Courtney Marabella

Patients who recived olaparib (Lynparza) after a median follow-up of 2.5 years revealed a 42% reduction in invasive disease–free survival (iDFS), including local and metastatic recurrence of breast cancer, other new cancers, and death due to any cause, (hazard ratio [HR], 0.58; 99.5% CI, 0.41-0.82; P < .0001), according to findings from the phase 3 OlympiA trial (NCT02032823; TABLE, page 37).

 Additionally, investigators noted a difference in 3-year iDFS rate between olaparib and placebo of 8.8% (95% CI, 4.5%-13.0%; stratified HR, 0.58; 99.5% CI, 0.41-0.82; P < .0001).

During a virtual press briefing ahead of the 2021 American Society of Clinical Oncology Annual Meeting, investigators reported clinically meaningful benefit 1 year after initiating standard of care therapies, such as surgery, chemotherapy, hormone therapy, or radiation therapy, in patients with BRCA1/2-mutant, early HER2-negative breast cancer who are at high risk for recurrence.

“The OlympiA study is the first to report the ben-efits of [an adjuvant] PARP inhibitor for early forms of germline BRCA1/2-mutation–associated cancer,” said presenting study author Andrew Tutt, PhD, MB ChB, head of the Division of Breast Cancer Research and director of the Breast Cancer Now Toby Robins Research Centre at the Institute of Cancer Research and Guy’s Hospital King’s College, London, United Kingdom, a clinician scientist with the Laboratory and Clinical Trials program, and a consultant clinical oncologist. “Patients who received olaparib after surgery and chemotherapy were more likely to be alive without cancer, [as well as] avoid metastasis, than the patients who received placebo.”

Patients with HER2-negative early breast cancer who harbor a BRCA1/2 mutation, present in approximately 5% of all breast cancers, are at high risk of disease recurrence. Although outcomes have been positive for patients with these mutations who have received standard treatments such as surgery, radiotherapy, and chemotherapy, the risk of recurrence remains high for some patients. As such, additional novel targeted therapies are needed to reduce the risk of recurrence in this patient population.

Olaparib is a PARP inhibitor that targets DNA repair defects in certain germline-mutant can-cers and was previously approved by the FDA in January 2018 for the treatment of patients with germline BRCA-positive, HER2-negative metastatic breast cancer. As such, investigators sought to examine the agent in patients with germline BRCA–mutated, HER2-negative early breast cancer.

The trial enrolled 1836 patients with HER2-negative breast cancer harboring a germ-line BRCA mutation who were randomized 1:1 to receive either 300 mg of oral olaparib (n = 921) twice daily for 1 year or placebo (n = 915). Additionally, patients needed to have been treated for early stage (stage II-III) breast cancer and have completed surgery and chemotherapy, with or without radiotherapy. Inclusion criteria also required that patients have a high risk of disease recurrence. Those who had received prior treatment with a PARP inhibitor were not eligible to enroll.

The primary end point for the study was iDFS; secondary end points included distant disease–free survival (DDFS), overall survival (OS), health-related quality of life, and safety. “Stringent criteria were applied for a planned interim analysis,” Tutt said. “At this analysis, OlympiA’s Independent Data Monitoring Committee found [that] these stringent criteria were met for early reporting.”

Additional findings indicated that after a median follow-up of 2.5 years, patients who were treated with olaparib experienced a 43% reduction in DDFS, including metastatic disease, new cancer, and death due to any cause (HR, 0.57; 99.5% CI, 0.39-0.83; P < .0001). The difference in 3-year DDFS rate between olaparib and placebo was 7.1% (95% CI, 3.0%-11.1%; stratified HR, 0.57; 99.5%, 0.39-0.83; P < .0001).

At the time of the early primary end point report, OS data were considered immature. However, although fewer deaths were reported in patients receiving olaparib vs placebo, OS was not significantly different between the 2 study cohorts at a median follow-up of 2.5 years (HR, 0.68; 99% CI, 0.44-1.05; P = .024). Moreover, the difference in 3-year OS rate between the 2 arms was 3.7% (95% CI, 0.3%-7.1%).

In terms of the safety profile, the adverse effects (AEs) reported in the olaparib group were consistent with what has been previously reported with the agent. Additionally, olaparib did not increase serious AEs, including hospital admissions or occurrences of other cancers such as leukemia. However, grade 3 or higher AEs were reported more often in patients receiving treatment with olaparib, and included anemia (9%), neutropenia (5%), leukopenia (3%), and fatigue (2%).

The most common AEs of any grade reported in patients who received olaparib included nausea (57%), fatigue (40%), anemia (23%), vomiting (23%), and headache (20%). Moreover, the most common any-grade AEs in the placebo arm were fatigue (27%), nausea (23%), headache (17%), diarrhea (14%), and arthralgia (12%).

