Although continuous lenalidomide (Revlimid) maintenance has been well established as the standard of care (SOC) after induction and autologous stem cell transplant (ASCT), its extended use in combination with carfilzomib (Kyprolis) and dexamethasone (KRd) could provide a viable post-ASCT alternative for patients with newly diagnosed multiple myeloma, according to Andrzej Jakubowiak, MD, PhD. Longer follow-up analysis is necessary to further confirm the regimen’s feasibility, necessary duration, and connection to minimal residual disease (MRD) negativity in this population.

Several previous studies evaluated pre- and post-ASCT KRd for the treatment of patients with newly diagnosed multiple myeloma, including the phase 2 FORTE trial (NCT02203643), which showed that KRd plus ASCT improved responses vs 2 other carfilzomib-based treatment approaches.

The phase 3 ATLAS trial (NCT02659293) aimed to build off these findings while addressing the need for more definitive research on alternative maintenance therapies in this setting. Unlike previous investigations of maintenance combinations, however, ATLAS directly compared KRd with lenalidomide maintenance to challenge its superiority.

Interim analysis occurred after 59 of 96 expected events were observed at a median follow-up of 33.8 months. Preliminary results demonstrated a significant improvement in median progression-free survival (PFS) with KRd, at 59.1 months vs 41.4 months with lenalidomide alone (HR 0.51; 95% CI, 0.31-0.86; 

 = .012). Notably, a 49% risk reduction was observed with KRd despite a shortened duration of 8 cycles of KRd treatment for patients with standard-risk disease and MRD negativity at cycle 6. Moreover, high MRD negativity in the KRd arm was associated with improved PFS.

“This difference in PFS between KRd and lenalidomide alone is a key finding. Moreover, we were able to show that a planned 36-month duration of post-transplant KRd treatment may not be required for all patients,” said Jakubowiak, a professor of medicine and director of the Myeloma Program at the University of Chicago in Illinois. “Overall, the interim data from the ATLAS trial support our hypothesis that post autologous stem cell transplant treatment with KRd may improve treatment outcome compared to standard of care lenalidomide maintenance.”

, Jakubowiak highlighted several key studies that influenced the development and design of ATLAS, introduced conclusions from the initial efficacy data, and discussed how ongoing analysis could further contextualize and inform post-transplant treatment approaches in multiple myeloma.

: What previous data inspired you to challenge the post-transplant maintenance SOC of lenalidomide monotherapy with KRd?

: Several developments influenced our study design and development. First, we learned from the phase 3 FIRST trial [NCT00689936], which investigated first-line lenalidomide for 18 months vs indefinite administration, that extended treatment is better than cutting intensive therapy after a certain period. I always wondered whether pre-transplant induction treatment for 3 to 4 cycles followed by transplant and single-agent lenalidomide maintenance was good enough for younger patients who wanted to extend their lives as much as possible.

What prompted us specifically were the results from our previous two KRd trials. The first phase 1/2 study investigating KRd without transplant or with deferred transplant in patients with newly diagnosed myeloma (NCT01029054) published in 2012, showed that responses to KRd continued to deepen after cycle 8 during an extended treatment with KRd up to 24 months. The second phase 2 trial (NCT01816971) investigating KRd with ASCT was published in 2020 showed that the rate of stringent complete responses continued to increase during the post-transplant extended KRd treatment in a similar way as in the prior KRd study without transplant, although we could not exclude that some of this could have been related to delayed transplant effect.

We correlated results from both trials and found that KRd deepens patient responses during the first 4 months post-transplant in the majority of patients and in an additional 20% to 30% of patients even beyond that time, where we would not expect to see delayed transplant effects.

What additional studies investigating post-ASCT maintenance strategies in multiple myeloma influenced the hypothesis and trial design of ATLAS?

The impetus for these various study design deliberations came from 2 important studies: the phase 3 STaMINA trial [NCT02322320] conducted in the US and the phase 3 EMN02/HO95 trial (NCT01208766) conducted in Europe. Both studies explored differences in patient outcomes with additional post-transplant treatments. STaMINA did not show any difference between lenalidomide alone vs 4 cycles of consolidation [treatment with bortezomib (Velcade), lenalidomide, and dexamethasone (VRd)] or second transplant.

In STaMINA, several patients in both the transplant and consolidation arms did not receive intended treatment, potentially contributing to no difference in outcome in these 3 arms in an intention-to-treat patient population. A later, less stringent, based on as treated evaluation of additional interventions like second transplant or consolidation did show benefit in this study.

That analysis correlated with data reported from EMN02/HO95, which showed that 2 cycles of VRd and transplant benefited patients, particularly those with high-risk disease. We concluded that longer treatment duration is better.

Since we have already tested KRd post-transplant, we knew that we could deliver it and that other than the inconvenience of coming to a center to receive treatment, patients do not appear to experience more toxicities than with other therapies. That was why we evaluated this strategy in this randomized phase 3 ATLAS trial.

