The incidence of grade 3 or higher TRAEs was 41.4%. TRAEs leading to treatment discontinuation occurred in 14.3% patients, the most common of which are liver injury and hypersensitivity (2.9% each).

The therapy’s developer, Hutchinson China MediTech, has applied for regulatory approval in China for the treatment of NSCLC with 

Ex14 skipping mutations, the first application globally and the first for a selective 

 inhibitor in China. China’s National Medical Products Administration has granted the therapy priority review status.

1. Yu Y, Ren Y, Fan J, et al. ctDNA analysis in the savolitinib phase II study in non‒small cell lung cancer (NSCLC) patients (pts) harboring 

ex14). Presented at: 2021 AACR Virtual Annual Meeting; April 10-15, 2021; Virtual. Poster CT158

2. Lu S, Fang J, Li X, et al. Phase II study of savolitinib in patients (pts) with pulmonary sarcomatoid carcinoma (PSC) and other types of non-small cell lung cancer (NSCLC) harboring 

 2020; 38, no. 15_suppl:9519-9519. doi: 10.1200/JCO.2020.38.15_suppl.9519

3. Chi-Med’s NDA for savolitinib in non‒small cell lung cancer granted priority review in China. Hutchinson China MediTech Limited. News release. July 28, 2020. Accessed April 10, 2020. https://www.hutch-med.com/nda-for-savolitinib-in-nsclc-granted-priority-review-in-china/

Articles

Patients with non‒small cell lung cancer with undetectable circulating tumor MET Exon 14 following treatment with savolitinib are more likely to have positive progression-free and overall survival outcomes.

Improved PFS and OS Correlated With Undetectable METex14 Following Savolitinib in NSCLC

Adding parsaclisib to the ruxolitinib (Jakafi) treatment of patients with myelofibrosis (MF) who had a suboptimal response on a standard dose of ruxolitinib alone led to improvements in spleen volume reduction (SVR) and symptom burden, according to data from a phase 2 study (NCT02718300) presented during the virtual AACR Annual Meeting 2021.

Responses to ruxolitinib with a parsaclisib add-on in the study occurred early on in the course of treatment and were durable. Moreover, the combination appeared well-tolerated in patients with MPNs.

The JAK 1/2 inhibitor ruxolitinib has long demonstrated the ability to improve outcomes like spleen volume, symptom burden, and survival in patients with MF. There is a subset of patients, however, who either have suboptimal responses to ruxolitinib or whose responses decline over time. Preclinical research into these phenomena suggested that activation of the PI3K pathway could benefit this patient population, therefore warranting the use of the next-generation PI3K inhibitor, parsaclisib.

To test the JAK and PI3K inhibitor combination in patients with MF, patients aged 18 years or older with primary or secondary MF were enrolled in the study. Patients were required to have an ECOG performance status of 2 or lower and have had a suboptimal response to ruxolitinib monotherapy after being treated with the agent at 5 to 25 mg twice daily for at least 6 weeks. On prior treatment with ruxolitinib, it was required that patients achieved stable disease that lasted at least 8 weeks and have a spleen that is over 10 cm below the left subcostal margin at the time of screening. Alternatively, patients could be eligible for the study with a spleen 5 cm to 10 cm below the left subcostal margin along with active MF symptoms at baseline, which may include night sweats, pruritis, abdominal discomfort, pain under the ribs, bone or muscle pain, and inactivity. MF symptoms observed at baseline are graded on a 10-point scale. Finally, all patients enrolled must have had a platelet count of at least 50 x 109/L in the 4 weeks prior to screening.

Once enrolled and while receiving a stable dose of ruxolitinib, patients in 1 arm of the study received the addition of parsaclisib at 10 mg or 20 mg once daily for 8 weeks and the same dosage once weekly in the weeks following. In a second arm, parsaclisib was administered at 5 mg or 20 mg once daily for 8 weeks and 5 mg once daily thereafter. On treatment with ruxolitinib and a parsaclisib add-on, patients were evaluated for the primary end point of change in spleen volume from baseline to week 12, which was determined by imaging. In addition, change in spleen volume from baseline to week 24, change in spleen length from baseline to each visit, total symptom score (TSS) from baseline to weeks 12 and 24, and safety determined by the number of patient with adverse events (AEs).

A total of 53 patients were included in the study, 10 of whom were evaluated in the safety run-in portion and 43 of whom were randomized to receive ruxolitinib plus 10 mg to 20 mg parsaclisib or ruxolitinib plus 5 mg to 20 mg parsaclisib. Thirty-three patients were dosed daily and weekly, and 20 received all daily dosing. As of the data cutoff date, 82% of patients who received both daily and weekly discontinued treatment in the study compared with 40% in the daily only group. Treatment was ongoing in 6 patients who were being treated on a daily and weekly schedule and 12 of those being treated on a daily-only schedule.