Tutt A, Garber J, Kaufman B, et al. OlympiA: a phase III, multicenter, ran-domized, placebo-controlled trial of adjuvant olaparib after (neo)adjuvant chemotherapy in patients with germline BRCA1/2 mutations and high-risk HER2-negative early breast cancer. Presented at: 2021 ASCO Annual Meeting; June 4-8, 2021; virtual. Abstract LBA1. Accessed July 1, 2021. https://bit.ly/2TOpnux

Articles

Patients who recived olaparib after a median follow-up of 2.5 years revealed a 42% reduction in invasive disease–free survival, including local and metastatic recurrence of breast cancer, other new cancers, and death due to any cause. 

Olaparib Improves Disease–Free Survival  in Early HER2-Negative Breast Cancer

The emergence of novel approaches, such as antibody-drug conjugates (ADCs), KRAS G12C inhibitors, and novel combinations such as tyrosine kinase inhibitor (TKI)/immune checkpoint inhibitors, exhibits promising outcomes in gastrointestinal (GI) cancers, according to Wells Messersmith, MD.

Several new ADCs have shown promising activity in small subgroups of patients, although disappointing results have been reported thus far with regard to their use in patients with RAS-mutant disease, outside of the KRAS G12C–mutated subgroup, said Messersmith, a professor of medicine and medical oncology at the University of Colorado Cancer Center. However, at least 3 studies are underway to evaluate approaches in patients with other RAS mutations.

The heterogeneity of tumors in GI cancers continues to pose a challenge, added Messersmith. As such, understanding how circulating tumor DNA will play into the treatment of patients as RAS inhibitors emerge in the clinic will be an area of interest going forward.

“There are some interesting signals with checkpoint inhibitors and TKIs but we just do not know who is going to respond,” Messersmith said during a presentation at the 6th Annual School of Gastrointestinal Oncology®, hosted by Physicians’ Education Resource® (PER®). “Most of these [efforts] have at least a biomarker hypothesis and how we fi nd these rare subsets is going to be a challenge for the fi eld.”

ADCs were first proposed as far back as the 1980s, but it took until the early 2000s for the first one to be approved for use, noted Messersmith. In 2013, adotrastuzumab emtansine (T-DM1, Kadcyla) was approved for use in patients with HER2-positive breast cancer. Since then, many of the ADCs to receive regulatory approval have emerged in the breast cancer paradigm, up until recently, he said.

The ADCs approved for use in the treatment of patients with solid tumors include trastuzumab emtansine and fam-trastuzumab deruxtecan-nxki (Enhertu) for HER2-positive breast cancer and HER2-positive gastric cancer,enfortumab vedotin-ejfv (Padcev) for locally advanced and metastatic urothelial carcinoma, and sacituzumab govitecan-hziy (Trodelvy) for triplenegative breast cancer.

“Several steps have to happen [with] ADCs; they need to bind to an antigen, it has to get internalized, and then through endosomal and lysosomal biology, which is as of yet not all that understood in terms of the predictors of efficacy, you release the payload,” Messersmith said. “That’s where the magic bullet part of this comes in, where it is really only supposed to release the payload at sites of tumor. Then the payload does its thing in terms of killing tumor cells. For each of these steps, you can see where you’d get mechanisms of resistance.”

ADCs are made up of an antigen, which is the target of the antibody, along with a cytotoxic payload. The most important advance in the past decade, however, has been in terms of linkers, according to Messersmith. Having a linker that is strong enough to hold the payload in circulation is critical, but it also must release the cytotoxic payload to the tumor site. “It took many, many years to get the right linkers in place to actually accomplish these goals,” he said.

In the phase 2 MATCH trial (NCT02465060), which examined T-DM1 in patients with HER2-amplified tumors, the rate of HER2 amplification was found to be low in patients with GI cancers; however, those numbers added up, Messersmith noted. Moreover, in those patients with GI cancers, T-DM1 elicited some responses, although the duration of benefit proved to be brief.

In January 2021, the FDA approved trastuzumab deruxtecan for the treatment of adult patients with locally advanced or metastatic HER2positive gastric or gastroesophageal junction (GEJ) adenocarcinoma who have received a previous trastuzumab (Herceptin)-based regimen. This ADC consists of an anti-HER2 antibody with a cleavable tetrapeptide-based linker, and a cytotoxic topoisomerase I inhibitor.

“That has actually been a more common payload [to emerge] over the past several years,” Messersmith said.