In ATLAS, we selected patients after any type of induction regimen, in contrast to those in other ongoing or reported studies. The strategy was similar to that of the phase 3 CALGB-100104 trial [NCT00114101] of lenalidomide vs placebo, which was one of 2 key studies leading to the approval of lenalidomide maintenance therapy. Patients in CALGB-100104 were eligible for maintenance therapy after receiving any induction therapy followed by transplant, provided they did not have disease progression. We applied similar eligibility criteria in ATLAS to allow for historical comparisons to CALGB-100104.

The FORTE trial, which was initiated after ATLAS, was primarily designed to investigate 2 induction regimens and then compare KRd with or without transplant, but also had a second randomization for maintenance with carfilzomib and lenalidomide (KR) vs lenalidomide (R). Updated data from the FORTE were just published in 2022. One-third of patients randomized to KR were after an extended 12 cycles of induction. The remaining two-thirds were patients who received induction for 4 cycles, transplant, and 4 cycles of either KRd or KCd (carfilzomib, cyclophosphamide, and dexamethasone). While FORTE trial had a different design than ATLAS, both similarly showed that KR (i.e carfilzomib added to lenalidomide) or KRd improve PFS compared with lenalidomide alone.

Cross-study comparison is tricky, but the results from ATLAS and FORTE both document that extended treatment with carfilzomib and lenalidomide combinations improves PFS, with a HR in ATLAS of 0.51. FORTE had a slightly higher HR. However, when you look at the Kaplan-Meier curves, the comparison is striking. There is a similar effect of KR in FORTE and KRd vs lenalidomide in ATLAS.

Could you expand on the methodology and patient population of ATLAS?

ATLAS was supported by Amgen, Celgene, and Bristol Myers Squibb, but was investigator led and coordinated by the University of Chicago, with key contributions from the Polish Myeloma Consortium. As an investigator-initiated study, we aimed to enroll the necessary number of patients to evaluate primary end-point – the difference in PFS between KRd and lenalidomide alone. We used historical data from CALGB-100104 for our statistical modeling for the lenalidomide arm, and data from the KRd with transplant trial for our KRd arm. Based on this model, we concluded that at 4 years, we should be able to see a statistically significant difference in PFS between the 2 arms.

In addition, based on prior result, we hypothesized that we could de-escalate the duration of KRd treatment for a group of patients with standard cytogenetics who achieved MRD negativity at 6 cycles of KRd post-transplant. In total, 44% of patients in the KRd arm were de-escalated to lenalidomide alone maintenance after 8 cycles of KRd according to these criteria.

What initial PFS data did you find in ATLAS? 

In total, 61% of projected events required for final analysis had been seen, and we have already observed a difference in PFS between the KRd and lenalidomide arms. The median PFS was 59.1 months for the KRd arm and 41.4 months for the lenalidomide arm, which represents 49% reduction of progression or death. Bearing in mind that ATLAS trial data come from an unplanned interim analysis, the results are indicating the benefit of post-transplant therapy with combination therapy (KRd) compared to lenalidomide alone.

In this interim analysis, patients who received only 8 cycles of KRd and then were de-escalated to lenalidomide alone treatment were doing as well as the patients who received KRd maintenance for 36 months. It’s a bit of an unfair comparison because these patients are selected based on low risk and MRD negativity, and the other group has a mix of patients. Still, this group does not appear to drive PFS down, although we cannot prove this without a control arm.

We need to wait for confirmation of these data from a final analysis, which will come in about a year and a half. However, we felt it was important to report these interim data earlier than planned.

How did MRD status factor into patient outcomes?

In addition to PFS, this trial, along with other reported or ongoing studies, seems to show that MRD may serve as a marker for successful treatment de-escalation that does not adversely affect outcomes. The FDA and other agencies are also looking into the role of MRD as a potential surrogate marker for patient outcomes. At this point, in our analysis, we see a statistically significant superiority of MRD negativity in the KRd arm vs the lenalidomide arm at 6 cycles. MRD negativity was measured by International Myeloma Working Group criteria, meaning 10-5 sensitivity and a complete response or better. We’ll report later MRD results at other landmark time points, but these results indirectly show that MRD may be a predictor of PFS.

How tolerable is this combination compared with lenalidomide monotherapy?

As expected, there was a slightly higher rate of toxicities and adverse events (AEs) of all grades in the KRd arm compared with the lenalidomide arm. Importantly, the incidence of grade 3 and 4 AEs was comparable between the 2 arms for most categories. Most major differences in higher-level toxicities were higher rates of infections in the KRd arm, mostly lower respiratory infections and thrombocytopenia. Slightly higher rates of other toxicities were also observed in the KRd arm. There was also a slight, but not dramatic, difference in serious AEs between the arms. Together considering the clinically meaningful PFS difference, the analysis of AE data do not indicate that putting patients on KRd is an unnecessary risk, or that the patients are inclined not to stay on KRd treatment.

