 as an assistant editor in October 2022. Leveraging an educational background in the life sciences and prior experience conducting interviews in a university setting, she plays a key role in shaping social media strategy, covering live conferences, and producing multimedia content for both print and digital platforms. Email: 

Results from a first-in-humanphase 1 trial (NCT04262466) evaluating the efficacy and safety of IMC-F106C in patients with PRAME-positive metastatic/unresectable tumors showed a significant clinical benefit with the first PRAME×CD3 ImmTAC therapy, and could specifically fulfill unmet needs for patients with melanoma, according to Omid Hamid, MD.

The findings, which were presented during the ESMO Congress 2022, showed that 7 of 31 patients across malignancies who received IMC-F106C produced a partial response (PR) lasting up to 9 months, while 90% of patients (n = 18) experienced a reduction in ctDNA across multiple tumor types. Thirteen patients (65%) had a 50% reduction in ctDNA.

Specifically, 3 PRs were observed in patients with tebentafusp-naïve uveal melanoma and 2 PRs were seen in those with cutaneous melanoma.

Thirty-five percent of patients in the safety population (n = 19/55) experienced at least 1 grade 3 or higher adverse effect (AE), and 77% of patients experienced cytokine release syndrome (CRS) during the initial 3 doses (n = 55).

“There [are] access issues, performance status issues, organ-specific issues, and [problems with] cardiac function and lung function that exclude [patients] from [adoptive T-cell therapies],” Hamid said in an interview with 

 during the congress. “[Not only] is this [drug] a T-cell directed therapy, the [only] major toxicities we saw were lab abnormalities, and they [did not] cause anyone to [discontinue] therapy.”

Hamid is chief of translational research and immuno-oncology, and co-director of cutaneous malignancies at The Angeles Clinic and Research Institute, Cedars-Sinai Medical.

In the interview, Hamid highlighted key points from the trial, including the importance of evaluating PRAME×CD3 Immune-mobilizing T cell receptor against cancer (ImmTAC®) for melanoma treatment, the key benefits provided to patients through improved disease control and circulating tumor (ct)DNA reduction, and the safety profile of the personalized therapy.

®: What was the rationale for evaluating a PRAME×CD3 ImmTAC®in patients with melanoma in this phase 1 dose-escalation study?

This type of therapy was investigated [because] we found that traditional immunotherapy—checkpoint inhibitors—doesn't help 100% of patients. The whole idea behind ImmTACs

, which is a T-cell receptor-driven therapy with CD3 engagers, is that our intra- and extra-cellular [cancer] proteins can be broken down and presented as peptides through [HLA-A*02] on tumor surfaces, [which] T-cell receptors can target. If we bridge that with a CD3 engager, [we] can bring the T cells into the tumor microenvironment. That gives us the ability to utilize our immune system in a different way.

[There is] proof of principle that this works with a drug called tebentafusp-tebn [Kimmtrak] for [patients with] ocular melanoma. This tumor [type] has historically been [characterized] as an “immune desert”, which means that no immunotherapy had shown efficacy [in treating patientd with melanoma]. [In] utilizing this type of [T-cell] therapy, we [demonstrated] a multitude of things, [including an] overall survival advantage and an immune active environment. [Furthermore, we have] shown that these ImmTACs

can be combined with anti–PD-1 therapies, anti–CTLA-4 therapies, and even [be incorporated as part of a triplet regimen].

that targets PRAME, the most common cancer-testis antigen expressed [in several tumor types]. Its highest expression [is observed in patients with] melanoma, uveal melanoma, endometrial carcinoma, lung cancer, and ovarian [cancer]. These cancers are immune active, and some of them have low response rates. [Besides IMC-F106C], we have yet to [find] another therapy [that has] a broad range, is tolerable, can be [administered] in an outpatient [setting], and is available off the shelf.

What is important to note about the patient population in this study?