The study population had a median age of 66 years (range, 41-89 years) at baseline and was predominantly male (47%). The median time since the initial diagnosis of MF was 31.2 months (range, 4.9-268.9 months), and the duration of prior ruxolitinib in patients was a median of 18 months (range, 4.8-94 months). Ninety-eight percent of patients had palpable spleen which measured a median of 13.5 cm (range, 5-30 cm). Median spleen volume at baseline was 1995 cm3 (range, 327-5324 cm3). According to the MPN Symptoms Assessment Form, the median TSS in patients at baseline was 25.5 (range, 0-69), and according to the Myelofibrosis Symptoms Assessment Form, the median baseline TSS was 12.9 (range, 0-47).

Hemoglobin levels assessed a baseline showed a median of 101 g/L (range, 63-159 g/L).

Patients presented with several different MF subtypes including primary MF (PMF), post-polycythemia vera MF (PPV-MF), and post-essential thrombocythemia (PET-MF).

In terms of efficacy, patients who received all daily parsaclisib had a higher SVR compared with those treated daily and weekly. A -15.4% reduction was achieved in patients treated daily compared with a -2.3% reduction in spleen volume in those in the daily/weekly group. Then, at 24 weeks, the daily group showed a -25.4% SVR compared with a -2.5% reduction in the daily/weekly group.

“Patients who received all daily parsaclisib dosing demonstrated a continued reduction in splenic length up to 24 weeks. By contrast, patients receiving the daily parsaclisib dosing appeared to plateau after switching to weekly dosing at week 8,” said Abdulraheem Yacoub, MD, associate professor of Medicine, University of Kansas Medical Center, during the AACR poster presentation.

By week 24, 18 patients in the daily/weekly parsaclisib dosing group had palpable spleen compared with 3 in the daily dosing group.

Yacoub also explained that a higher percentage of patients who received all daily dosing demonstrated improvement in symptoms at 12 and 24 weeks. At week 12, there was a 50% or greater symptom reduction in 31% of the all-daily dosing population versus 15% of the daily/weekly dosing population, and at 24 weeks, the same symptom reduction was observed in 17% versus 4%, respectively.

The safety results also favored the daily dosing schedule over the daily/weekly schedule. Overall, the majority of the hematologic treatment-emergent AEs (TEAEs) were grade 1 or 2 in severity. The most common any-grade hematologic TEAEs observed in the all-daily dosing group were cough (25%) and nausea (20%). In the daily/weekly dosing group, the most common any-grade hematologic TEAEs were diarrhea, nausea, and fatigue, which occurred in 33%, 30%, and 30% of patients, respectively.

At least 2% of patients in the study experienced serious TEAEs which included urinary tract infection in 3 patients, and pneumonia, pyrexia, and fall in 2 patients each. AEs were fatal for 1 patient who received all daily dosing and 6 treated daily/weekly. New onset of grade 3 thrombocytopenia was observed in 30% of patients in the all-daily dosing population versus 18% with daily/weekly dosing. No patients who received all daily dosing had new-onset grade 4 thrombocytopenia compared with 21% of the daily/weekly group.

Notably, hemoglobin levels in all study subjects remained stable during the study and there were no cases of anemia. Also, in the daily dosing-only group, there was no colitis, grade 2 or higher diarrhea, or rash. One AE of special interest in the all-daily dosing group was varicella-zoster virus infection, which occurred in only 1 patient. AEs of special interest among patients treated daily/weekly were grade 2 or greater diarrhea in 4 patients, elevated liver function tests in 2 patients, grade 2 or greater rash in 1 patient, and varicella-zoster virus infection in 1 patient.

Grade 3/4 AEs were rare overall, and the AEs commonly observed with PI3K inhibitors were infrequent after adding parsaclisib to ruxolitinib.

Results from the study lead to the development of a phase 3 study exploring parsaclisib as an add-on to ruxolitinib or in combination with ruxolitinib as frontline treatment of patients with MF (NCT04551053).

Yacoub A, Wang ES, Rampal RR, et al. Addition of parsaclisib (INCB050465), a PI3Kδ inhibitor, in patients with suboptimal response to ruxolitinib: A phase 2 study in patients with myelofibrosis. Presented at: 2021 AACR Annual Meeting 2021; April 10-15, 2021; Virtual. Abstract CT162.

Adding parsaclisib to the ruxolitinib treatment of patients with myelofibrosis who had a suboptimal response on a standard dose of ruxolitinib alone led to improvements in spleen volume reduction and symptom burden.

Parsaclisib Plus Ruxolitinib to Treat Myelofibrosis Improves Spleen Size and Symptom Burden

The highly potent and selective oral allosteric pan-v-akt murine thymoma viral oncogene homolog (Akt) inhibitor, TAS-117, showed limited clinical efficacy in treating patients with ovarian cancer harboring 

 E545K mutations and in those with breast cancer harboring 

Findings from the single-center, phase 2 K-BASKET trial (NCT03017521) conducted at Yonsei Cancer Center in Seoul, South Korea, were presented in a poster during the 2021 AACR Annual Meeting. These data were also published online in 

“TAS-117 had limited antitumor activity and a manageable safety profile,” said lead author Jii Bum Lee, MD, a physician in the 

Division of Medical Oncology at Yonsei Cancer Center.