I would not use carfilzomib-based therapy in frail patients or those with with a significant history of cardiac events. However, patients who met the eligibility criteria for any standard lenalidomide-based maintenance therapy were enrolled, and our analysis indicated that this enrollment approach is reasonable also for carfilzomib-based maintenance.

Notably, this paper did not include quality of life [QOL] data, which we have collected and which we will report later. These data may help us find greater granularity between the 2 arms. We expect that those QOL data may be in line with the toxicity trends we have seen so far, as these therapies are well tolerated, with some trends toward higher toxicities and life inconvenience from frequent treatment visits in the KRd arm.

What next steps are planned for this research, and how might they better inform post-transplant treatment selection for these patients?

This study is ongoing, although the enrollment is completed. We will conduct our final analysis when the last enrolled patient has been in follow-up for 4 years, which will come around the fall of 2024. By that time, we may have more data to support what we have reported from this interim analysis.

Although this study was not designed with regulatory objectives in mind, the National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology has already included considerations for using KR post-transplant based on FORTE data. Our initial ATLAS data align with those guidelines and provide additional evidence for carfilzomib-based post-transplant maintenance.

In the meantime, we anticipate increased interest in more intensive post-transplant treatments like KRd based on risk-benefit analyses. The final analysis will include additional data on MRD results from other landmark time points, as well as QOL data. It will help us see whether any patient subsets may benefit more from KRd vs lenalidomide.

As discussed after our oral presentation at the 2022 ASCO Annual Meeting, this regimen may be considered for patients with high-risk disease, although we don’t have that clear signal yet. However, we have strong evidence to support KRd use in patients with standard-risk disease with or without MRD negativity, as we see a striking difference outcomes for stadard risk patients who receive KRd vs those who receive lenalidomide alone. KRd may also benefit patients with standard-risk disease. Conducting a subgroup analysis at later time points will be critical for clarifying those results and helping us navigate post-transplant treatment.

Dr Jakubowiak has consulting and advisory board roles with honoraria with ABBVIE, AMGEN, BMS, Gracell, GSK, Janssen, and Sanofi-Aventis.

Mina R, Musto P, Rota-Scalabrini D, et al. Carfilzomib induction, consolidation, and maintenance with or without autologous stem-cell transplantation in patients with newly diagnosed multiple myeloma: pre-planned cytogenetic subgroup analysis of the randomised, phase 2 FORTE trial. 

. 2023;24(1):64-76. doi:10.1016/S1470-2045(22)00693-3

Dytfeld D, Wróbel T, Jamroziak K, et al. Carfilzomib, lenalidomide, and dexamethasone or lenalidomide alone as maintenance therapy after autologous stem-cell transplantation in patients with multiple myeloma (ATLAS): interim analysis of a randomised, open-label, phase 3 trial. 

2023;12(1):S1470-2045(22)00738-0. doi:10.1016/S1470-2045(22)00738-0

Articles

Andrzej Jakubowiak, MD, PhD, highlighted several key studies that influenced the development and design of the ATLAS trial, introduced conclusions from the initial efficacy data, and discussed how ongoing analysis could further contextualize and inform post-transplant treatment approaches in multiple myeloma.

Post-Transplant KRd Maintenance May Allow for Superior Outcomes in Newly Diagnosed Multiple Myeloma

Poziotinib produced an encouraging overall response rate (ORR) in patients with non–small cell lung cancer (NSCLC) harboring 

 exon 20 mutations, meeting the primary end point in cohort 1 of a phase 2 trial (NCT03066206), according to findings published in 

 Notably, poziotinib sensitivity was highly dependent on the location of exon 20 insertions, with data showing that near-loop insertions were more sensitive to the EGFR TKI than far-loop insertions.

Data showed that patients treated with poziotinib (n = 50) achieved an investigator-assessed ORR of 32% (95% CI, 20.7%-45.8%), with all responders experiencing a partial response (PR). Additionally, 52% of patients had stable disease, 12% experienced disease progression, and 4% were not evaluable. The disease control rate (DCR) was 84% (95% CI, 71.5%-91.6%).

Among patients evaluated retrospectively by blinded independent central review (BICR; n = 42), poziotinib elicited an ORR of 31% (95% CI, 19.1%-46%), with all responders experiencing a PR. Furthermore, 45% of patients had stable disease, 19% experienced disease progression, and 5% were not evaluable. The DCR was 76% (95% CI, 61.5%-86.5%).

“These data demonstrate that poziotinib is a clinically active and tolerable inhibitor of 

 exon 20 insertion mutations with meaningful clinical activity in platinum-refractory patients, for whom limited therapeutic options are currently available, and that mechanisms of resistance to poziotinib in patients with 

 exon 20–mutant NSCLC at least in part overlap with reported mechanisms of resistance to other EGFR inhibitors in patients with classical 

-mutant NSCLC,” lead study author Yasir Y. Elamin, MD, an assistant professor in the Department of Thoracic/Head and Neck Medical Oncology of the Division of Cancer Medicine at The University of Texas MD Anderson Cancer Center, and colleagues, wrote.