This platform looked at patients across multiple solid tumors, including cutaneous melanoma, uveal melanoma, non–small cell lung cancer [NSCLC], ovarian [cancer], endometrial [cancer], and others. Patients [in the efficacy population] were heavily pretreated. Patients with ovarian cancer had 4.5 median lines of therapy, those with cutaneous melanoma had a median 3 lines of therapy, and patients with uveal melanoma had a median 3.5 lines of therapy.

All of the patients with cutaneous melanoma had [previously received anti–PD-1] and [anti–CTLA-4 therapy] in some fashion. Patients with ovarian cancer [previously received platinum-based therapy], PARP inhibitors, VEGF-targeted [therapy] and some had already seen [anti–PD-1 treatment]. Patients with NSCLC all previously received seen [anti–PD-1] therapies.

What were the key results from the study?

have the] ability to benefit these patients [through] disease [control]. We [observed] deep, rapid, and durable responses in patients, just as we see with other checkpoint inhibitors. We [also] saw that durable tumor response or disease [stabilization] benefits our patients long term. A host of patients who did not have a traditional response, but [did have] a long-term stable disease, benefit in that fashion.

[Additionally, these findings gave us a preliminary] understanding of frame expression as an indicator of [which patients] will have better responses [to T-cell therapy], and [emphasized the role of] ctDNA in the context of multiple solid tumors, including melanoma.

We saw a benefit in patients with cutaneous and uveal [cancer] who had decreases in ctDNA, and a significant proportion cleared their DNA. Despite the fact that we didn't see [a] PR in patients with lung cancer, all of [them] had a greater than 50% decrement in ctDNA, which [caused] us to reevaluate how we understand benefit from this type of therapy.

Interestingly, we saw PRs in patients with ovarian carcinoma following a PD-1, PARP inhibitor, VEGF inhibitor, and [platinum-based] therapy. 

What should physicians know about the safety profile of IMC-F106C?

[The most observed AE] in this [drug] class was CRS, [followed by] low blood pressure, fevers, chills, etc. Most of these instances were grade 1 and 2. [Overall, there was] no treatment-related discontinuation nor grade 5 toxicity [originating] from this therapy. [As a result], IMC-F106C is now one of the most tolerable ImmTACs

out there. Clearly [there are] interesting data that set a [new] paradigm for T-cell therapy that can be part of its therapeutic regimen.

What next steps are planned for this research?

This trial is still accruing for expansion cohorts, and is going to accrue in combination cohorts [in order to study] what [IMC-F106C] can do when combined with anti–PD-1 or traditional chemotherapy. Interestingly, early data that lend itself to multiple solid tumors, including lung, ovarian, melanoma, etc., and the ability to combine with a manageable toxicity profile.

What are the main takeaway from this study?

We have expanded the toolbox for patients who are seeking immunotherapy or immune active therapy beyond just checkpoint inhibitors [with] adoptive T-cell regimens [like] ImmTAC

Not only have we shown that these therapies exist, and [that] they have a legitimate [place] in the immunotherapy toolbox, [we have also shown] that they can be combined. As an investigator, that gives me hope that we can solve some of these issues with primary refractoriness and low response rate. [I also hope] that we can bring something to market that is valuable for almost all the patients who walk through our doors.

Hamid O, Sato T, Diwakar D, et al. Results from phase I dose escalation of IMC-F106C, the first PRAME × CD3 ImmTAC bispecific protein in solid tumors. 

. 2022;33(suppl 7):S875. doi:10.1016/j.annonc.2022.07.854

Articles

Omid Hamid, MD, highlights the importance of evaluating PRAME×CD3 Immune-mobilizing T cell receptor against cancer for melanoma treatment, the key benefits provided to patients through improved disease control and circulating tumor DNA reduction, and the safety profile of the therapy.

IMC-F106C Shows Potential as T-cell Receptor–Driven Therapy in Melanoma 

Preliminary data from a phase 2 study (NCT04154943) indicated that neoadjuvant cemiplimab (Libtayo) was highly active in patients with resectable cutaneous squamous cell carcinoma (CSCC). If long-term outcomes prove to be favorable, this approach may improve quality of life (QOL) for this population and positively disrupt the treatment paradigm, according to Neil D. Gross, MD, FACS.

