The combination of nivolumab (Opdivo) plus platinum-doublet chemotherapy led to a significant improvement in event-free survival (EFS) compared with chemotherapy alone as neoadjuvant treatment in patients with resectable non–small cell lung cancer (NSCLC), according to findings from the phase 3 CheckMate 816 trial (NCT02998528).

The hazard ratio for the EFS benefit observed with neoadjuvant nivolumab and chemotherapy vs chemotherapy alone was 0.63 (97.38% CI, 0.43-0.91), according to a presentation given during the AACR Annual Meeting 2022.

“Event-free survival benefit favored nivolumab plus chemotherapy in most subgroups. Preliminary overall survival analysis showed a trend of improvement with nivolumab plus chemotherapy versus chemotherapy alone with a hazard ratio of 0.57 [99.67% CI, 0.30-1.07]. The study continues to mature with a longer follow up,” presented Nicolas Girard, MD, pneumonologist, professor, respiratory medicine, Versailles Saint Quentin University, head, Curie-Montsouris Thorax Institute, Institut Curie, at the American Association for Cancer Research (AACR) Annual Meeting 2022.

CheckMate 816 aims to compare nivolumab plus chemotherapy and chemotherapy alone and describe the safety and effectiveness of nivolumab plus ipilimumab for treatment of resectable NSCLC.

The randomized, open-label, phase 3 trial enrolled an overall sample size of 358 patients with early stage IB-IIIA, operable NSCLC, a lung capacity capable of tolerating the proposed lung surgery, an ECOG performance status of 0 or 1, and available tissue of primary lung tumor.

Patients were randomized 1:1 to receive either nivolumab at 360 mg and chemotherapy for 3 cycles or just chemotherapy alone. The majority of the patients enrolled were men with a median age in the nivolumab plus chemotherapy arm of 64.

Of the 358 patients randomized in CheckMate 816, 94% completed the neoadjuvant treatment. In the experimental arm, 83% of patients (n = 149) had definitive surgery while 75% (n = 135) in the chemotherapy arm did. Additionally, 20% of patients in the experimental arm received adjuvant therapy (n = 35) while 32% did in the control arm (n = 56).

The dual primary end points of the study include EFS and pathological complete response at the time of surgery. Secondary end points include overall survival, major pathological response at the time of surgery, and time to death or distant metastases.

The study met its primary end point of pathological complete response at a median follow-up of 29.5 months. Median EFS was 31.6 months in the nivolumab plus chemotherapy arm and 20.8 months in the control arm. The 1-year EFS was 76% in the experimental arm and 63% in the control while the 2-year EFS was 64% versus 45%. EFS was consistently approved across most subgroups observed in the trial.

These findings revealed a statistically significant and clinically meaningful improvement in EFS to be shown in patients given nivolumab plus chemotherapy, including in patients who have a partial complete response.

Overall survival was also tested in this study but did not cross predefined statistical boundaries. This is expected given the small number of OS events, but future research should help experts learn more.

In regard to safety, adverse events (AEs) of any grade occurred in 93% of patients in the nivolumab plus chemotherapy arm and in 97% of those who received chemotherapy alone. Grade 3 or 4 AEs occurred in 41% in the experimental arm versus 44% in the control arm. Additionally, treatment-related AEs of any grade led to discontinuation in 10% of patients given nivolumab and chemotherapy as well as 10% of those given chemotherapy alone.

There were 2 patients in the nivolumab plus chemotherapy arm who reported grade 5 surgery-related AEs consisting of pulmonary embolism and aortic rupture, but they were deemed to be unrelated to the study

Neoadjuvant nivolumab plus chemotherapy demonstrated a safety profile which was consistent with previous reports and did not change the feasibility of surgery when compared to chemotherapy alone.

“CheckMate 816 is the first phase 3 study with a neoadjuvant immunotherapy-based combination for resectable NSCLC to show improved event-free survival and partial complete response, along with promising overall survival results. These results support neoadjuvant nivolumab in combination with chemotherapy as a standard of care for patients with resectable NSCLC,” Girard.

Girard N, Spicer J, Provencio M, et al. Nivolumab (NIVO) + platinum-doublet chemotherapy (chemo) vs chemo as neoadjuvant treatment for resectable (IB-IIIA) non-small cell lung cancer (NSCLC): Event-free survival (EFS) results from the phase 3 CheckMate 816 trial.Presented at: 2022 AACR Annual Meeting; April 8-13, 2022; New Orleans, LA. Abstract CT012.