Approximately 15% of all patients with NSCLC harbor 

 mutations. Most of those cases feature classical 

 exon 19 deletions and L858R mutations, where treatment with TKIs can produce meaningful ORRs. However, the approximately 10% of patients with NSCLC harboring 

 exon 20 mutations are generally more resistant to EGFR TKIs.

the FDA accepted for review a new drug application for poziotinib

 in patients with previously treated locally advanced or metastatic NSCLC with 

 exon 20 insertion mutations, based on results from cohort 2 of the phase 2 ZENITH20 trial (NCT03318939).

 In cohort 1 of that trial, which featured patients with 

 exon 20–mutated NSCLC, poziotinib produced an ORR of 14.8% with a DCR of 68.7%.

The phase 2 study detailed here further explored the efficacy, safety, potential mechanisms of resistance, and molecular determinants of response for poziotinib. The trial enrolled patients who were at least 18 years of age with histologically or cytologically confirmed stage IV or recurrent solid tumors not amenable to curative intent therapy.

Other key eligibility criteria included the need for adequate tissue for molecular profiling, measurable disease per RECIST v1.1 criteria, and an ECOG performance status of 0 or 1. Patients with stable brain metastases were permitted to enroll if they did not require treatment with anticonvulsants or escalating doses of steroids.

Key exclusion criteria included the presence of an 

 exon 20 mutation (though patients with coexisting primary 

 exon 20 and T790M mutations were eligible); prior or current treatment with an investigational agent or other systemic anticancer treatment within 2 weeks of first study dose; any concurrent chemotherapy, immunotherapy, biologic, or hormonal therapy for cancer treatment; or known or suspected brain metastases or spinal cord compression, unless the condition was asymptomatic, was treated with surgery/radiation, and has been stable without treatment at least 4 weeks prior to first study dose.

Once enrolled, patients were administered 16 mg of oral poziotinib once daily until objective disease progression. Patients were allowed to continue beyond progression if clinical benefit was observed. Patients who discontinued poziotinib for reasons other than disease progression continued to be assessed until progression occurred.

ORR per investigator and BICR assessments served as the primary end point of the trial. Secondary end points included DCR, progression-free survival (PFS), overall survival (OS), duration of response (DOR), and safety.

The median age of patients in cohort 1 was 62 years (range, 29-77), 60% were female, and 76% were White. Additionally, 28% had brain metastases at baseline, 68% never smoked, and 96% presented with adenocarcinoma. Ninety-four percent of patients had 

 exon 20 insertion mutations, and 6% had exon 20 point mutations. Prior lines of therapy included 0 (6%), 1 (26%), 2 (34%), 3 (22%), and 4 or more (12%). Prior treatments included platinum-based chemotherapy (88%), a TKI (34%), and a PD-1/PD-L1 inhibitor (54%).

Additional investigator-assessed data showed that the median DOR was 8.6 months (95% CI, 3.7-19.3). Patients achieved a median PFS of 5.5 months (95% CI, 5.4-10.4), and the 6- and 12-month PFS rates were 43% (95% CI, 30%-60%) and 29% (95% CI, 18%-46%), respectively. The median OS was 19.2 months (95% CI, 11.8-24.1).

Patients who received prior platinum-based chemotherapy experienced an ORR of 34.1% (95% CI, 21.9%-48.9%) and a median PFS of 5.5 months (95% CI, 5.0-9.4). In patients with baseline brain metastases, the intracranial ORR and DCR were 14% and 86%, respectively.

 exon 20 mutations, patients with insertions occurring in the near-loop region proximal to the αC helix achieved an ORR of 46% compared with 0% for patients with insertions in the distal far-loop region (

 = .0015). Although the median PFS was not significantly different based on insertion location, the 6- and 12-month PFS rates were 47% (95% CI, 33%-67%) and 32% (95% CI, 19%-52%), respectively, for patients with near-loop insertions, compared with 30% (95% CI, 12%-76%) and 20% (95% CI, 6%-68%), respectively, for patients with far-loop insertions.

“The likelihood of response was highly dependent on the location of the exon 20 insertion, and that there was an inverse correlation between distance of the insertion from the αC helix and sensitivity to the drug both preclinically and in patients,” study authors wrote.

Additionally, study authors also revealed factors linked to resistance to poziotinib.

“Acquired resistance to poziotinib in preclinical models of 

 exon 20 was associated with both EGFR-dependent mechanisms, including acquired T790M and C797S mutations, and EGFR-independent mechanisms, such as EMT,” they wrote. “Notably, T790M, but not C797S, mutations were detected in patients resistant to poziotinib treatment. In addition, signal bypass through MET amplifications and 

 mutations was also observed in patients but not in preclinical models.”

