The FDA has granted a breakthrough therapy designation to teclistamab for the treatment of patients with relapsed/refractory multiple myeloma, according to Janssen, the developer of the bispecific antibody.

The designation was based on data from a phase 1 study (NCT03145181), an open-label, multicenter trial evaluating the safety and efficacy of teclistamab in adults with relapsed/refractory disease.

Primary data from the phase 1 study, which were presented at the 2020 ASCO Virtual Scientific Program, showed that teclistamab led to a 67% objective response rate (ORR) and a very good partial response rate (VGPR) or better of 50% in patients with relapsed/refractory myeloma at a dose of 270 µg/kg.

Updated results from the study showed that at the recommended phase 2 dose (RP2D), which was 1500 μg/kg given subcutaneously (SC), the ORR with teclistamab was 73% and the VGPR or better was 55%; the complete response (CR) rate or better was 23%.

The agent was also well tolerated at the RP2D; the maximum-tolerated dose (MTD) was not identified, and all reports of cytokine release syndrome were of grades 1/2 and were mostly a result of step-up doses and the first full doses of treatment.

“We are pleased to have received Breakthrough Therapy and PRIME Designations for our novel bispecific antibody, teclistamab,” said Peter Lebowitz, MD, PhD, Global Therapeutic Area Head of Oncology at Janssen Research & Development, LLC. “This program exemplifies our commitment to advancing science for patients living with multiple myeloma, and it builds upon our robust portfolio in this disease.”

Teclistamab is an off-the-shelf, T-cell redirecting, bispecific antibody that targets BCMA and CD3. Teclistamab redirects CD3-positive T cells to BCMA-positive myeloma cells to induce malignant cell death. Preclinical data have shown that teclistamab kills myeloma cell lines and bone marrow–derived myeloma cells from heavily pretreated patients.

To be eligible for enrollment in the phase 1 study, patients had to have measurable myeloma that was relapsed/refractory to standard therapies or be intolerant to standard treatments, hemoglobin that was at least 8 g/dL, platelets that were at least 75 x 109/L, and white blood cell counts that were at least 1.0 x 109/L. Patients could not have received prior BCMA-targeted treatment.

The study comprised 2 cohorts: intravenous (IV; n = 84) and SC (n = 65) administration. The dosing schedule in each cohort comprised 1 to 3 step-up doses prior to week 1, followed by full doses in weeks 1 to 3. In the IV cohort, doses increased following 0.3 to 19.2 μg/kg with a maximum dose of 720 μg/kg; the SC cohort started at 80 μg/kg and increased up to 3000 μg/kg. The initial every-2-week IV dose was switched to weekly IV or SC plus or minus step-up dosing.

Premedication with dexamethasone were limited to the step-up doses and the first full dose, and there was no steroid requirement following the first full dose.

In the overall study population (n = 149), the median age is 63 years (range, 24-84), and 22% of patients were 70 years and older; 54% of patients were male. Twenty-five percent of patients had at least 60% of bone marrow plasma cells, 12% had at least 1 extramedullary plasmacytomas, and the median years since diagnosis was 7 years. A total 32% of patients had high-risk cytogenetics, and 85% had prior transplantation.

The median number of prior lines of therapy was 6 (range, 2-14); most patients (96%) were exposed to 3 classes of therapy, and 69% were penta-refractory. Patients were refractory to carfilzomib (Kyprolis; 66%), pomalidomide (Pomalyst; 77%), and anti-CD38 antibodies (93%), and 91% of patients were refractory to their last line of therapy.

The primary end point in part 1 of the trial was the RP2D; in part 2, the key objective was safety and probability at the RP2D, as well as antitumor activity, pharmacokinetics, and pharmacodynamics.

The updated findings also showed that at the RP2D, the median time to first confirmed response was 1 month (range, 0.3-3); 70% of patients who were triple-class refractory responded to treatment, and 75% of patients who were penta-refractory responded.

Most of the active doses were reported to be between 270 to 720 μg/kg given IV and 720 to 3000 μg/kg given SC. At these doses, the ORR was 69%, 59% of patients had a VGPR or greater, and a CR or better occurred in 26% of these patients. In the IV cohort (n = 27) and SC cohort (n = 41), the ORRs were 67% and 71%, respectively.

In the SC cohort, the ORR was 46% at the 80 μg/kg plus 240 μg/kg dose (n = 13), 60% at the 720 μg/kg dose (n = 15), and 73% at the 1500 μg/kg dose (n = 22), in which the VGPR or better was 55%.

Of 11 evaluable patients across the IV and SC doses thus far, 8 patients had a minimal residual disease–negative (MRD) CR at 10-6 and 1 patient experienced this at 10-5 sensitivity.

Responses were durable and deepened over time. Among responders who received the RP2D (n = 16), and at a median follow-up of 3.9 months, 94% of patients are alive and progression free. Of those in the SC cohorts (n = 35), 91% of patients are on treatment with ongoing responses; the median follow-up is 6.5 months.

Patients receiving the active IV and SC doses (n = 47) remained on treatment with ongoing responses (94%) at a median follow-up of 6.5 months. All 5 evaluable patients across the IV and SC cohorts showed sustained MRD negativity.

The pharmacokinetic and pharmacodynamic data supported the RP2D.

The safety profile was similar in both the overall and RP2D population. Overall, the most common (≥20%) all-grade and grade 3 or higher adverse effects (AEs) were neutropenia (57% and 46%, respectively), anemia (55% and 32%), thrombocytopenia (40% and 22%), and leukopenia (28% and 14%). Nonhematologic all-grade AEs were all-grade CRS (55%), pyrexia (30%), diarrhea (23%), nausea (22%), fatigue (22%), headache (22%), and cough (21%). Grade 3 or higher AEs were cough (2%), and diarrhea, nausea, and fatigue (1% each).