She added that combination treatments with chemotherapy, targeted therapy, and immunotherapy may overcome 

Lee and her colleagues enrolled 13 patients with advanced solid tumors harboring PI3K/Akt gene aberrations from November 2017 to June 2019. Four (31%) patients had breast cancer, 2 (15%) had ovarian, and 1 each had endometrial (8%) or non‒small-cell lung cancer. Five other patients had gastrointestinal (GI) cancers, including colon (n = 2, 15 %), rectal (n = 1, 8 %), gastric (n = 1, 8 %), and gallbladder cancer (n = 1, 8 %).

The 5 patients with GI cancers were assigned to 16 mg daily TAS-117. The remaining patients were assigned to 24 mg TAS-117 for 4 days followed by a 3-day rest. The study was conducted over 21-day treatment cycles.

Twelve patients (92%) had 2 or more metastatic organs. Twelve harbored 

“Most of the patients were heavily treated,” Lee said. “Ten patients were treated during fourth or subsequent treatment.”

The median duration of follow-up was 6.6 months (range, 1.0-18.1 months) and the median duration of treatment was 1.4 months (range, 0.4-3.2 months). Patients received a median of 2 treatment cycles (range, 1-5).

There were no complete responses at the February 19, 2020, data cutoff. At the time of data cutoff, 9 patients had disease progression, 2 experienced adverse events, 1 withdrew, and 1 patient discontinued treatment due to physician’s decision.

One patient with ovarian cancer showed a confirmed partial response for an overall response rate of 8%. Two patients with breast cancer had stable disease, for a disease control rate (DCR) of 23%.

The median progression-free survival was 1.4 months (95% CI, 1.2-1.6) and the median overall survival was 4.8 months (95% CI, 2.6-11.2).

Overall, 85% of patients experienced treatment-related adverse events. Three (27%) experienced 3/4 events—1 grade 3 anorexia, 1 grade 3 hyperglycemia, and 1 grade 4 hyperglycemia.

In previous studies, investigators found that TAS-117 inhibits the proliferation of human cancer cell lines 

 including breast, endometrial, lung, and ovarian cancer cells. Tumor cell lines with Akt2 and HER2 gene amplification, PI3K mutations, and PTEN loss were also found to be sensitive to TAS-117.

 In a phase 1 study of patients with advanced solid tumors, TAS-117 induced a DCR of 61.5% in 13 patients with 

-mutated endometrial cancer, 80.0% in 5 patients with 

-altered endometrial cancer, and 37.5% in 16 patients with ovarian clear cell carcinoma.

1. Lee JB, Jung M, Beom SH, et al. Phase 2 study of TAS-117 in advanced solid tumors harboringphosphatidylinositol 3-kinase/v-akt murine thymoma viral oncogene homolog gene aberrations. Presented at: the 2021 AACR Annual Meeting; Virtual; April 10-15, 2021. Abst CT151.

2. Lee JB, Jung M, Beom SH, et al. Phase 2 study of TAS-117, an allosteric akt inhibitor in advanced solid tumors harboring phosphatidylinositol 3-kinase/v-akt murine thymoma viral oncogene homolog gene mutations. 

3. Abe T, Ichikawa K, Fujita R, et al. 356 characterization of TAS-117, a novel, highly potent and selective inhibitor of AKT. 

. 2012;48:108-109. doi:10.1016/S0959-8049(12)72154-8

4. Yunokawa M, Takahashi S, Aoki D et al. First-in-human phase I study of TAS-117, an allosteric AKT inhibitor, in patients with advanced solid tumours. 

. 2019;30:v169. doi:10.1093/annonc/mdz244.018

TAS-117 showed limited clinical efficacy in treating patients with ovarian cancer harboring PIK3CA E545K mutations and in those with breast cancer harboring PIK3CA H1047R and Akt1E17K mutations.

Limited Efficacy, Manageable Safety Profile Found With TAS-117 to Treat Ovarian and Breast Cancer

Lifileucel (LN-144), the tumor-infiltrating lymphocyte (TIL) therapy, showed a positive objective response rate (ORR) with the median duration of response (DOR) not yet reached after more than 28 months of follow-up in patients with advanced melanoma who previously received immune checkpoint inhibition, according to data from the phase 2 C-144-01 trial (NCT02360579) presented at the 2021 American Association for Cancer Research (AACR) Annual Meeting.

“It is clear based on these data that lifileucel has demonstrated efficacy and durability of response for patients with metastatic melanoma represents a viable therapeutic option warranting further investigation,” said Jason A. Chesney, MD, PhD, who presented the findings during the AACR meeting. Chesney is the chief of the Division of Medical Oncology and Hematology and director of the James Graham Bron Cancer Center, University of Louisville in Kentucky.

Currently, few treatment options exist for patients with advanced melanoma who are refractory to or develop resistance to an immune checkpoint inhibitor, including retreatment with immunotherapy or chemotherapy, and neither has a significant impact on response or survival.

Previously, autologous TIL therapy has had the most efficacy in melanomas and has demonstrated antitumor efficacy and durable complete responses (CRs) in patients with heavily pretreated metastatic melanoma.

The C-144-01 trial was a global, open-label, multicohort, multicenter study of the centrally manufactured and cryopreserved autologous TIL therapy lifileucel in patients with unresectable or metastatic melanoma who have progressed on immune checkpoint inhibitors and BRAF/MEK inhibitors if the patient is 

Patients were eligible if they had 1 tumor lesion (about 1.5 cm in diameter) resectable for TIL generation, at least 1 tumor lesion for assessment of response, aged 18 years old or older, and had an ECOG performance status of 0 or 1.