The median duration of treatment with poziotinib was 5.8 months (interquartile range, 3.6-12.3). Of the 32 patients to experience disease progression, 32 were still alive at data cutoff, and 16 patients continued treatment with poziotinib following progression. The median duration of treatment after progression was 3.2 months (IQR, 2.5-5.6). Overall, 56% of patients had died at the time of data cutoff, and all deaths were considered related to NSCLC.

Regarding safety, the most common adverse effects (AEs) of any grade included diarrhea (92%), skin rash (90%), paronychia (68%), oral mucositis (68%), dry skin (60%), anorexia (40%), alopecia (38%), hypokalemia (34%), nausea (28%), vomiting (32%), fatigue (20%), weight loss (16%), and pruritus (14%). Grade 3 AEs included skin rash (34%), diarrhea (22%), paronychia (10%), hypokalemia (6%), nausea (6%), weight loss (4%), and oral mucositis (2%).

Elamin YY, Robichaux JP, Carter BW, et al. Poziotinib for EGFR exon 20-mutant NSCLC: clinical efficacy, resistance mechanisms, and impact of insertion location on drug sensitivity. 

. 2022;40(7):754-767.e6. doi:10.1016/j.ccell.2022.06.006

Spectrum Pharmaceuticals announces acceptance of new drug application filing for poziotinib. News release. Spectrum Pharmaceuticals; February 11, 2022. Accessed July 13, 2022. 

Poziotinib in EGFR exon 20 mutant advanced NSCLC. ClinicalTrials.gov. Updated June 27, 2022. Accessed July 13, 2022. 

https://clinicaltrials.gov/ct2/show/NCT03066206

Poziotinib produced an encouraging overall response rate in patients with non–small cell lung cancer harboring EGFR exon 20 mutations, meeting the primary end point in cohort 1 of a phase 2 trial. 

Poziotinib Elicits Encouraging Responses in EGFR Exon 20–Mutated NSCLC

Neoadjuvant mFOLFIRINOX induced favorable overall survival (OS) results for patients with borderline resectable pancreatic ductal adenocarcinoma (PDAC) when administered prior to pancreatectomy, according to findings from the phase 2 A021501 trial (NCT02839343). However, the trial could not clearly demonstrate that neoadjuvant mFOLFIRINOX followed by hypofractionated radiation therapy was similarly effective.

At a median follow-up of 42.9 months (95% CI, 39.7-43.4), the Kaplan-Meier–estimated 18-month survival rate was 66.7% (95% CI, 56.1%-79.4%) for patients assigned to mFOLFIRINOX, which is a regimen comprised of oxaliplatin at 85 mg/m

, leucovorin at 400 mg/m2, and fluorouracil at 2400 mg/m

. That survival rate was noted to exceed the preselected historical control of 50%.

For patients who received mFOLFIRINOX along with radiotherapy, the Kaplan-Meier–estimated 18-month survival rate was 47.3% (95% CI, 35.8%-62.5%). Investigators closed the radiation arm at the interim futility analysis because statistical requirements to conclude efficacy were not met.

, lead investigator Matthew H. G. Katz, MD, CMQ, FACS, FASCO, chair of surgical oncology at the University of Texas MD Anderson Cancer Center, expressed disappointment that the radiation arm closed early.

“My interpretation of existing data, and the data provided by this trial is pretty clear: I do not believe that the 

 use of radiation therapy is indicated for any anatomic stage of localized pancreatic cancer” Katz said. “I do believe that there is a role for radiation therapy in selected patients with localized pancreatic cancer. The problem is we just have not figured out precisely who those patients are. I have heard that this is the end of radiation therapy. I think that is a gross overstatement. We just have to figure out who benefits.”

Patients with borderline resectable PADC have tumors that involve major abdominal blood vessels. However, surgery is difficult and not all patients benefit from the procedure. Furthermore, the cancer often recurs shortly after surgery if patients do not receive neoadjuvant therapy, which can include chemotherapy and possibly radiation treatment.

Although investigators have conducted multiple studies to determine the optimal treatment regimen in this setting, the use of radiation in the neoadjuvant setting remains controversial. Investigators conducting A021501 sought to assess the efficacy of neoadjuvant treatment with and without radiotherapy.

This study was not designed to directly compare chemotherapy with chemotherapy and radiotherapy in the neoadjuvant setting, and the role of radiation therapy in this setting remains undefined. Future studies will have to determine whether certain patients can benefit from neoadjuvant radiation and to identify who those patients are.

Investigators enrolled 70 patients to the mFOLFIRINOX arm and 56 to the mFOLFIRINOX/radiation arm at 50 sites across the United States. Those in the mFOLFIRINOX arm received 8 cycles of treatment. Patients assigned to radiation received 7 cycles of mFOLFIRINOX plus 33 Gy to 40 Gy of stereotactic body radiation therapy in 5 fractions (n = 35) or 25 Gy of hypofractionated image-guided radiation therapy in 5 fractions (n = 5).