A neoadjuvant study of nivolumab plus ipilimumab or nivolumab plus chemotherapy versus chemotherapy alone in early stage non-small cell lung cancer (NSCLC) (CheckMate 816). Clinicaltrials.gov. Accessed April 11, 2022. https://clinicaltrials.gov/ct2/show/NCT02998528

Articles

The combination of nivolumab plus platinum-doublet chemotherapy led to a significant improvement in event-free survival compared with chemotherapy alone as neoadjuvant treatment in patients with resectable non–small cell lung cancer, according to findings from the phase 3 CheckMate 816 trial.

Nivolumab Plus Chemotherapy Improves Event-Free Survival in Resectable NSCLC

GD2-directed CAR T-cell therapy (GD2-CART) demonstrated prolonged periods of radiographic and clinical improvement in pediatric and young adult patients with 

-mutated diffuse intrinsic pontine gliomas (DIPG) and spinal diffuse midline gliomas (DMG), according to findings from a phase 1 trial (NCT04196413) presented during the AACR Annual Meeting 2022.

“This is a really important series because it is 1 of the first that has shown durable benefit in multiple individuals with solid tumors and clearly in incurable solid tumors,” Robbie G. Majzner, MD, said during the presentation. “We have identified the maximum-tolerated dose of intravenous infused GD2 CAR T cells [as 1e6/kg], and that was around dose-limiting toxicities due to high-grade cytokine release syndrome [CRS].”

-mutated DMGs are universally lethal pediatric tumors of the central nervous system. Disialoganglioside GD2 specifically is highly expressed on 

-mutated glioma cells and has demonstrated promising preclinical efficacy of GD2 CAR T cells.

A mice model found that most subjects given GD2 CAR T cells survived compared to those given CD19 CAR T cells.

“GD2 is identical between mouse and human and it is expressed at low levels on neurons," Majzner said. "Despite that, the neurons appear normal, and we saw no evidence that the GD2 CAR T cells were attacking the normal nervous cells that expressed low levels of GD2.”

Additionally, GD2 CAR T cells are associated with fatal hydrocephalus in some models. The toxicity that the mice developed was due to the tumors and because of that, the first-in-human phase 1 trial was created to test whether GD2 CAR T cells can be successfully made from immune cells which are collected from children and young adults with 

Eligibility for enrollment was open to patients aged 2-30 located in the United States. Other requirements included a tissue diagnosis of 

-mutated DIPG with radiographically evident tumor restricted to the brainstem, or tissue diagnosis of H3K27M-mutated DMG of the spinal cord, at least 6 weeks following completion of front-line radiation therapy, at least 3 weeks post chemotherapy or 5 half-lives, and an ECOG performance status of 0 or 1. 

mutant testing will occur as part of standard of care prior to enrollment.

A total of 13 subjects were enrolled and 11 were treated including 4 in dose level 1 and 9 in dose level 2. Two subjects were removed prior to treatment due to rapid progression. The median number of intracerebroventricular (ICV) infusions between patients was 5 and the median month from diagnosis was also 5.

The design of the study was a standard 3+3 dose escalation administered to subjects with DIPG which tested GD2 CAR T cells in subjects with 

-mutant DIPG. Dose level 1 consisted of 1x10

 CAR T cells/kg body weight, dose level 2 was 3x10

 CAR T cells/kg body weight, and dose level 3 was 10x10

Dose level 1 was explored if the first subject treated experienced dose-limiting toxicity (DLT) or if more than 2 of 6 subjects treated experienced DLT. Once the maximum tolerated dose or RP2D was determined in the dose expansion of subjects with DIPG and spinal DMG, up to 20 evaluable subjects with 

-mutant DIPG and 10 evaluable subjects with 

-mutant spinal DMG would be treated at the RP2D. This includes subjects treated during dose escalation.

Primary end points include rate of successful manufacture of GD2 CAR T, maximum tolerated dose, and safety with secondary end points including assessing the clinical benefit of GD2 CAR T at the RP2D in children and young adults with 

 gliomas and evaluating the safety and impact on the clinical benefit of repeat ICV administrations of GD2 CAR T.

While no DLTs were observed on dose level 1, 3 subjects experienced DLT on dose level 2 (2 DIPG/1 sDMG). This was due to grade 4 CRS, successfully managed with tocilizumab (Actemra), anakinra, and corticosteroids. CRS occurred earlier on dose level 2 versus 1 (Day 3 vs 7).