The study consisted of 4 cohorts, 3 of which are now closed to enrollment. Cohort 1 included treatment of 30 patients with a first-generation non-cryopreserved TIL therapy, cohort 2 included 66 patients who were treated with a second-generation cryopreserved TIL therapy, and 75 patients were included in the pivotal cohort and received treatment with a cryopreserved second-generation TIL product. The ongoing third cohort includes 10 patients who will receive re-treatment with a TIL therapy. During the AACR meeting, Chesney focused on findings from the second cohort.

Primary end point for the second cohort was investigator-assessed ORR by RECIST 1.1; the secondary end points included safety and other efficacy assessments.

At baseline, the 66 patients had a median age of 55 (range, 20-79) 59% were male, 56% had an ECOG performance status of 0, 68% had 

wild-type disease, and 35% were PD-L1 positive (tumor proportion score ≥5). The median number of prior therapies was 3.3 (range, 1-9), which included anti–PD-1/PD-L1 therapy in all patients, anti–CTLA-4 therapy in 80%, and BRAF/MEK inhibition in 23%.

Patients in the cohort also had a high tumor burden at baseline, Chesney pointed out, with a mean target lesion size of 10.6 cm in diameter (range, 1.1-34.3), 77% had more than 3 target and non-target lesions, and 42% had liver and/or brain lesions.

The process of manufacturing lifileucel consisted of tumor tissue procurement across various resection sites, and the tissue was then sent to the central manufacturing facility where the tissue was fragmented and the TILs were isolated and cultured ex vivo before being expanded, reinvigorated, harvested, and cryopreserved—a process which took 22 days to complete. The cryopreserved products were then shipped back to the treatment center where the patients received a nonmyeloablative lymphodepletion regimen of cyclophosphamide 60 mg/kg for 2 days followed by fludarabine 25 mg/m2 for 5 days. Then, lifileucel was infused followed by administration of up to 6 doses of a interleukin-2 (IL-2) at 600,000 U/kg every 8 to 12 hours for 2 to 4 days.

Lifileucel was successfully manufactured regardless of the organ site of the resected tumor, Chesney noted.

The median study follow-up was 28.1 months, at which point the ORR was 36.4%, which consisted of CRs in 4.5% and partial responses in 31.8%. Additionally, 43.9% had stable disease for a disease control rate of 80.3%. The median DOR was not reached (range, 2.2-35.2+ months).

Responses were observed in patients regardless of 

mutational status or tumor PD-L1 expression and were also seen in patients with various lactate dehydrogenase levels, baseline tumor burdens, the presence of liver and/or brain metastases, and in patients who previously received anti–CTLA-4 therapy or BRAF/MEK inhibition.

The response and disease control rates were consistent with that of prior reports from the cohort presented at the 2020 American Society of Clinical Oncology Annual Meeting.

 However, with extended follow-up, 17.7% of patients had further reduction in target lesion size since the prior data cutoff period. A total of 81% of evaluable patients had a reduction in their tumor burden.

Of the 24 responders, 79% had previously received ipilimumab (Yervoy) and 4% had a partial response converted to a CR after 2 years following infusion with lifileucel; 49% of responders were still on the study at data cutoff.

Chesney noted that the target lesion sum diameter reduction was seen across the range of total TIL doses and that the investigators believed that the target lesion sum diameter reductions were seen across the range of TIL CD4-positive and CD8-positive cell doses.

At least 1 treatment-emergent adverse event (TEAE) was observed in all 66 patients and were of grade 3/4 in severity in 97%. Two patients experienced a grade 5 event due to intra-abdominal hemorrhage that was possibly due to TIL therapy in one patient and acute respiratory failure not related to TIL therapy in the second patient.

“The adverse event profile is manageable and consistent with the underlying advanced disease and known profiles of the nonmyeloablative lymphodepletion regimen and high-dose IL-2,” Chesney commented.

The most common any-grade TEAEs were thrombocytopenia (89.4%), chills (80.3%), anemia (68.2%), pyrexia (59.1%), neutropenia (56.1%), and febrile neutropenia (54.5%). The most common grade 3/4 TEAEs were thrombocytopenia (81.8%), anemia (56.1%), febrile neutropenia (54.5%), and neutropenia (39.4%).

No new safety risks were identified with the longer follow-up. Additionally, the number of TEAEs reduced over time.

“The decreasing frequency of adverse events over time supports the risk/benefit proposition of one-time therapy of lifileucel for these patients,” Chesney said.

1. Chesney JA, Larkin JMG, Kirkwood JM, et al. Lifileucel (LN-144), a cryopreserved autologous tumor infiltrating lymphocyte (TIL) therapy in patients with advanced (unresectable or metastatic) melanoma: durable duration of response at 28 month follow up. Presented at: 2021 American Association for Cancer Research Annual Meeting; April 10-15, 2021; Virtual. Abstract CT008.