Among the first 30 evaluable patients enrolled to each arm, 17 in the chemotherapy arm and 10 in the combination arm had undergone complete resection with negative margins. This led investigators to close the combination arm and proceed to full enrollment in the chemotherapy arm.

Thirty-eight patients in the chemotherapy arm and 28 patients in the chemotherapy and radiation arm underwent surgery on protocol. Thirty-two patients in the chemotherapy arm and 19 in the radiation arm received pancreatectomy. Among those who underwent pancreatectomy, 88% in the chemotherapy arm and 74% in the radiation arm had complete resection with negative margins.

Follow-up continued every 4 months after the end of treatment until 24 months post registration or documented progression, whichever occurred first. Thereafter, investigators collected survival information every 6 months for 5 years post registration.

The primary end point of the trial was 18-month OS rate, which was defined as the number of patients who were alive at 18 months after randomization divided by the total number of evaluable patients in each arm. Secondary end points included event-free survival (EFS), surgery with R2 resection, recurrent disease following surgery, any-cause death, R0 resection rate, pathologic complete response rate, and rate of adverse effects.

The median OS reported in patients within the mFOLFIRINOX arm was 29.8 months (95% CI, 21.1-36.6) compared with 17.1 months (95% CI, 12.8-24.4) in those who were in the radiation arm. The median EFS was 15.0 months (95% CI, 11.2-21.9) vs 10.2 months (95% CI, 6.7-17.3) in favor of the mFOLFIRINOX arm.

Katz noted that the prospective, multicenter trial enrolled patients at sites all over the United States. “When you think about that in that context, I think that the data are really impressive,” Katz said. “30 months of OS for a group of patients who were selected only by their anatomically advanced disease and who were operated on in centers across the United States is really impressive.”

Katz MHG, Shi Q, Meyers J, et al. Efficacy of preoperative mFOLFIRINOX vs mFOLFIRINOX plus hypofractionated radiotherapy for borderline resectable adenocarcinoma of the pancreas: the A021501 phase 2 randomized clinical trial. 

. Published online July 14, 2022. doi:10.1001/jamaoncol.2022.2319

Neoadjuvant mFOLFIRINOX induced favorable overall survival results for patients with borderline resectable pancreatic ductal adenocarcinoma when administered prior to pancreatectomy, though neoadjuvant mFOLFIRINOX followed by hypofractionated radiation therapy did not prove to be similarly effective.

Neoadjuvant mFOLFIRINOX Produces Favorable OS Results Without Radiation in Borderline Resectable Pancreatic Cancer

Although CAR T-cell therapies have demonstrated unprecedented activity in patients with heavily pretreated relapsed/refractory hematologic malignancies, they are marked by a significant risk of infections and may limit the efficacy of COVID-19 vaccines. As such, data are needed to inform how to optimize COVID-19 vaccination and booster strategies among CAR T-cell therapy recipients, according to findings from a review published in 

“Although CAR T[-cell] therapy prolongs the survival of patients with relapsed/refractory diseases, the associated on-target, off-tumor toxicities, particularly infections, limit the effective utilization of this curative therapy,” wrote lead study author Juliet Meir, MD, a PL2 categorical resident at Westchester Medical Center of the Westchester Medical Center Health Network, and coauthors in the study publication.

To date, several CD19- and BCMA-directed CAR T-cell therapies have been FDA approved across multiple relapsed/refractory hematologic malignancies, including acute lymphoblastic leukemia, diffuse large B-cell lymphoma and other lymphomas with similar histopathological features, mantle cell lymphoma, and multiple myeloma.

With all products, CAR T-cell therapy is associated with unique short- and long-term toxicities and infection risks in patients with hematologic malignancies who were heavily pretreated with anti-cancer agents and, often, allogeneic hematopoietic stem cell transplant (allo-HSCT).

Acute toxicities, such as cytokine release syndrome (CRS) and immune effector cell–associated neurotoxicity syndrome, confer an early risk of infection following CAR T-cell therapy infusion. CAR T-cell therapy recipients are further predisposed to severe infections from long-term toxicities, including prolonged B-cell aplasia, hypogammaglobulinemia, and cytopenias. Moreover, these long-term adverse effects hinder the chance for remission associated with CAR T-cell therapy.

Ultimately, the risk of infections with CAR T-cell therapy is largely variable and depends on several patient-, disease-, and CAR T-cell therapy–related factors. Some of these factors include age at the time of CAR T-cell therapy, race/ethnicity, body mass index, Karnofsky performance status, disease status, cytogenetics, prior lymphodepletion chemotherapy regimens, the interval between cell collection and infusion, bridging therapy, minimal residual disease status at CAR T-cell therapy infusion, disease burden, CAR T-cell dose, signaling and costimulatory domains, target antigen, and duration of lymphopenia and hypogammaglobulinemia.

Notably, data suggest that CD19-directed CAR T-cell therapies induce more bacterial infections, whereas BCMA-directed therapies induce more viral infections because of differential expression patterns on the B-cell surface.