There were 2 dose-limiting toxicities across all doses, but no DLTs were at the RP2D. These were grade 4 delirium, which occurred at the 20 μg/kg IV step-up dose, and grade 4 thrombocytopenia, at the 180 μg/kg IV dose.

Infections occurred in 52% of patients, and 27% occurred at the RP2D; 15% percent of these patients had grade 3 or higher infections across all doses, and 6% had grade 3 or higher infections at the RP2D.

Neurotoxicity occurred in 7 patients (5%), 1 (3%) which occurred at the RP2D. Two events of grade 3 or higher neurotoxicity occurred at the IV dose, and none of which were reported with SC dosing. Injection-site reactions occurred in 32% of patients, 36% occurred at the RP2D, all of which were grades 1/2. One treatment-related AE, grade 5 pneumonia at 80 μg/kg after 16 cycles, led to death; no treatment-related deaths occurred at the RP2D.

CRS occurred in 55% of patients overall; the median time to CRS onset was 2 days (range, 1-5 days) and the median duration of CRS was 2 days (range, 1-8). Fifty-one percent of patients had supportive interventions to treat CRS: tocilizumab (Actemra; 23%), steroids (13%), low flow oxygen (6%), and single low-dose vasopressor (1%).

There were no treatment discontinuations because of CRS; CRS was generally confined to the step-up and first full doses. CRS occurred in 54%, 57%, and 64% of patients in the IV, SC, and RP2D groups, respectively. Step-up dosing was implemented to reduce the risk of severe CRS, and no cases of grade 3 or higher CRS.

Teclistamab is also under study in a phase 2 trial (NCT04557098) for the treatment of patients with relapsed/refractory multiple myeloma and in several combination studies (NCT04586426; NCT04108195; NCT04722146).

Updated results of the phase 1 trial will be presented at the 2021 ASCO Annual Meeting.

Janssen Announces U.S. FDA Breakthrough Therapy Designation Granted for Teclistamab for the Treatment of Relapsed or Refractory Multiple Myeloma. News release. Janssen. June 1, 2021. Accessed June 1, 2021. 

Usmani SZ, Mateos M, Nahi H, et. al. Phase I study of teclistamab, a humanized B-cell maturation antigen (BCMA) x CD3 bispecific antibody, in relapsed/refractory multiple myeloma (R/R MM). Presented at: 2020 ASCO Virtual Scientific Program. May 29-31, 2020. Abstract 100.

Garfall AL, Usmani SZ, Mateos M-V, et al. Teclistamab, a B-cell maturation antigen (BCMA) X CD3 bispecific antibody, in relapsed and/or refractory multiple myeloma (RRMM): updated phase 1 results. Presented at: 2nd European Myeloma Network Meeting; March 3-6, 2021; virtual. Abstract B11.

Krishnan Amrita Y., Garfall AL, Mateos MV, et al. Updated phase 1 results of teclistamab, a B-cell maturation antigen (BCMA) × CD3 bispecific antibody, in relapsed/refractory multiple myeloma (MM). 

. 2021;39(suppl 15):8007. doi:10.1200/JCO.2021.39.15_suppl.8007


This article was originally published on OncLive as, "

FDA Grants Breakthrough Status to Teclistamab for Relapsed/Refractory Multiple Myeloma

Articles

The FDA has granted a breakthrough therapy designation to teclistamab for the treatment of patients with relapsed/refractory multiple myeloma.

Teclistamab Granted Breakthrough Status for Relapsed/Refractory Myeloma

Age was associated with overall survival (OS) and the time to Richter transformation in adolescent and young adult (AYA) patients with chronic lymphocytic leukemia (CLL), according to findings from a single-institutional, retrospective study published in the 

The results showed that there was a significant difference in OS when sub-stratifying patients into younger than 30, 30 to 34, and 35 to 39 years age groups (

 = .049). The HR for OS was 1.72 (95% CI, 1.10-2.70) when comparing patients aged less than 30 years vs 35 to 39 years, and 2.33 (95% CI, 0.83-6.25) when comparing patients aged less than 30 years vs 30 to 34 years.

 = .03) were associated with a shorter time to developing Richter transformation. The probability of being free from Richter transformation at 5 years from diagnosis was 86%, 92%, and 99% for patients aged less than 30, 30 to 34 and 35 to 39 years at diagnosis, respectively.

“CLL presents very rarely in AYA patients younger than 40. Here, we found that the same validated prognostic biomarkers, such as 

mutation status and FISH abnormalities, used for all CLL patients could also predict outcomes in this rare subset, which included AYA patients treated with novel oral targeted therapies. Richter transformation into an aggressive lymphoma and need for allogeneic stem cell transplant were significant sources of mortality for this young population,” said Hua-Jay J. Cherng, MD, of The University of Texas MD Anderson Cancer Center, in a statement to 

Patients included in the review included those with a diagnosis of CLL or small lymphocytic lymphoma (SLL) who had been evaluated at least once at The University of Texas MD Anderson Cancer Center.

Patients with monoclonal B-cell lymphocytosis were excluded. AYA patients, defined as those aged between 15 and 39 years old at the time of diagnosis, were selected from all patients diagnosed between January 1, 2000, and December 31, 2019.

Complex karyotype was defined as 3 or more chromosomal abnormalities. Second primary malignancies were defined as any neoplasm diagnosed after CLL diagnosis, excluding non-melanoma skin cancers. Novel oral targeted therapy was defined as any therapy containing an oral targeted agent, including a BTK inhibitor, BCL-2 inhibitor, or PI3K inhibitor.

The majority of patients were between the ages of 35 and 39 years (n = 159; 70%) and male (n = 140; 62%). Moreover, most patients had mutated 

 (n = 82; 52%) and non-complex karyotype (n = 114; 84%).