Data presented at the 2022 ESMO Congress showed that the pathologic complete response (pCR) rate achieved in evaluable patients treated with cemiplimab (n = 79) was 50.6% (95% CI, 39.1%-62.1%); the major pathologic response rate was 12.7% (95% CI, 6.2%-22.0%). The combined pathologic response rate in these patients was 63.3% (95% CI, 51.7%-73.9%). Moreover, the agent induced an objective response rate (ORR) by RECIST v1.1 criteria of 68.4% (95% CI, 56.9%-78.4%).

“Right now, the standard of care [SOC] for advanced CSCC is surgery and adjuvant radiation, and the impact of these treatments can be devastating to patients,” said Gross, who is the lead study author and director of clinical research in the Department of Head and Neck Surgery at The University of Texas MD Anderson Cancer Center, in Houston, Texas. “If patients can be successfully treated with a few doses of neoadjuvant immunotherapy, with relatively low toxicity, [they could] potentially avoid radiation or in the future, [they might] avoid surgery altogether, that's a win for our patients.”

, Gross discussed the current deficits in the treatment of patients with CSCC in the curative setting, avenues for continued research generated by the primary analysis of the phase 2 trial examining neoadjuvant cemiplimab in this population, and how immunotherapy has emerged as a viable option for this disease.

: What was the rationale for investigating the use of cemiplimab as a neoadjuvant treatment for patients with CSCC in the phase 2 study presented at the 2022 ESMO Congress?

: CSCC is extremely ubiquitous. [The disease] is so common in the United States that it’s not even included in our national registries. Most patients are successfully treated with surgery alone, so local therapy; [however,] a certain percentage will advance and require more extensive surgery, and often, adjuvant radiation.

The cumulative effects of [all of this] can be devastating to patients and can have a real impact on their QOL. Some patients can lose significant function, because most of these cancers affect the head and neck region, which is sun exposed. The proximity of pathology to structures [that are] critical to speech, vision, and hearing, make it a high-risk area. The impetus for the trial was to improve not only the oncologic outcomes, but the functional outcomes for these patients.

Please expand on the patient population included on the study.

We focused on patients with stage II to IV, resectable, CSCC. The patients [with stage II disease] had to have tumors that were greater than 3 centimeters in size, and [located] in an aesthetically sensitive area. The vast majority of the patients included in the trial had advanced stage disease. [The] SOC for [these patients] would be surgery and radiation. These patients [have] the most to gain [from] a neoadjuvant approach if the surgery can be tailored, as it was [here], and if adjuvant therapy can be more judiciously applied.

Is there anything you would like to note regarding the trial design?

This study does not track the long-term outcomes; those data are not mature yet, so we don’t know long-term survival. We don’t know which patients received radiation or not, because [the choice of adjuvant therapy] was at investigator discretion. However, it will be very telling once we have those data. [We will be able to better] understand the impact this approach had on QOL.

What were the key findings presented at the meeting?

The neoadjuvant approach [with cemiplimab resulted in] a dramatic pathologic complete response [pCR] rate in [patients with resectable CSCC]. Over half of patients had no residual viable tumor within the specimens and another 10 patients had a major pathologic response, so [approximately] two-thirds of patients [experienced] a deep pathologic response to treatment.

These [data were produced in a] multicenter trial, [which was done] across Europe, the United States, and Australia. [Moreover,] an independent central pathology review had confirmed these responses. [The results] could hearken to a paradigm shift in how we manage this disease in the future, given the deep pathologic responses.

We’re very excited about the preliminary outcome of this study, meaning its primary clinical endpoint of pCR. The responses were similar to what we saw with the pilot data, but still very, very dramatic. The data presented during the meeting were [also] accepted for [concurrent] publication in the 

What will be even more exciting to see is the long-term outcomes of these patients. We know from the pilot data that at 3 years [follow-up], patients who had a complete or near-complete response to neoadjuvant treatment did well with or without adjuvant therapy. [Accordingly], the long-term prognosis is excellent, but it needs to be confirmed in this multicenter trial.