It is known that patients with cancer, particularly those with hematologic malignancies, are at an increased risk of developing severe and potentially fatal COVID-19 infections. Patients who have received CAR T-cell therapy or undergone allo-HSCT are at a heightened risk of morbidity and mortality from COVID-19 infections.

Additionally, data suggest that COVID-19 vaccine responses could be substantially decreased in patients who receive CAR T-cell therapy vs those who undergo allo-HSCT. Early data suggest that adequate humoral and cellular responses to COVID-19 vaccines may not be obtained in patients with hematologic malignancies.

Currently, the FDA is advising against checking vaccine responses; however, in select CAR T-cell therapy recipients, routine serological assessment could gauge vaccine responses and inform the need for additional vaccine doses.

Additionally, because of the potential diminishing effect corticosteroid use has on immune responses, the timing and intensity of steroids for prevention and treatment of CAR T-cell therapy–related toxicities should be weighed in the context of available COVID-19 vaccine platforms.

Regardless, patients who receive CAR T-cell therapy should continue implementing precautionary measures even if an immune response is confirmed. When possible, telemedicine should be utilized to minimize the risk of exposure to COVID-19 in immunosuppressed CAR T-cell therapy recipients. Telemedicine should be considered for long-term follow-up in the hospital and community settings.

Additionally, all health care professionals and caregivers should be vaccinated to minimize the risk of spreading COVID-19 to CAR T-cell recipients. Transplantation and cellular therapy centers should continue to implement strict mitigation strategies as well.

Ultimately, significant research is needed to determine how CAR T-cell therapy recipients are responding to COVID-19 vaccinations, particularly as booster vaccine dosing and heterologous prime-boosting strategies become more actualized.

“Given the immunosuppressed milieu as a driver for mutational SARS-CoV-2 variants, antiviral agents and long-acting monoclonal antibodies or small molecules, potentially resistant to current SARS-CoV-2 mutations, merit evaluation in prospective studies to halt the development of mutations and spread to close contacts,” Meir and coauthors wrote.

“Immunity to SARS-CoV-2 is conferred by intricate crosstalk of both antibody and T-cell responses. Insight into both responses is needed for an optimal understanding of protection in this vulnerable patient group,” Meir and coauthors concluded.

Meir J, Abid MA, Abid MB. State of the CAR-T: risk of infections with CAR-T therapy and determinants of SARS-CoV-2 vaccine responses. 

. Published online September 26, 2021. Accessed October 26, 2021. doi:10.1016/j.jtct.2021.09.016

Although CAR T-cell therapies have demonstrated unprecedented activity in patients with heavily pretreated relapsed/refractory hematologic malignancies, they are marked by a significant risk of infections and may limit the efficacy of COVID-19 vaccines.

COVID-19 Vaccination Strategies Should Consider Infection Risks for CAR T-Cell Therapy Recipients

COVID-19 vaccination has been shown to induce high rates of seroconversion in patients with cancer, although those with hematologic malignancies have demonstrated lower immunogenicity and those who previously received immunosuppressive therapies appear to be less responsive, according to data from a study published in 

When utilizing a validated antibody assay against the SARS-CoV-2 spike protein, investigators revealed a 

 among 200 patients with cancer in New York City who had received a full dose of 1 of the FDA-authorized COVID-19 vaccines.

Patients with solid tumors experienced an impressive seroconversion rate of 98% compared with a rate of 85% in those with hematologic malignancies, 70% in those who had received highly immunosuppressive therapies like anti-CD20 agents, and 73% in those who had previously undergone stem cell transplantation. Notably, patients who received treatment with immune checkpoint inhibitors or hormonal therapies experienced seroconversion rates of 97% and 100%, respectively, following vaccination.

“We saw very encouraging [data] showing that most patients with a cancer diagnosis have a really high chance of responding to vaccinations—as long as the vaccinations are done in an appropriate manner, [with] both doses administered,” Balazs Halmos, MD, MS, study author, director of Thoracic Oncology, and director of Clinical Cancer Genomics at Montefiore Medical Center, told 

® in an exclusive interview on the research. “This was [true] even for [patients who were receiving] active treatment with chemotherapy, targeted therapy, or immunotherapy.”

Halmos and colleagues launched this study to develop a better understanding with regard to the immunogenicity of vaccines in a group of patients with a cancer diagnosis in New York City by examining the rates of anti-spike immunoglobulin G (IgG) antibody positivity after receiving 1 of the 3 authorized COVID-19 vaccines.

A total of 213 patients were enrolled to the study through an informed-consent process. Twenty-nine additional patients with cancer who received the SARS-CoV-2 spike IgG testing were identified through retrospective chart review.

A total of 18 patients did not have this test conducted following consent, and thus, they were excluded from the analysis. Twenty additional patients were excluded because they had their test done before having received full vaccination in accordance with FDA guidance. Four additional patients were excluded for other reasons.