Of 6074 patients who had been diagnosed with CLL between the prespecified period and seen at MD Anderson, 227 (3.7%) AYA patients were selected for analysis.

The median age at the time of diagnosis was 37 years (range, 17-39). The median follow-up time from diagnosis was 7.1 years (range, 0.1-19.3) with a data cutoff of June 30, 2020.

Six (3%) patients had a first-degree relative with CLL. A total of 161 (71%) patients received CLL treatment, and the median time to first treatment was 2.2 years. A total of 39 patients died, and the 5- and 10-year OS rates were 90% and 78%, respectively.

Beta 2-microglubin of at least 3.5 mg/L was the only significant predictor of OS in the reduced model (HR, 2.34; 95% CI, 1.63-3.38; 

 < .001) because of the small number of death events.

Reduced model multivariate analysis indicated that beta 2-microglubin of at least 3.5 mg/L (HR, 1.72; 95% CI, 1.36-2.16; 

 <.001), Rai stage I to IV vs 0 (HR, 2.01; 95% CI, 1.07-3.79; 

 =.03), and del(17p) or del(11q) vs del(13q) or negative FISH (HR, 1.89; 95% CI, 1.03-3.45; 

 =.04) were significantly associated with a shorter time to first treatment.

There were no differences in baseline characteristics or rate of receipt of oral targeted therapy between the age groups.

 mutations by next-generation sequencing was not associated with outcomes, likely because of the small numbers of patients with available pre-treatment somatic gene mutation data.

Of the 161 treated patients, 72 (45%) patients received oral targeted therapy at any time during their disease course. A total of 30 of the 72 oral targeted therapy-treated patients (42%)

received an oral targeted therapy as part of their first treatment.

Within the subgroup of the 72 patients who received oral targeted therapy at any time, hemoglobin of less than 11 g/dl (

 <.001), presence of del(17p) or del(11q; 

The median time to second treatment from start of first-line therapy was 4.2 years.

There was a significant difference in time to second treatment when sub-stratifying by type of first-line therapy (

The HR for oral targeted therapy vs purine/alkylator combination therapy was 0.51 (95% CI, 0.12-2.19) and for oral targeted therapy vs other therapies was 0.42 (95% CI, 0.20-0.85).

“The advent of oral targeted therapy in CLL has revolutionized treatment, including for AYA patients. We did find that patients treated with oral targeted therapy in the first-line setting enjoyed the longest time to second treatment. However, this advantage was not statistically significant compared with classic chemoimmunotherapy regimens such as FCR. AYA patients are much more likely to tolerate chemotherapy better than their older counterparts. For now, some clinicians may still offer FCR to young patients with low-risk disease as a treatment option,” said Cherng.

A total of 18 (8%) patients underwent allogeneic stem cell transplant (allo-SCT), 4 for Richter transformation and 14 for relapsed or refractory disease. Patients with del(11q) or del(17p; 

 = .006) were more likely to undergo allo-SCT in their treatment course. A total of 10 (4%) patients developed Richter transformation a median of 2.7 years (range, 0-16) after their diagnosis of CLL.

The median OS after diagnosis of Richter transformation was 8 months. Therapy-related myelodysplastic syndromes/acute myeloid leukemia (t-MDS/AML) developed in three (1%) patients; they had received fludarabine, cyclophosphamide, and rituximab (Rituxan) chemoimmunotherapy 2.8, 3.3 and 10.3 years prior to diagnosis of t-MDS/AML. A second primary malignancy occurred in eight (4%) patients a median of 9.0 years from CLL diagnosis.

“Our findings stress the importance of vigilance for disease-related complications such as second cancers and Richter transformation and therapy-related complications such as MDS and AML. The risk of developing these [diseases] increases over time. AYA patients may live a long time with respect to their CLL, so age-appropriate cancer screening and monitoring for other complications is needed,” said Cherng.

Of the total of 39 patients who died, 19 (49%) developed Richter transformation and/or underwent allogeneic stem cell transplant, and 4 (10%) developed t-MDS/AML or a second primary malignancy. Of the 6 patients younger than 30 years who died, 5 (83%) developed Richter transformation and/or underwent allogeneic stem cell transplant, and none developed t-MDS/AML or a second primary malignancy.

“It is worth taking a look at this data again with longer follow-up so we can again investigate how AYA patients are doing on newer oral therapies compared with chemotherapy,” concluded Cherng.

Cherng HJJ, Jammal N, Paul S, et al. Clinical and molecular characteristics and treatment patterns of adolescent and young adult patients with chronic lymphocytic leukaemia. 

. Published May 10, 2021. doi:10.1111/bjh.17498

This article was originally posted on OncLive as, "

OS and Time to Richter Transformation Linked With Age in Adolescent and Young Adults With CLL.

Age was associated with overall survival and the time to Richter transformation in adolescent and young adult patients with chronic lymphocytic leukemia, according to findings from a single-institutional, retrospective study.

Age Associated With Survival, Time to Richter Transformation in AYA Patients With CLL

Patients with oncogene-driven non–small cell lung cancer (NSCLC) stand to benefit from the availability of targeted therapy in the clinic, but also in clinical trials, explained Andrea Saltos, MD, making broad molecular testing all the more essential to lung cancer care.

“These are very effective new drugs that were not available a couple of years ago for mutations that may not have been considered standard to test for a couple of years ago. [The availability of these drugs] highlights the importance of broad genomic profiling for every patient with advanced NSCLC,” said Saltos. “It’s always important to know the full genetic makeup of your patient’s cancer, because there really are a lot of new targeted treatments that are being worked on beyond [those for mutations in], 

, and it’s really exciting to see that these drugs are effective in the populations that they’re targeted for.”