On both dose levels, all subjects exhibited transient symptoms related to on-tumor inflammation, termed Tumor Inflammation-Associated Neurotoxicity (TIAN), which was successfully managed with anakinra and, in some cases, CSF drainage and dexamethasone. No DLT due to TIAN has occurred.

Ten patients have reported adequate follow-up to assess benefit with 9 having experienced radiographic and/or clinical benefit after IV infusion. Additionally, they received subsequent ICV GD2 CAR T infusions (median = 4 ICV infusions/pt, range 1-6). While ICV infusions were not associated with high-grade CRS, some subjects developed transient fever, headache, meningismus, nausea, and/or vomiting, and several subjects developed tumor inflammation associated with neurotoxicity.

A total of 4 patients continue to receive ICV infusions on study and have experienced continued clinical and radiographic benefit at 11, 9.5, 8, and 7 months following enrollment. One participant, a 31-year-old with sDMG, has experienced a near-complete (> 95%) reduction in tumor volume and a 17-year-old with DIPG experienced a near-complete (> 98%) reduction in volume of a pontine tumor.

Toxicity was largely related to the location of the tumor and was reversible with intensive supportive care. On-target, off-tumor toxicity was not observed. A total of 3 of the 4 patients exhibited clinical and radiographic improvement. Pro-inflammatory cytokine levels were increased in the plasma and cerebrospinal fluid. Transcriptomic analyses of 65,598 single cells from CAR T cell products and cerebrospinal fluid elucidate heterogeneity in response between participants and administration routes.

“ICV treatment has been tolerated at a flat dose of 30 million CAR T cells without lymphodepletion as a retreatment strategy. We are currently enrolling on an ICV-only arm without lymphodepletion,” added Majzner.

These early results underscore the promise of this therapeutic approach for patients with 

Majzner RG, Mahdi J, Ramakrishna S, et al. Major tumor regressions in H3K27M-mutated diffuse midline glioma (DMG) following sequential intravenous (IV) and intracerebroventricular (ICV) delivery of GD2-CAR T cells. Presented at: 2022 AACR Annual Meeting; April 8-13, 2022; New Orleans, Louisiana. Accessed April 10, 2022. Abstract CT001.

GD2 CAR T cells in diffuse intrinsic pontine gliomas (DIPG) & spinal diffuse midline glioma (DMG). Clinicaltrials.gov. Accessed April 10, 2022. 

GD2-directed CAR T-cell therapy demonstrated prolonged periods of radiographic and clinical improvement in pediatric and young adult patients with H3K27M-mutated diffuse intrinsic pontine gliomas and spinal diffuse midline gliomas.

GD2-Directed CAR T-Cell Therapy Elicits Durable Benefit in H3K27M-Mutated Diffuse Intrinsic Pontine Gliomas

Elacestrant (RAD-1901) was found to result in a statistically significant and clinically meaningful improvement in progression-free survival (PFS) over standard-of-care treatment in patients with estrogen receptor (ER)–positive, HER2-negative metastatic breast cancer who previously received CDK4/6 inhibitors, according to data presented during the 

Results come from the phase 3 EMERALD study (NCT03778931) which examined the safety and efficacy of the oral selective estrogen receptor degrader versus the standard of care (SOC) for the treatment of patients with ER-positive, HER2-negative metastatic breast cancer in the second-/third-line, post-CDK4/6 inhibitor setting.

While endocrine therapy plus CDK4/6i is the main first-line therapy used to manage patients with ER-positive, HER2-negative metastatic breast cancer, most of these patients eventually experience disease progression due to therapeutic resistance, including the development of 

The use of sequential endocrine therapy before chemotherapy is recommended in treatment guidelines when there is an absence of visceral crisis or until all endocrine therapy options have run out. Standard single-agent endocrine therapies including fulvestrant (Faslodex) are associated with poor median PFS at 2 months in second-/third-line setting post-CDK 4/6i, making the clinical need for better endocrine therapy for these patients very apparent.

Thus, the multicenter, randomized, open-label trial, EMERALD, was created. The study enrolled 466 participants consisting of both men and postmenopausal women with advanced or metastatic ER+/HER2- breast cancer. These subjects must have progressed or relapsed on or after 1 or 2 lines of endocrine therapy for advanced disease, had an ECOG score of 0 or 1, and had visceral metastasis which included lung, liver, brain, pleural and peritoneal involvement.