2. Rosenberg SA, Yang JC, Sherry RM, et al. Durable complete responses in heavily pretreated patients with metastatic melanoma using T-cell transfer immunotherapy. 

2011;17(13):4550-4557. doi:10.1158/1078-0432.CCR-11-0116

3. Sarnaik A, Khushalani NI, Chesney JA, et al. Long-term follow up of lifileucel (LN-144) cryopreserved autologous tumor infiltrating lymphocyte therapy in patients with advanced melanoma progressed on multiple prior therapies. 

2020;38(suppl 15):10006. doi:10.1200/JCO.2020.38.15_suppl.10006

Lifileucel (LN-144), the tumor-infiltrating lymphocyte therapy, showed a positive objective response rate with the median duration of response not yet reached after more than 28 months of follow-up in patients with advanced melanoma.

Positive Efficacy Data Found With Lifileucel TIL Therapy for Pretreated Advanced Melanoma

Pembrolizumab (Keytruda) monotherapy demonstrated robust, durable antitumor activity in patients with locally advanced or recurrent/metastatic cutaneous squamous cell carcinoma (CSCC), according to a second interim analysis of the phase 2 KEYNOTE-629 trial presented at week 1 of the virtual AACR Annual Meeting.

“Pembrolizumab has demonstrated robust durable anti-tumor activity and promising survival in both the locally advanced and recurrent metastatic cutaneous SCC cohorts,” Brett G.M. Hughes, MD, Royal Brisbane and Women’s Hospital, said during a presentation of the data. “… This data establish pembrolizumab as a promising treatment option for those with locally advanced, recurrent/metastatic cutaneous SCC.”

In the multicenter, open-label, nonrandomized, phase 2 KEYNOTE-629 trial, patients with locally advanced disease demonstrated an objective response rate (ORR) of 50.0% (95% CI, 36.1-63.9), while the recurrent/metastatic cohort showed an ORR of 35.2% (95% CI, 26.2-45.2). ORR in the total population was 40.3% (95% CI, 32.6-48.3).

Disease control rate (DCR), defined as stable disease (SD) for 12 weeks or more plus ORR, in the locally advanced and recurrent/metastatic cohorts were 64.8% (95% CI, 50.6-77.3) and 52.4% (95% CI, 42.4-62.2), respectively. DCR in the entire patient population was 56.6% (95% CI, 48.5-64.4).

“From the subgroup analysis, overall response was generally consistent across most subgroups analyzed in both cohorts,” Hughes added. “In the recurrent/metastatic cohort, there was a slightly higher response rate observed in patients who received pembrolizumab in the first line. This was more in the range of 50% versus 33% for those that have had prior treatment. Although responses were observed, regardless of PDL1 expression, an increase in objective response was observed in those who had a CPS of 1 or greater, or a TPS score of more than 50%.”

In the locally advanced and recurrent/metastatic cohorts, 9 (16.7%) and 11 (10.5%), respectively, had a complete response (CR), 18 (33.3%) and 26 (24.8%) with a partial response (PR), 13 (24.1%) and 30 (28.6%) with SD, 8 (14.8%) and 18 (17.1%) with SD for 12 weeks or more, and 9 (16.7%) and 28 (26.7%) with progressive disease (PD). Amongst the entire patient population, 20 (12.6%) patients experienced a CR, 44 (27.7%) had a PR, 43 (27.0%) had SD, 26 (16.4%) had SD for 12 weeks or more, and 37 (23.3%) had PD.

“Most responses were quite deep and significant in the local advanced cohort,” Hughes noted. “… Notably for the first two interim analyses, despite similar overall response and disease control rates being observed, more patients are now achieving a complete response that have improved from a partial response, with 7 patients now added to the complete response cohort.”

The 12-month progression-free survival (PFS) rates in the locally advanced and recurrent/metastatic cohorts were 54% and 36.4%, respectively. Median PFS was not reached (NR) in the locally advanced cohort (95% CI, 5.5-NR). In the recurrent/metastatic group, median PFS was 5.7 months (95% CI, 3.1-8.5).

The 12-month overall survival (OS) rates in the locally advanced and recurrent/metastatic cohorts were 73.6% and 61.0%, respectively. Median OS was not reached in the locally advanced group (95% CI, NR-NR). Median OS in the recurrent/metastatic group was 23.8 months (95% CI, 13.4-29.8).

Any grade treatment-related adverse events (TRAEs) occurred in 69.2% of patients, including 11.9% of patients with grade 3 to 5. TRAES led to discontinuation in 8.8% of patients and death in 1.3% of patients. The most common TRAEs of any grade were pruritis (18.2%), fatigue (14.5%), asthenia (12.6%), rash (10.7%), diarrhea (9.4%), hypothyroidism (8.8%), arthralgia (6.3%), and nausea (5.7%).

“CSCC is the second most common non-melanoma skin cancer in the world representing approximately 20% of all non-melanoma skin cancers and 20% of all skin cancer-related mortality,” Hughes said. “In the first interim analysis of this study, we demonstrated that pembrolizumab monotherapy had a clinically meaningful and durable anti-tumor activity with manageable safety profile for recurrent and metastatic disease.”