® during an Institutional Perspectives in Cancer webinar on lung cancer, Saltos, a medical oncologist and Clinical Research Medical Director in the Department of Thoracic Oncology at Moffitt Cancer Center, provided perspective on the use of targeted therapy across 

®: With regard to the ADAURA trial, is it necessary to wait to see an overall survival (OS) benefit with adjuvant osimertinib (Tagrisso) before you start recommending it to your patients with early-stage

: It’s a key first step to wait for the long-term data, but it’s always going to come down to a patient and physician discussion. As far as the risks and benefits go, it’s very true that OS is not necessarily always found to be significant in a study where [disease]-free survival [DFS] was significant. There are examples with other EGFR-targeted therapies, such as erlotinib [Tarceva], where that was true.

On the other hand, the hazard ratio [for DFS] is very striking. There’s also something to be said of having a markedly improved DFS. Some patients who progress may have brain metastases or very symptomatic events, so sometimes if the therapy can forestall progression, it may have some merits on its own in that context, especially if the therapy is tolerable.

That’s where the tolerability of osimertinib really comes into play. Certainly, there are patients who have a lot of adverse effects [AEs] with osimertinib, but there are some who don’t, and individualization of a plan and careful monitoring are going to be a key part of that anyway.

In a bigger context, when we’re designing these adjuvant therapy clinical trials, we know there’s a tradeoff between having a more readily available outcome for quick readout like DFS vs the gold standard of OS.

What research is being done to build off of the benefit achieved with osimertinib in the advanced

The big ones are the combination of osimertinib and chemotherapy and the combination of osimertinib with anti-VEGF therapy, both of which have some have some pretty good clinical backgrounds to support the hypothesis that those combinations might be of benefit to patients.

The FLAURA 2 study is looking at randomization of osimertinib with or without platinum-based chemotherapy in the first-line setting. Hopefully that trial will answer the question about the chemotherapy combination. As far as the combination in the RELAY trial, which was conducted with erlotinib plus the VEGF inhibitor ramucirumab [Cyramza], this was positive and led to the FDA approval of the combination. Where that exactly fits into first-line therapy compared with osimertinib is not completely clear.

We’re also running a clinical trial at Moffitt Cancer Center looking at combining ramucirumab with osimertinib, taking the next logical step. Hopefully, we’ll have information on whether those [combinations] work [soon].

Poziotinib showed encouraging data in patients with

-exon 20 mutant NSCLC in the ZENITH20 trial. What are your thoughts on the doses that are being tested?

The tolerability of EGFR TKIs has been kind of a concern, especially in the early days with some of the earlier agents that had more wild-type EGFR inhibition. Some of those same toxicities are emerging with drugs like poziotinib. A lot of clinical experience with these agents and knowing what supportive care to institute and when can maximize the ability to tolerate the drug for many patients. Early institution of things like topical steroids, topical antibiotics, or oral antibiotics for dermatologic toxicities [can help]. I even often institute things like oral non-absorbable steroids, such as budesonide, for patients who have severe diarrhea. There are a lot of different tricks that can help.

 exon 20 mutations, historically, have been very difficult to target, but there are a few drugs [in development]. There’s also amivantamab, which is a bispecific antibody targeting 

fusions, how do the data seen with pralsetinib (Gavreto) and selpercatinib (Retevmo) stack up against the data with next-generation EGFR and ALK inhibitors?

 fusions are proving to be like a true driver mutation that is highly targetable, much in the same way of 

. The clinical benefit rates and response rates to both of these drugs, from the LIBRETTO[-001] and ARROW studies, are phenomenal. Patients who had no prior therapy on the selpercatinib trial had an 85% response rate, and only 3% of patients had confirmed progression of disease on the drug. That’s pretty much in line with what we see with the ALK and EGFR next-generation TKIs. It’s a very similar story with pralsetinib. The treatment-naïve patients had about a 75% response rate, but these are small trials.

It’s difficult to do cross-trial comparison, but clearly, most of these drugs are highly effective and fairly well tolerated. The incidence of grade 3 toxicity with both of these drugs is very acceptable. With both drugs, a majority of patients with central nervous system (CNS) metastases had a significant response, which means that patients with asymptomatic brain metastases, who have historically been treated with whole brain radiation, can maybe be spared that [approach] up front, which can be very meaningful for quality of life.

amplification, how have capmatinib (Tabrecta) and tepotinib (Tepmetko) affected the paradigm? Where do you see research headed?

 amplification is its own entity in lung cancer, and sometimes it goes hand in hand with exon 14 skipping, but clearly the patients who are more sensitive to these drugs are the ones who have the exon 14 skipping mutations.

The response rates are not quite as high as what we see with the EGFR, ALK, and RET inhibitors, but still a majority of patients have a response to both of these drugs in the frontline setting, somewhere in the 50% to 60% range. Both agents are quite well tolerated and also have good CNS activity.

We know how to target patients who have these high-level 

 amplifications. Both of these drugs do show activity in that amplification setting. There certainly are some patients who have 

 amplification, independent of any driver mutations, but there are also some patients with EGFR-mutant lung cancer who progress on osimertinib. It’s a very common scenario where they become resistant to osimertinib through 

 amplification. Many clinical trials are looking at these drugs in combination with EGFR inhibitors for those patients, as well as those who have 

The second area of important research will be novel drugs to target 

 and what the resistance mechanisms might end up being for patients who progress on these drugs. Some patients may progress through resistance mutations within the 

 gene, but a lot of patients may progress through alternate pathways, which is what we see with the other driver mutations in NSCLC. Being able to characterize and develop more targeted strategies beyond the first line will be important, but for now, these 2 new drug approvals represent a nice milestone for those patients.

This article was originally published on OncLive as, "

Targeted Therapies Continue to Make Strides in Oncogene-Driven NSCLC

Molecular testing is more essential than ever, thanks to the targeted therapy options for non-small cell lung cancer.