Subjects within the first arm received elacestrant orally at 400 mg a day while those in arm 2 received the investigators choice of one of the SOC drugs including fulvestrant, anastrozole, letrozole (Femara), or exemestane (Aromasin). Fulvestrant was administered at 500 mg intramuscularly (IM) into the buttocks as two 5 mL injections on C1D1, C1D15 and C2D1 and day 1 of every subsequent 28-day cycle, anastrozole at 1 mg a day on a continuous dosing schedule, Letrozole at 2.5 mg a day on a continuous dosing schedule, or exemestane at 25 mg a day on a continuous dosing schedule.

Primary outcomes consisted of PFS in all patients as well as in 

-mutated subjects with a time frame from the date of randomization until disease progression or death up to 12 months after. The secondary outcome was overall survival (OS).

The study was designed with ≥ 90% power to evaluate a PFS hazard ratio (HR) of 0.667 in all patients and ≥80% power for a PFS HR of 0.610 in the 

-mutant subset. The OS analysis at the final PFS analysis allocated a 2-sided alpha level of 0.0001.

Findings revealed there to be a 30% reduction in the risk of progression or death within the patients administered elacestrant compared to those who received the SOC (HR, 0.697; 95% CI: 0.552-0.880; 

 = .0018). A 45% reduction in the risk of progression or death with elacestrant compared to the SOC in patients with 

 mutations (HR, 0.546; 95% CI: 0.387-0.768; 

In the overall population, there was an extended median PFS by 2.79 months in the elacestrant arm versus 1.91 months in the SOC arm. In the 

 mutation population, an extended median PFS was reported by 3.78 months for those administered elacestrant versus 1.87 months for SOC.

Additionally, higher PFS rates were observed at 6 months (34.3% versus 20.4%) and 12 months (22.3% vs 9.4%) with elacestrant versus the SOC, endocrine therapy group. Results of elacestrant versus fulvestrant were also found to be consistent. Ultimately, both primary end points of the trial were met and found to be statistically significant in favor of the elacestrant arm.

No statistically significant differences were reported in regard to OS, but an evident trend which favored elacestrant over SOC was shown in both groups. A final OS analysis with updated data is expected to come out between late 2022 and early 2023.

In regard to safety, elacestrant was shown to be well tolerated and have an encouraging safety profile. Treatment-related adverse events (TRAEs) led to discontinuation in both elacestrant and SOC arms (3.4% and 0.9%). Of the 237 patients in the elacestrant arm, grade 3 and higher TRAEs were reported in 7.2% compared to 3.1% for the SOC (n = 229).

Some grade 3/4 and higher treatment-emergent adverse events (TEAEs) for elacestrant included back pain (2.5%), nausea (2.5%), fatigue (0.8%), vomiting (0.8%), decreased appetite (0.8%), and arthralgia (0.8%).

Comparatively, the SOC arm reported TEAEs grade 3/4 and higher to be nausea (0.9%), fatigue (0.9%), decreased appetite (0.4%), and back pain (0.4%). Other TEAEs reported include diarrhea (0.9%) and aspartate aminotransferase increased (0.9%).

Elacestrant is shown to have the potential to become a new treatment option in the studied patient population. Other elacestrant combinations in earlier lines and with other targeted therapies, including CDK4/6 and mTOR inhibitors, are ongoing/planned for patients with ER+/HER2- breast cancer.

Bardia A, Neven P, Montero AJ et al. Elacestrant, an oral selective estrogen receptor degrader (SERD), vs investigator’s choice of endocrine monotherapy for ER+/HER2- advanced/metastatic breast cancer (mBC) following progression on prior endocrine and CDK4/6 inhibitor therapy: Results of EMERALD phase 3 trial. Poster presented at: 

 Miami Breast Cancer Conference. March 3-6, 2022; Miami Beach, FL.

Phase 3 Trial of Elacestrant vs. Standard of Care for the Treatment of Patients With ER+/HER2- Advanced Breast Cancer (EMERALD).ClinicalTrials.gov. Accessed March 4, 2022. https://bit.ly/3KhBoxf

Elacestrant was found to result in a statistically significant and clinically meaningful improvement in progression-free survival over standard-of-care treatment in patients with estrogen receptor–positive, HER2-negative metastatic breast cancer who previously received CDK4/6 inhibitors.

Jordyn Sava

Articles

Nivolumab Plus Chemotherapy Improves Event-Free Survival in Resectable NSCLC

GD2-Directed CAR T-Cell Therapy Elicits Durable Benefit in H3K27M-Mutated Diffuse Intrinsic Pontine Gliomas

Elacestrant Significantly Improves PFS Over SOC in Advanced ER+ Metastatic Breast Cancer