At the meeting, Hughes reported initial efficacy and safety data from the locally advanced cohort of patients after a median follow-up of 13.4 months, and updated data from the recurrent/metastatic cohort after a median follow-up of 23.8 months.

Patients with locally advanced (n = 54) or recurrent/metastatic (n = 105) CSCC received 200 mg pembrolizumab once every 3 weeks for up to 35 cycles, or approximately 2 years, or until protocol-specified treatment discontinuation criteria were met.

To be eligible for the trial, patients must have been 18 years or older, had histologically confirmed CSCC with measurable disease per RECIST 1.1 by blinded independent central review (BICR), an ECOG PS score of 0 or 1, and adequate organ function. “Of note patients in the recurrent metastatic disease [cohort] at initial design of the study, all had to have prior systemic therapy,” Hughes said.

ORR per RECIST 1.1 by BICR served as the primary end point of the study. Secondary end points included DOR, DCR, and PFS (all per RECIST 1.1 by BICR), OS, and safety/tolerability.

Median age was 74 years (IQR, 62-82). The majority of patients were male (74.8%) and had an ECOG PS of 1 (63.5%). “Most patients had a PDL1 combined proportion score of more than 1 in the locally advanced cohort; 22% of the 54 were treated with prior systemic therapy with curative intent. Most commonly this was platinum-based chemotherapy with radiation,” Hughes said. “In the metastatic cohort, 91 of the 105, or 86.7% had received prior systemic therapy. A small number of patients after a protocol modification received treatment as their first recurrent metastatic line of therapy.”

The median time from the first dose to data cutoff on July 29, 2020, was 14.9 months (range, 10.1-19.4) for the locally advanced cohort and 27.2 months (range, 24.6-32.0) for the recurrent/metastatic cohort.

Hughes BG, Munoz-Couselo E, Mortier L, et al. Phase 2 study of pembrolizumab (pembro) for locally advanced (LA) or recurrent/metastatic (R/M) cutaneous squamous cell carcinoma (cSCC): KEYNOTE-629. Presented at: AACR Annual Meeting; April 10-15, 2021; Virtual. Abstract CT006.

These data establish pembrolizumab as a promising treatment option for those with locally advanced and recurrent/metastatic cutaneous squamous cell carcinoma, according to Brett G.M. Hughes, MD.

Pembrolizumab Induces Robust, Durable Antitumor Activity in Advanced CSCC

The combination adjuvant treatment of ipilimumab (Yervoy) plus nivolumab (Opdivo) did not meet the dual primary endpoints of the phase 3 CheckMate-915 trial (NCT03068455), failing to improve relapse-free survival (RFS) in the intent-to-treat (ITT) and PD-L1 of less than 1% populations when compared with nivolumab alone to treat patients with resected stage IIIB to D/IV melanoma, according to data that were presented during the virtual 

Findings showed that, in the ITT population, the 2-year RFS rate was 64.6% vs 63.2% with nivolumab alone. The median RFS was not reached (NR) in either arm (HR, 0.92; 97.295 CI, 0.77-1.09; 

In those who had PD-L1 expression of less than 1%, the 2-year RFS rate was 53.6% vs 52.4% in the doublet and monotherapy arms, respectively. Here, the median RFS was 33.2 months and 25.3 months in each arm, respectively (HR, 0.91; 95% CI, 0.73-1.14).

“The dual primary end points of RFS in the [ITT population] and PD-L1 of less than 1% population were not met,” lead study author Georgina V. Long, BSc, PhD, MBBS, FRACP, FAHMS, co-medical director of the Melanoma Institute Australia (MIA) and chair of melanoma medical oncology and translational research at MIA and Royal North Shore Hospital, The University of Sydney, said during a virtual presentation on the findings.

“Nivolumab combined with ipilimumab vs nivolumab in resected stage IIIB to D and IV melanoma did not improve the RFS or distant metastasis-free survival; these results reaffirm nivolumab as an adjuvant standard of care.”

The rationale for the research was based on several prior studies, one of which was the phase 3 EORTC 18071 trial of adjuvant ipilimumab vs placebo in patients with stage III melanoma who had undergone complete resection.

 Results showed that a 10-mg/kg dose of ipilimumab every 3 weeks elicited an improved 5-year RFS rate vs placebo (65% vs 54%, respectively; HR, 0.72; 95% CI, 0.58-0.88).

The phase 3 CheckMate-238 trial, which examined the role of nivolumab vs ipilimumab in patients who had experienced recurrent melanoma after complete resection of stage IIIB/C or stage IV melanoma, helped to establish nivolumab as a standard of care in this patient population.

 The 3-mg dose of nivolumab every 2 weeks yielded a 4-year RFS rate of 52% vs 41% in patients who received a 10-mg/kg dose of ipilimumab (HR, 0.71; 95% CI, 0.60-0.86).

Early data from phase 3 CheckMate-067 trial (NCT01844505), which examined nivolumab or nivolumab/ipilimumab vs ipilimumab alone in patients with previously untreated advanced melanoma, indicated that patients regardless of PD-L1 expression may experience benefit from the combination.