Targeted Therapies Move Forward in Oncogene-Driven Lung Cancer

The optimal treatment of patients with early-stage and locally advanced non–small cell lung cancer (NSCLC) in 2021 consists of multidisciplinary management, 

 gene testing, and consolidation treatment with durvalumab (Imfinzi) in addition to clear pathways that enable the successful delivery of such care to all patients, explained Jacob Sands, MD.

“We’ve discussed all these best ways to treat patients based upon the data that we have, and one element of this in the real world that then becomes a challenge is the logistics,” said Sands. “One of the things within our health care system and within our hospital systems to start really recognizing more and doing a better job of is how to help make [high level care] feasible for everybody.”

®, Sands, a physician at Dana-Farber Cancer Institute, and an instructor in medicine at Harvard Medical School, discussed current approaches to the treatment of patients with early-stage and locally advanced NSCLC.

®: How would you define the multidisciplinary treatment of patients with early-stage NSCLC?

: In early-stage disease, treatment can involve a few different things. Often patients end up with surgically resectable disease, so there’s surgery, and then there’s the postoperative pathology that we look at, which really defines what we do after surgery. That pathology gives us a lot more information. If the size [of the tumor] is greater than 4 cm, particularly if there are lymph nodes involved, we are talking about adjuvant chemotherapy in the case of NSCLC. In the case of small cell lung cancer, we really give adjuvant chemotherapy to anybody.

What is your optimal approach to molecular testing?

In early-stage disease, when we’re talking about something that has been resected and there’s no evidence of disease, those individuals often end up getting adjuvant chemotherapy. If [the tumor is] greater than 4 cm, if there’s any lymph node involvement, that becomes a stage in which adjuvant chemotherapy is important.

As far as genomic testing, we have the recent ADAURA publication that showed a substantial improvement in [disease-]free survival. The overall survival data are going to [require] more [time to mature], but [the results] led to [the] approval [of osimertinib in the adjuvant setting]. Now [the results of] 

 testing, in particular, on the pathology of these patients [is important]. 

As far as doing genomic testing for other potential targets, the data are really compelling [in the metastatic setting] and given how osimertinib [Tagrisso] works for patients with 

 mutations, what about alectinib [Alecensa] for patients with 

 fusions, or some of these other really effective targeted therapies that we use as a standard of care in stage IV disease? Should we be using those agents in earlier-stage disease as well? Those [questions] have led to a number of other trials that are ongoing and now getting started.

Would you say that, if not for standard practice, but for clinical trials, that next-generation sequencing should be ordered rather than a single-gene panel for

Right now, we really don’t have a number of different approved therapies. In the earlier-stage setting, we just have osimertinib right now as an approved adjuvant therapy. It is really important for those patients to also be offered chemotherapy, assuming that they qualify for it. In the ADAURA publication, I was a little surprised by the number of people that actually didn’t get chemotherapy, so it’s important to highlight that these patients should get offered adjuvant chemotherapy, and then, if appropriate, osimertinib.

We don’t really have other approved therapies, so testing for 

 alone right now as far as what you’re clinically going to do is meaningful. Other agents we don’t really have a defined role for, but consideration of enrollment to these various other trials, I would really encourage. In that sense, getting genomic testing to drive enrollment to some of these other studies is really compelling.

What is the role of postoperative radiation in treatment?

For patients who get surgical resection and have N2 mediastinal node involvement, there is really kind of a question now about radiation. There was a recent trial that was negative for inclusion of postoperative radiation. That being said, there are still patients where I would expect postoperative radiation to provide some potential benefits. This is really a population that requires interaction with radiation oncologists and discussion about each individual case, and whether you think that someone is going to really benefit from radiation in that setting.

What are your thoughts on immunotherapy entering the early-stage treatment paradigm?

We have seen great results with immunotherapy in metastatic disease. We have seen also really impressive results after chemoradiation. Now the question is: In resectable disease, do these checkpoint inhibitors have a potential role to play? There are multiple studies that are being done or have enrolled [to that end]. These are studies that enroll after chemotherapy, but a study that is currently open within the ALCHEMIST portfolio is a study called ACCIO. This is a study I’m running, and I would love for people to enroll and to be aware of this. It’s a 3-arm study [that is enrolling patients] after surgical resection, an R0 resection, who are 

 negative, wild-type. Patients need PD-L1 testing for stratification, but all-comers with any level of PD-L1 can enroll, and all [patients with] NSCLC can enroll, [be it] squamous [or] nonsquamous [histology].

The [treatment arms will consist of] standard chemotherapy, followed by observation standard of care vs chemotherapy, followed by pembrolizumab [Keytruda] in a sequential arm, and then the third arm consists of concurrent chemotherapy plus pembrolizumab. Both the sequential and the concurrent arm [will administer] the same duration [of pembrolizumab], which is 1 year, just [at] different starting [points]. This trial is currently open throughout the country, and we certainly welcome enrollment.

Shifting to the stage III setting, what are some of the best practices for ensuring that patients receive durvalumab after concurrent chemoradiation?

The PACIFIC data have really showed pretty impressive and durable results in patients who get chemotherapy plus radiation with curative intent. Specifically, concurrent chemoradiation followed by durvalumab. I was a little skeptical at first [based on] the initial data that were reported. There was separation of curves, the progression-free survival was statistically significant, [but] at the time, I thought maybe some of the people who were in the control arm later on at recurrence [would] end up getting immunotherapy and [the curves] might even out.

[However,] we’ve really seen impressive separation of the curves that has persisted, and the longer these data mature, the more impressive [the data look] to me. In the control arm of the study, there was a pretty good number of patients who at recurrence did end up getting immunotherapy, so we really have a fair comparator arm, which is an important thing to look into.