As such, 233 patients with cancer were noted to have received all required doses of their COVID-19 vaccine; all these patients were included in the safety analysis. A subset of 200 patients received the IgG test and were included in the immunogenicity analysis. Serological information from these patients were utilized in association studies between cancer subtypes and therapies.

Investigators also examined the link between the quantitative titer of SARS-CoV-2 spike IgG and cancer subtypes and therapies. If the 200 patients, 185 had available IgG titers that were at least 2 days following the last vaccine dose. A total of 15 patients were excluded from the vaccination cohort with titers; these patients had received the vaccine, but titers were checked less than 1 week from their last dose.

Among those included in the efficacy analysis (n = 200), the median age was 67 years (range, 27-90), 58% were female, and 42% were male. The study population was noted to be representative of the diverse population that resides in the Bronx, New York, with 32% of patients identifying as African American, 39% as Hispanic, 22% as Caucasian, 5% as Asian, and 3% as other ethnicities.

Additionally, 67% of patients had a solid tumor diagnosis and 33% had a hematologic malignancy. Among those with solid tumors, 26% had breast cancer, 14% had gastrointestinal cancer, 9% had genitourinary cancer, 5% had gynecologic cancer, 13% had thoracic or head and neck cancer, 1% had skin or musculoskeletal cancer, and 1% had carcinoma of an unknown primary. Among those with hematologic malignancies, 13% had lymphoid disease, 9% had myeloid disease, and 11% had plasma cell disease.

Seventy-five percent of patients had an active malignancy and 67% were receiving active treatment at the time that they received the COVID-19 vaccine. Fifty-six percent of patients were on active chemotherapy. Moreover, 19% of patients were on active chemotherapy within 48 hours of receiving at least 1 of their COVID-19 vaccine doses.

Fifty-four percent of patients completed vaccination with the Pfizer vaccine, 31% with the Moderna vaccine, and 10% with the Johnson & Johnson vaccine. A total of 3 patients had received a complete mRNA vaccination series but the information regarding the type of vaccine (Pfizer vs Moderna) are not yet available.

Additional findings from the study showed that significantly higher titer values were observed in solid tumors vs hematologic malignancies among a subgroup of 185 patients with available IgG titers longer than 7 days post vaccination, at a median of 7858 AU/mL vs a median of 2528 AU/mL, respectively (

When comparing patients who were receiving active cancer treatment vs those who were not, no significant differences in seroconversion were reported, at 96% and 93%, respectively. However, investigators did report lower seropositivity rates in those who were on active cytotoxic chemotherapy versus other treatments, at 92% vs 99%, respectively (

= .04). Moreover, significantly lower seroconversion rates were also noted in those who received immunosuppressive therapies like stem cell transplant (73%; 

= .0001), or CAR T-cell therapy (all seronegative; 

Significantly lower titer levels were observed in patients who received CD20 antibody therapy vs the overall patient population, which underscored the susceptibility of patients receiving these treatments during the pandemic.



No statistically significant associations between age, ethnicity, time since immunosuppressive therapy, steroid use, or treatment within 48 hours of a vaccine dose, and seropositivity were reported.

Although all patients who were receiving CDK4/6 inhibitor treatment demonstrated positive anti-spike IgG test results, notably antibody titers were noted to be “very low” in this subset (n = 5), at a median of 1242 AU/mL vs a median of 6887 AU/mL in the overall cohort. “Given the known involvement of the CDK4/6 pathway in immune activation, this might be biologically plausible and warrants further studies into the impact of CDK4/6 inhibitors on vaccine efficacy,” the study authors noted.

A trend to lower titers were also reported among subsets of patients who received BCL-2 or BTK inhibitors.

Among a subset of 22 patients with cancer who had previously been infected with COVID-19, the seroconversion rate was 95%. Notably, antibody titers in those who had prior infection with the virus were found to be significantly higher than those who did not have a known prior infection, at a median of 46,737 AU/mL and a median of 5296 AU/mL, respectively (

“Our study, along with other emerging data, strongly highlights the continued need to vaccinate patients with a cancer diagnosis urgently and broadly, as vaccinations are likely to be highly effective,” the study authors concluded. “On the other hand, our study highlights at-risk cohorts of patients, in particular patients with hematologic malignancies following receipt of immunosuppressive therapies such as stem cell transplantation, anti-CD20 therapies, and CAR T-cell treatments. These cohorts of patients could potentially benefit from passive immunization with anti-COVID antibodies in the face of the ongoing pandemic.”

Thakkar A, Gonzalez-Lugo JD, Goradia N, et al. Seroconversion rates following COVID-19 vaccination among patients with cancer. 

. 2021;39(8):1081-1090.e2. doi:10.1016/j.ccell.2021.06.002

COVID-19 vaccination has been shown to induce high rates of seroconversion in patients with cancer, although those with hematologic malignancies have demonstrated lower immunogenicity and those who previously received immunosuppressive therapies appear to be less responsive.

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