In the CheckMate-915 trial, which was conducted at 122 sites across 19 countries, randomized patients with completely resected stage IIIB to D or IV no evidence of disease melanoma to receive either 240 mg of nivolumab every 2 weeks and 1 mg/kg of ipilimumab every 6 weeks (n = 920) or 480 mg of nivolumab every 4 weeks (n = 924). Treatment was given for 1 year.

The trial also included an ipilimumab-monotherapy arm, wherein patients received the CTLA-4 inhibitor at 10 mg/kg (n = 99), though this arm was discontinued on July 20, 2017.

Stratification factors were by tumor PD-L1 expression (<1% vs 1% to <5% vs ≥5%), as well as by disease stage (IIIB vs IIIC-D vs IV). Complete lymph node dissection was not required.

The median follow-up was 28 months. Dual primary end points were RFS both in the ITT population and the PD-L1 less than 1% population. Key secondary end points included OS, correlation between PD-L1 and RFS, and outcomes on subsequent therapies. Exploratory end points consisted of distant metastasis-free survival and quality of life (QoL).

The median age was 55 years and the majority of patients (57%) were male. Thirty-eight percent of patients on both arms had a PD-L1 of less than 1% and 31% of patients had a 

 mutation. Overall, 31% of patients had stage IIIB disease, 52.5% had stage IIIC disease, 3% had stage IIID disease, and 13% had stage IV disease. Fifty-three percent of patients on the nivolumab/ipilimumab arm and 52% of patients on the nivolumab arm had stage IIIC disease.

Notably, patients who received the combination regimen had a median duration of therapy of 7.6 months vs 11.1 months in the nivolumab-alone arm.

“The cumulative dose of nivolumab in the [combination] arm was 3840 mg, which was considerably lower than the cumulative dose in the nivolumab monotherapy [cohort], which was 6240 mg,” Long explained. “If we break down duration by time periods, we can see that nearly one-third of patients in the combination arm received less than 3 months of drug therapy, whereas only 13% in the nivolumab monotherapy arm received less than 3 months of therapy.”

Additional data showed that when examining RFS by stage, patients with stage III disease who were treated with nivolumab/ipilimumab and single-agent nivolumab experienced a 2-year RFS rate of 64.7% and 63.6%, respectively. The median RFS was NR in either arm (HR, 0.94; 95% CI, 0.80-1.11).

In patients with stage IV disease, the 2-year RFS rate in the doublet arm was 63.6% compared with 61.1% in the single-agent arm. Similarly, the median RFS was NR in either arm (HR, 0.88; 95% CI, 0.58-1.32).

Additionally, patients with stage III disease who were treated with the combination had a 2-year dMFS rate of 75.4% with the combination compared with 77.4% with nivolumab alone. The median dMFS was NR in either arm (HR, 1.01; 95% CI, 0.83-1.23).

In those with stage IV disease, the 2-year dMFS rates were 68.4% and 67.9% in the nivolumab/ipilimumab and nivolumab-alone arms, respectively. Similarly, the median dMFS was not reached in this subgroup in either arm (HR, 0.94; 95% CI, 0.70-1.25).

A post hoc analysis of the combination arm evaluated whether duration of therapy impacted RFS by comparing patients who discontinued the regimen after 6 months or less with those who did not discontinue after 6 months or less, according to Long.

“Although we do see a 5% difference in the landmark RFS for the combination in these 2 groups, it is not sufficient to explain the overall negative results of this trial,” Long said.

Use of subsequent therapies was comparable in both arms, she noted, at 32% with the combination and 36% with the monotherapy.

Regarding safety, 94% of patients on nivolumab/ipilimumab experienced all-grade treatment-related adverse effects (TRAEs) and 33% experienced grade 3/4 TRAEs; these rates were 86% and 13% in the nivolumab arm, respectively. Thirty-two percent and 19% of patients in the combination arm experienced any-grade and grade 3/4 TRAEs, respectively, that led to treatment discontinuation compared with 10% and 6% in the monotherapy arm, respectively. No treatment-related deaths occurred in the monotherapy arm vs 4 in the combination arm.

The most common any-grade AEs with nivolumab/ipilimumab were pruritis (33%), rash (24%), fatigue (30%), diarrhea (27%), and hypothyroidism; the most common grade 3/4 AEs were increased lipase (5%), increased alanine amino transferase (3%), diarrhea (2%), hypophysitis (2%), and increased aspartate amino transferase (2%).

In the nivolumab-alone arm, the most common any-grade AEs were fatigue (30%), rash (21%), pruritis (21%), and diarrhea (20%), with common grade 3/4 AEs consisting of increased lipase (2%), rash (1%), and diarrhea (1%).

“A persistent, stable quality of life [was experienced] by both arms through the duration of the study. There were no improvement or deterioration in [clinically meaningful differences] during the course of the study for both arms. Similar trends were observed for both EQ-5D utility index and EQ-5D visual-analogue scale,” Long concluded.

1. Long G, Schadendorf D, Del Vecchio M, et al. Adjuvant therapy with nivolumab (NIVO) combined with ipilimumab (IPI) vs NIVO alone in patients (pts) with resected stage IIIB-D/IV melanoma (CheckMate 915). Presented at: AACR Annual Meeting 2021; April 10-15, 2021; Virtual. Abstract CT004.