Not in all of the immunotherapy trials did the control arm later on get immunotherapy in the appropriate setting, but [those in the PACIFIC trial] did, so this is a very fair comparison that had a good standard-of-care control arm. The responses have really been impressive as the data mature. For everybody that gets concurrent chemoradiation for stage III unresectable disease, I then put them on durvalumab for 1 year. We can use [every-4-week] dosing, which is a little better than the initial [every-2-week] week dosing and is easier for patients.

Also, in PACIFIC, those who got durvalumab earlier seemed to do better. That being said, I suspect that those [were] patients who tolerated their prior treatment and had better prognosis. Specifically, individuals who got chemoradiation and recovered immediately and didn’t really have any problems who were then able to start durvalumab earlier. I don’t necessarily take that [to mean that] people have to immediately start durvalumab earlier.

That being said, I want to start it about 4 weeks after, get that scan, making sure that there’s no new disease, and then start durvalumab. However, if somebody is really struggling to recover, for whatever reason, I don’t really stress pushing back or not immediately starting durvalumab after that. That’s probably still okay [to do].

On durvalumab there are people that then end up with adverse effects [AEs] from the treatment. Thankfully, most people getting these checkpoint inhibitors generally do really well, so AEs are somewhat limited. But I certainly have patients that have had AEs, and pneumonitis is always the tough one. Someone with pneumonitis [should be] started on steroids and make sure that they recover. I have patients restart [durvalumab] if it wasn’t a really severe pneumonitis. If [the pneumonitis] recovers well—when I start prednisone, once we complete the taper, and if they’re doing well off of steroids—I do restart durvalumab. In some cases, that’s worked out. In other cases, I’ve had patients who had pneumonitis again, so I haven’t been able to get everybody through 1 year of therapy. We do as much as we can. If patients are having really significant AEs, then we stop at that time.

In the trial, we did see that not everybody was able to complete the full year [of durvalumab], but those who were able to complete the full year had really impressive outcomes. If you’re more than a year out from finishing the chemoradiation, your prognosis is better in that setting as well, so I would expect those numbers to look better, but the results are actually really impressive. I try to get as much of [durvalumab] in as I can over the course of that year. If we have to start a little bit later than I want to start the therapy, that’s fine. I don’t stress about that. If there are AEs that really don’t allow for further treatment, then we stop at that time. However, getting durvalumab is very meaningful [for those patients].

What are some important resources regarding the management of immune-related adverse effects?

I really benefit from being at a center with so many specialists. I’m able to draw in specialists who really focus on some of these specific AEs. When AEs come up on some of these checkpoint inhibitors, whether it be durvalumab after chemoradiation, or any of the others in any setting, there are guidelines on how to manage them, which is important. Thankfully, most people really tolerate the therapy well, but when there are AEs, we really need to make sure that we’re managing them appropriately. Checking the guidelines on how to do that [is important]. There are publications on this, there are the National Comprehensive Cancer Network guidelines on how to manage these AEs, and it’s important to look at those.

For patients who do complete the full year of durvalumab, is there ever a situation where you would continue it?

As far as whether or not to continue treatment after 1 year, I really wouldn’t. A percentage of these patients are cured of their disease. The trouble is, we can’t define and identify prospectively who’s cured and who’s not. That is an area of important research. We know that a percentage of patients are, and the data that we have doesn’t really support doing any treatment beyond 1 year, so I would stop the treatment at 1 year and then monitor patients closely at that time going forward.

Does PD-L1 status affect whether you recommend durvalumab to patients who do not progress on concurrent chemoradiation?

As far as giving durvalumab after concurrent chemoradiation, PD-L1 expression really isn’t something that drives my decision making. If I have somebody who never smoked where I have a high suspicion of them having an 

 mutation, for example, then I’d look for that and that then becomes harder to know. We know that these checkpoint inhibitors aren’t as effective in general in people who never smoke and have an 

 mutation. At the same time, I do worry a little bit about somebody being on a checkpoint inhibitor and then having recurrence of disease where we would then use osimertinib because we know that the culmination of osimertinib and durvalumab leads to a higher incidence of pneumonitis. What to do in that setting is a little less clear. The PACIFIC trial did enroll patients that fit this population, although there wasn’t a big population of them. Based on the study results, everyone would get durvalumab. If you’re looking at that subpopulation, that’s where I still kind of have a question about whether or not to add durvalumab in that setting. 

What are some treatment barriers that may prevent patients from receiving optimal care that you would like to see addressed?

Within different communities, [treatment] really looks different. There are some communities where the patient is able to take time off work or is retired or is really financially stable and able to come in at any time and get their treatment at any time. There are other communities where patients are having [to organize their treatment] in the middle of trying to hold everything else together, and those are entirely different situations. When we’re talking about these data, and the different drugs and the different curves, it’s without the challenges of real life, but that’s not how it is for everybody.

There are communities where it’s going to take more coordination and more resources to help people get in [for optimal care]. I have some patients who having to navigate the public transportation system to come in and get chemotherapy and get home is a challenge. Having nurse navigation and having some of these other resources is something that’s overwhelmingly important within our health care system to really provide this very high level of care to everybody throughout society and is clearly something we need to address much better within our health care system and within the country.

An expert gives an overview of recent advancements in the lung cancer space.

Lung Cancer Advancements Highlight the Need for Multidisciplinary Care

Chemotherapy, PARP inhibitors, and VEGF inhibitors have all been vetted as promising combination partners for immunotherapy in ovarian cancer, according to Robert Wenham, MD, MS, FACOG, FACS, who added that only time will tell which, if any of these combinations, should make their way into clinical practice.

Although biomarker-driven approaches have fallen short of expectations, he added, the field has not given up hope that folate receptor α (FRα) could prove to be an effective target for mirvetuximab soravtansine.