The one caveat [of these data] is that the radiographic responses underestimated pathologic responses. [As such, these findings] underscore that patients still need tissue confirmation to know that they’re responding to treatment.

What else might be learned from the long-term outcome data? What remaining questions do you hope to see addressed in the future?

First and foremost, we need to follow these patients to confirm the oncologic results [we have seen thus far] and to track QOL. We did check circulating tumor DNA as part of the study, so it will be very interesting to see whether that correlates with outcome. We did check baseline tumor mutational burden and PD-L1 status and that was not informative in selecting patients for the neoadjuvant approach.

Many questions were generated from this research, [such as, what is] the optimal number of treatments before surgery? What the role of adjuvant radiation in this case and are there patients who can avoid radiation [or surgery] altogether? We don’t know the answer to these [questions, and] it will take a lot of work to sort that out. However, I think the future is very bright for our patients in improving not only outcomes, but QOL.

What should your colleagues take away from this research?

These data are very exciting, and we are delighted that they would be published in the 

, but [it is still early. Right now, we only have information on] pathologic response rates. We know from [what we have seen in] melanoma and [from] the PILOT [trial done] in CSCC, that pathologic responses to immunotherapy can be durable. I expect that will prove to be the case [in our research, as well]—but we need to know that [for certain] before [we] implement [this approach] into practice.

[It is also important to] really define the appropriate use of surgery in patients who respond and the appropriate use of adjuvant radiation or even adjuvant immunotherapy. [Addressing these] unanswered questions in future studies will be [key].

Gross N, Miller DM, Khushanlani N, et al. Neoadjuvant cemiplimab in patients (pts) with stage II–IV (M0) cutaneous squamous cell carcinoma (CSCC): primary analysis of a phase II study. 

. 2022;33(suppl 7):S904-S905. doi:10.1016/j.annonc.2022.07.915

Neil D. Gross, MD, FACS, discusses the current deficits in the treatment of patients with cutaneous squamous cell carcinoma in the curative setting and avenues for continued research generated by the primary analysis of the phase 2 trial examining neoadjuvant cemiplimab in this population.

Early Data Underscore the Potential of Neoadjuvant Immunotherapy in Advanced Resectable CSCC

Seven-year follow-up data from the phase 3 SOLO-1/GOG-3004 trial (NCT01844986) provide further confirmation of the long-term survival benefit achieved with maintenance treatment with olaparib (Lynparza) vs placebo in patients with newly diagnosed, advanced ovarian cancer harboring a 

 mutation, according to Paul A. DiSilvestro, MD.

Data from the trial, presented at the 2022 ESMO Congress, showed that the median overall survival (OS) was not yet reached in patients treated with olaparib (n = 260) vs 75.2 months in those who received placebo (n = 131; HR, 0.55; 95% CI, 0.40-0.76; 

 = .0004).¹ The 60-month OS rate in the experimental arm was 73.1% compared with 63.4% in the control arm; at 84 months, these rates were 67.0% vs 46.5%, respectively.

“[It was] exciting to see that separation of the curves [that we saw in the progression-free survival [PFS] analysis] persist; [this indicates that] there was an enduring benefit beyond the 2-year treatment cap,” said DiSilvestro, who is director of the Program in Women’s Oncology for Women & Infants Hospital of Rhode Island and Care New England Health System. “We treated people for 2 years, but 5 years later we're still seeing that separation. These data are really compelling.”



®, DiSilvestro, who is also the division director of gynecologic oncology in the Department of Obstetrics and Gynecology at The Warren Alpert Medical School of Brown University, discussed the pivotal SOLO-1 trial of maintenance olaparib in patients with 

-mutated ovarian cancer, updated survival data with the agent in this population, and the next steps for future research.

: Please provide some background on the pivotal SOLO-1/GOG-3004 trial.


: SOLO-1 was a randomized phase 3 trial looking at the role of maintenance olaparib vs placebo in women with [newly diagnosed] advanced ovarian cancer and a 

 mutation. [Patients] were randomly assigned in a 2:1 ratio to either olaparib or placebo and treated for [up to] 2 years or until disease progression, whichever came first. The preliminary primary end point was PFS and one of the secondary end points was OS. I [presented] a descriptive 7-year OS analysis [of follow-up data] at this meeting.