2. Eggermont AMM, Chiarion-Sileni V, Grob JJ, et al. Prolonged survival in stage III melanoma with ipilimumab adjuvant therapy. 

. 2016;375(19):1845-1855. doi:10.1056/NEJMoa1611299

3. Ascierto P, Del Vecchio M, Mandalá M, et al. Adjuvant nivolumab versus ipilimumab in resected stage IIIB–C and stage IV melanoma (CheckMate 238): 4-year results from a multicentre, double-blind, randomised, controlled, phase 3 trial. 

. 2020;21(11):1465-1477. doi:10.1016/S1470-2045(20)30494-0

4. Larkin J, Chiarion-Sileni V, Gonzalez R, et al. Five-year survival with combined nivolumab and ipilimumab in advanced melanoma. 

. 2019;381:1535-1546. doi:10.1056/NEJMoa1910836

The combination adjuvant treatment of ipilimumab plus nivolumab did not meet the dual primary endpoints of the phase 3 CheckMate-915 trial, failing to improve relapse-free survival in the intent-to-treat and PD-L1 of less than 1% populations.

Adjuvant Nivolumab Plus Ipilimumab Combo For Late-Stage Melanoma Did Not Meet RFS End Point

Recent findings from the Gabriella Miller Kids First (GMKF) neuroblastoma X01 cohort study showed that the presence of pathogenic or likely pathogenic germline variants in cancer predisposition genes, which were identified in approximately 1 in 5 patients with neuroblastoma and were mostly inherited, was shown to correlate with worse event-free survival (EFS) and overall survival (OS) vs the absence of germline variants,

The results, presented ahead of the AACR Annual Meeting 2021, showed that 16% of the cohort (n = 90) harbored 93 pathogenic or likely pathogenic germline variants across 197 predefined cancer predisposition genes. The presence of a pathogenic or likely pathogenic germline variant in a cancer predisposition gene was associated with worse EFS (n = 82; 

 = .0015) compared with the absence of a germline variant (n = 421). The association between a pathogenic or likely pathogenic germline variant and high-risk and high-stage disease trended towards significance.

“The GMKF neuroblastoma cohort provides a rich and unique dataset that is allowing unanswered questions to be addressed,” said Emily Blauel-Bocko, MD, lead study author and a clinical fellow at the Children’s Hospital of Philadelphia, during a virtual presentation of the data.

Neuroblastoma is an embryonal tumor arising from the sympathetic nervous system. The solid tumor comprises 8% of childhood cancers and 12% to 15% of childhood cancer deaths.

Neuroblastoma is characterized by diverse clinical behavior, ranging from spontaneous regression to aggressive progression. Additionally, only 1% to 2% of patients have a family history of the disease, and the remainder of cases are believed to develop sporadically.

 mutations are responsible for 75% to 80% of pedigrees, and 

 mutations are responsible for 5% to 10% of pedigrees. In sporadic neuroblastoma, genome wide association studies have aided in the discovery of susceptibility loci.

However, gaps in knowledge remain because of insufficient parental data, resulting in an inability to definitively determine heritability.

To that end, investigators worked with the GMKF program, which supports large-scale genomic research in the fields of childhood cancer and structural birth defects.

“The neuroblastoma cohort is a large-size cohort, which allowed us to identify rare germline variants. The cohort included germline data from patients and parents, allowing for establishment of heritability patterns of these germline variants. Additionally, the dataset included paired DNA and RNA, which allowed us to evaluate the role of these germline variants in tumor development or propagation,” said Blauel-Bocko.

The cohort included a total of 556 patients accompanied by germline data from the patient and both parents in the majority of cases. Approximately two-thirds of patients had matched tumor data.

The clinical characteristics of the neuroblastoma cohort generally mirrored that of the general neuroblastoma population, although there was a slight skew toward low-risk patients owing to the point of entry into the study, said Blauel-Bocko.

Additional results from the data collection indicated that one canonical 

 mutation in R1275Q was identified, and no evidence of a 

 mutation was found. All pathogenic or likely pathogenic germline variants were identified in the tumor.

Enrichment was also seen in patients with identified pathogenic or likely pathogenic variants (

 = .0006) overall, in genes associated with DNA repair defects (

 < .0001), and in cancer predisposition genes, including BARD1 (

 < .0001) compared with control individuals,

Moreover, 94% of germline variants were inherited. Of the inherited variants, an equal percentage of maternal and paternal inheritance patterns were reported, at 47% each.

 variants (6%) were identified in syndromes predisposing to neuroblastoma, including Costello syndrome, Noonan syndrome, and Sotos syndrome.

“Our current work is focused on deeper investigations of the role of the role of these germline variants in tumor development and/or propagation in understanding the differing phenotype and genotype relationship between patients who have the disease and parents who do not have the disease despite the known inheritance patterns,” concluded Blauel-Bocko.

Blauel E, Vaksman Z, Lee A, et al. Heritability of cancer predisposition gene mutations in 556 neuroblastoma patients with paired parental DNA whole genome sequences. Presented at: AACR Annual Meeting 2021; April 9-14; Virtual. Abstract 3030.

Germline variants in cancer predisposition genes were associated with worse event-free and overall survival in patients with neuroblastoma.