“In the recurrent setting, there are some promising hints that combining checkpoint inhibition with other drugs may lead to some new [options] for patients. The challenge is going to be defining exactly which patients may get the best results from [those approaches],” said Wenham. “Biomarkers so far have been somewhat elusive. The ADCs [antibody-drug conjugates] probably hold the most promise right now, but we’re going to have to wait to see what the new results are of the mirvetuximab [soravtansine] study. Immunotherapy will [make its way into the field] but trying to figure out [how] is not going to be as simple as in some of the other cancers.”

®, during an Institutional Perspectives in Cancer webinar on ovarian cancer, Wenham, a gynecologic oncologist and chair of the Gynecologic Oncology Program at Moffitt Cancer Center, discussed the basis for combining chemotherapy, PARP inhibitors, and VEGF inhibitors with immunotherapy in ovarian cancer and ongoing research with ADCs in the field. 

®: What is the rationale to combine immunotherapy with chemotherapy, PARP inhibitors, and VEGF inhibitors?

: The theoretical benefits of combining [these agents] is to make [the combination] more antigenic and to make checkpoint inhibitors work better. [Checkpoint inhibitors] work best when the immune system is stimulated and when [the checkpoint is] released from its inhibition. The idea behind combining [checkpoint inhibitors] with chemotherapy is that you are killing cells, via cytotoxic activity that’s releasing antigens and perhaps increasing the amount of antigen exposure, and at the same time chemically debulking the tumor.

In terms of PARP inhibitors, it makes sense that although they’re trying to repair DNA, you might inhibit the PARP enzyme and therefore increase the number of DNA replication errors. Then you increase number of antigens because of a poorly made product. That would increase cytotoxicity as well because you’d have more antigen exposure if you’re releasing [the] checkpoint. The combination of checkpoint inhibitors plus PARP inhibitors is an attractive [regimen].

There’s also VEGF inhibition with bevacizumab [Avastin], which has been a proven active agent in ovarian cancer. Combining that with checkpoint inhibitors is attractive, because VEGF in itself is not just an antiangiogenic molecule but may have some processes involved in the immune response, so inhibiting VEGF simultaneously with a checkpoint inhibitor [may be effective]. Also, VEGF is partly responsible for the ability for cells to migrate through vessels and for vessel stabilization.

All of these 3 different [modalities], which are active in ovarian cancer, are attractive to combine with checkpoint inhibitors. Everybody’s looking at these 3 [modalities] in combination with a checkpoint inhibitor in the frontline and recurrent settings.

What data have we seen so far that indicate such combinations are the way forward?

None of those combinations are standard of care right now. Some interesting early data have come out that may lead us in directions that we want to go. PLD [pegylated liposomal doxorubicin] plus checkpoint inhibition [has shown] about a 25% response rate and oral cyclophosphamide plus bevacizumab [Avastin] and a checkpoint inhibitor [has shown] about a 50% response rate. Weekly dose-dense paclitaxel plus a checkpoint inhibitor had about a 50% response rate. There may be some chemotherapies that may combine well with a checkpoint inhibitor, but these things need to be validated and approved before they enter widespread stream use.

Some other studies have looked at a checkpoint inhibitor plus a PARP inhibitor. The MEDIOLA study comes to mind. Besides MEDIOLA, there is the TOPACIO trial. Those studies have shown proof of principle that you can combine checkpoint inhibitors with PARP inhibitors and get responses. However, these studies have mainly been done in 

-mutated patients so far. We’re going have to wait to find out whether there’s a real group that benefits [outside of that subpopulation]. Part of the problem is that PARP inhibition is really good for 

-mutated patients, so whether a checkpoint inhibitor plus a PARP inhibitor offers an advantage over a PARP inhibitor alone [in that population] has yet to be determined.

Why are antibody-drug conjugates (ADCs) such an attractive option in ovarian cancer?

ADCs are the current state of what people are looking at in ovarian cancer. [ADCs] are attractive if you can find a selective target on a cancer cell and you can deliver a very toxic payload that you couldn’t normally give; that gives you the potential to have more efficacy [than a systemic therapy]. That’s been borne out in some of the early studies with FRα targets. There is a whole host of [studies] that are ongoing right now. There is a host of [targets] that are currently under investigation. None of these are currently standard and still need to be vetted.

The one that was furthest along was mirvetuximab [soravtansine], which [targets] FRα as well. The agent showed early activity in some of the phase 2 studies, but FORWARD I deflated some of that enthusiasm, because it didn’t meet its end point. FORWARD I evaluated platinum-resistant patients [who had received] 3 or [fewer prior] therapies. [Patients were randomized to] investigator’s choice chemotherapy, which was PLD, topotecan, or paclitaxel, or mirvetuximab [soravtansine]. However, when [the lead study author, Kathleen Moore, MD, of Stephenson Cancer Center] went back and worked with the people who are developing it, and really looked at how they did the cutoff for FRα, it appeared that changing the way that they did the analysis may have influenced the results.

When they went back to the same way that they had analyzed it [in the earlier studies], where they were looking at the intensity plus the number of high-powered [patients with FRα] vs just the intensity alone of the staining, it looked like it would have been a positive study.

However, you can’t go back and redo the rules. When you define the rules for a study, you are not allowed to go back and change it afterwards. This led to them wanting to go back and look at the exact same question again. The MARISOL study is there to answer that question but using the prior staining for levels of activity that they used in the [earlier] studies.

What other combinations are you excited about?

We give taxanes all the time, which are microbial drugs. If we’re using a taxane as an ADC or a microtubule agent, can we combine it with the same things that have shown efficacy with taxanes so far, such as bevacizumab? FORWARD II is currently looking at bevacizumab vs pembrolizumab [Keytruda] vs the combination of carboplatin and bevacizumab plus mirvetuximab [soravtansine] to see if there is additional benefit.