Could you expand on the study design? Why was 7-year OS selected as a clinically meaningful end point for this research?

There has been [research investigating at what point] women who have advanced ovarian cancer experience their greatest risk of death. There have been some eloquent data [presented] by [Robert L. Dood, MD, MSCE, of the University of Utah,] which demonstrated that the first 7 years after diagnosis are probably the principal risk years. [After this,] you begin to see a leveling of the curve. As such, in this descriptive analysis, we did not want to ‘spend’ too much alpha. [This means that] we wanted to look at the data, but not our primary OS end point.

What were the survival findings presented at the 2022 ESMO Congress?

The results were compelling: the median OS for the maintenance olaparib arm had yet to be reached and median OS for the placebo arm was [75.2] months; that yielded a hazard ratio of 0.55, [which translated to] a 45% reduction in the risk of death for those patients 7 years after their diagnosis. If you look at it in a different way, 67.0% of women in the olaparib arm were alive at 7 years after their diagnosis vs [45.6%] in the placebo arm.

What was reported in terms of time to first subsequent treatment?

[That was] another interesting variable that we looked at; [this] is really a proxy for progression-free analysis. The interesting thing here is [that] if you look at the women who are surviving in the olaparib arm, the majority are surviving without ever having received a subsequent therapy. Specifically, 7 years out [from their last administered treatment, 45.3%] of women in the olaparib arm have yet to receive subsequent therapy vs [20.6%] in the placebo arm. [Time to first subsequent treatment really is] an important variable.

What should be taken away from the analysis with regard to safety?

The adverse effect profile remains the same. The [incidence of] special events of interest, such as myelodysplastic syndromes [MDS] or acute myeloid leukemia [AML], and new primary malignancies, remains well balanced. We had 1 extra case of MDS or AML in each arm of the trial. As you can imagine, breast cancer [was the] most common [new primary malignancy] in this at-risk population [harboring 

Is there anything else that you would like to add regarding the data presented?

[It was] exciting to see that separation of the curves [that we saw in an earlier analysis] persist; [this indicates that] there was an enduring benefit beyond the 2-year treatment cap. We treated people for 2 years, but 5 years later we're still seeing that separation. These data are really compelling.

Are any next steps planned for this research?

We [need to wait for the] OS [data to mature]. When we [performed] this analysis, the OS end point was set to be determined at 60% data maturity. Right now, we are at 38% maturity. That's a good thing, [because the event of interest is death]. That means that the event rate is low, and not as many people are dying. Hopefully it [takes] many years before [we] reach [this] because that would just mean [there are] more positive outcomes.

What is your key take-home message regarding this research?

Knowing [a patient’s] germline and tumor-based 

 mutational status is critically important. It's [even more] critically important to [test for this] early in the lifespan of a woman with an advanced ovarian cancer, because that knowledge [provides the] power to make a great treatment decision going forward.

DiSilvestro P, Banerjee S, Colombo N, et al. Overall survival (OS) at 7-year (y) follow-up (f/u) in patients (pts) with newly diagnosed advanced ovarian cancer (OC) and a BRCA mutation (BRCAm) who received maintenance olaparib in the SOLO1/GOG-3004 trial. 

. 2022;33(suppl 7):S779. doi:10.1016/j.annonc.2022.07.645

Paul A. DiSilvestro, MD, discussed the pivotal SOLO-1 trial of maintenance olaparib in patients with BRCA-mutated ovarian cancer, updated survival data with the agent in this population, and the next steps for future research.

Courtney Flaherty

Articles

IMC-F106C Shows Potential as T-cell Receptor–Driven Therapy in Melanoma

Early Data Underscore the Potential of Neoadjuvant Immunotherapy in Advanced Resectable CSCC

SOLO-1 Data Support Use of Olaparib Maintenance to Achieve Long-Term Remission in BRCA+ Advanced Ovarian Cancer