What can we anticipate with immunotherapy in the imminent future?

We don’t yet have immunotherapy for ovarian cancer, but we have a lot of promising leads on what may develop. The near future is going to tell us a lot. We have major phase 3 randomized trials that will be coming out in the frontline [setting] soon.

Thus far, if you look across the board, there hasn’t been one defined approach to using checkpoint inhibition for patients with ovarian cancer at this point. Some of the major up-front phase 3 studies did not meet their end point, but maybe that’s because they weren’t the right combinations. We’re going to have a lot of different views of what the right competitors and combinations are in the trials that will be reporting over the next 1 to 2 years.

Immunotherapy Research Instigates More Questions Than Answers in Ovarian Cancer.

Robert Wenham, MD, MS, FACOG, FACS, discusses the basis for combining chemotherapy, PARP inhibitors, and VEGF inhibitors with immunotherapy in ovarian cancer and ongoing research with ADCs in the field.

Immunotherapy in Ovarian Cancer: Don't Give Up, Yet

Circulating tumor DNA (ctDNA) and total neoadjuvant therapy (TNT) are reshaping the landscape of early-stage colorectal cancer (CRC), explained Tony Philip, MD, who added that the paradigm shift in the advanced setting came from moving less-intensive treatment to the first-line setting.

“We should keep an eye on what’s going to come out with ctDNA, because it’s exciting stuff. It’s nice to have these new toys to play with. We’ve just got to figure out how and when to use them,” said Philip. “Total neoadjuvant therapy for rectal cancer is really changing the landscape. For patients who have distal rectal cancers, we really should think about nonoperative management. How do we [avoid] a permanent colostomy [in some patients]? How can we preserve organ function for some of those patients?”

In the advanced setting, the addition of trifluridine/tipiracil (TAS-102; Lonsurf) to bevacizumab (Avastin) led to an improvement in overall survival (OS) vs capecitabine/bevacizumab in the frontline treatment of patients with unresectable metastatic CRC who are not eligible for standard chemotherapy, according to data from the phase 2 TASCO1 trial. In results presented during the 2021 Gastrointestinal Cancers Symposium, patients in the TAS-102/bevacizumab arm had a median OS of 22.31 months (95% CI, 18.00-23.69) vs 17.67 months (95% CI, 12.58-19.81) in the capecitabine/bevacizumab arm (HR, 0.78; 95% CI, 0.55-1.10).

“Based on the TASCO1 trial, we do have options for patients that are not able to get aggressive treatment,” said Philip.

® during an Institutional Perspectives in Cancer webinar on gastrointestinal malignancies, Philip, a medical oncologist at Monter Cancer Center of the North Shore, LIJ Cancer Institute, and an assistant professor of medicine at Hofstra-North Shore LIJ School of Medicine and New York Institute of Technology College of Osteopathic Medicine, provided insight into the utility of ctDNA in the early-stage setting, trials that could determine its role in clinical practice, and detailed the shift toward nonoperative and less-intensive interventions in the early-stage and advanced settings, respectively.

®: What is the role of ctDNA in early-stage CRC, and how could it be used to detect MRD and inform a patient’s risk of recurrence?

: Some of the data that was presented at [the 2021 Gastrointestinal Cancers Symposium] suggests that ctDNA may be able to pick up disease recurrence approximately 8 months prior to traditional methods, such as carcinoembryonic antigen tumor markers, or even CT scan. It lays the groundwork for some interesting data and may change how we do things moving forward. However, we definitely need a lot more clinical trials to validate whether that’s truly the case and how to use it in a day-to-day setting.

Several clinical trials are ongoing [in that regard]. Some of the trials are looking at [ctDNA] in stage II/III disease and [are studying] whether giving chemotherapy and changes in ctDNA validate its use [as] both a predictive test and a prognostic test. BEACON and COBRA are some of the trials that are ongoing, amongst many others.

How have the RAPIDO and OPRA trials contributed to our understanding of how to manage patients with locally advanced rectal cancer?

[It’s] interesting timing for RAPIDO because in the COVID-19 environment that we’re in currently, the ability to do short-course radiation might reduce patients’ time in the hospital or clinic. The outcomes for response to treatment might be preserved, so that’s one benefit.

In terms of OPRA, as we evolve the nonoperative management of distal colorectal cancers, [the data] suggest that the nonoperative management route, which was not even considered many years ago, of up-front chemoradiation followed by chemotherapy may be a better strategy.

What research is being done to improve care for patients who aren’t eligible for intensive therapy?

The TASCO1 trial is interesting because we normally think of TAS-102 as one of the last resorts of treatment. The drug is generally thought to be fairly well tolerated, but traditionally, given its approval in the fourth- or fifth-line setting, people don’t think of it as effective. However, when we look at this drug for patients that have disease, but are not really eligible for aggressive treatment, this presents an option and may be better than what we perceive to be some of the standards before, without any added toxicity. It allows us to treat some of those patients that can’t get more aggressive chemotherapy. It gives them those options as well. Many trials are ongoing, trying to figure out how to harness immunotherapy for MSS [microsatellite stable] CRC and other treatment options.

What ongoing efforts have the potential to impact practice?

Ongoing trials looking at ctDNA are really going to change practice. In trying to figure out for patients that have stage II/III disease that we think based on traditional markers of risk recurrence make them high risk, [we’ll ask whether we] can we tease out patients that may be cured from just surgery alone and don’t need chemotherapy. That would be a great practice changing result from all of this [research].

Tony Philip, MD, provides insight into the utility of ctDNA in the early-stage setting, trials that could determine its role in clinical practice, and detailed the shift toward nonoperative and less-intensive interventions in the early-stage and advanced settings, respectively.

Caroline Seymour

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