The regulatory decision was based on data from the phase 2 DESTINY-Gastric01 trial (NCT03329690), which included patients with HER2-expressing advanced gastric or GEJ adenocarcinoma who had received at least 2 prior treatments, including fluoropyrimidine and a platinum agent. Eighty-six percent of patients had received prior treatment with taxanes, and 33% had prior treatment with checkpoint inhibitors.

Investigators randomized a total of 187 participants 2:1 to receive either trastuzumab deruxtecan at a dose of 6.4 mg/kg in a 3-week cycle (n = 125), or physician’s choice of either irinotecan or paclitaxel (n = 62). The primary end point of the study was overall response rate (ORR), and secondary end points included overall survival (OS), duration of response (DOR), progression-free survival (PFS), confirmed ORR, and safety.

The results showed an ORR of 51.3% (95% CI, 41.9%-60.5%; P < .0001) for trastuzumab deruxtecan (TABLE). “In the third-line setting, to have a response rate that high is actually pretty impressive,” Messersmith noted. “You can see that 10 patients had a complete response, whereas 41 patients had a partial response, and the disease control rate was 85.7%. [The agent] was quite active, so you could see why the FDA would approve it, despite the fairly limited patient numbers.”

Additionally, the median OS with the ADC was 12.5 months (95% CI, 9.6-14.3) vs 8.4 months (95% CI, 6.9-10.7) with physician’s choice (HR, 0.59; 95% CI, 0.39-0.88; 

 = .0097). The median PFS in the investigative and control arms was 5.6 months (95% CI, 4.3-6.9) vs 3.5 months (95% CI, 2.0-4.3), respectively (HR, 0.47; 95% CI, 0.31-0.71).

“[These survival rates] go down gradually; they are not leveling like they do with immunotherapy,” noted Messersmith. “However, [these are still] fairly impressive results when you compare them with [those of] trifluridine and tipiracil [TAS-102, Lonsurf], regorafenib [Stivarga], or some of these other drugs that we use in the third-line setting for other GI cancers.”

In the phase 2 DESTINY-CRC01 trial (NCT03384940), investigators examined trastuzumab deruxtecan in patients with unresectable and/or metastatic, HER2-expressing colorectal cancer (CRC). The primary end point for this trial was ORR by independent central review in cohort A. Notably, previous HER2targeted treatment was permitted.

Results showed an ORR of 45.3% (95% CI, 31.6%59.6%), and tumor shrinkage over time was well sustained, said Messersmith. The median PFS was 6.9 months (95% CI, 4.1-not evaluable) and the median OS was not reached.6 “These data are immature but are still impressive for the third-line setting and beyond,” he noted.

A majority of the treatment-emergent adverse events (TEAEs) reported in this study were grade 1 or 2, and many of them were GI-related toxicities. The most common TEAEs included nausea, anemia, and decreased neutrophil count.

“It’s not surprising given that you have an irinotecan-type of drug,” Messersmith said. “It shows that some of the payload is clearly getting into the circulation…. The idea is that there is a much higher amount of drug being delivered to the tumor site.”

Additionally, 5 incidents of interstitial lung disease were observed during this study, 2 of which were grade 5. The median time to investigator-reported onset of these incidents was 80 days (range, 22-132), and all 5 patients were treated with corticosteroids. Two of the patients with interstitial lung disease recovered, 1 did not recover and later died from disease progression, and 2 died as a result of the interstitial lung disease.

In the 2 patients who died, the onset of interstitial lung disease ranged from 40 to 126 days; both received steroids as treatment and death occurred 6 to 18 days after diagnosis. As a result, new protocol recommendations encourage monitoring for symptoms, and holding ADC treatment and starting steroids immediately if interstitial lung disease is suspected.

“[Trastuzumab deruxtecan showed] promising and durable activity. For a third-line response rate to be around 45% is impressive,” Messersmith said. “[Also, we saw] a median PFS of around 7 months and we’re used to seeing a median PFS of less than 2 months in this population. This [agent] could be an option down the line as further data come out.”

Other HER2-targeted ADCs in development include A166, XMT-1522, MEDI-4276, ARX788, RC48-ADC, BAT8001, and PF-06804103.

“Nowadays, [these ADCs] are able to dial in the exact number of warheads per antibody, and as you do that, you seem to get a much better efficacy to toxicity ratio,” Messersmith said.

However, overexpression does not always equate to benefit with ADCs in GI cancers. For example, there have been many challenges with Trop2 targeting. Trop2 is a glycoprotein that was initially identified as a surface marker of trophoblast cells and has subsequently been found to be overexpressed in many solid tumors, including most GI cancers.

Sacituzumab govitecan was examined in patients with GI cancers and only yielded 1 response; as such, the agent is not moving forward, noted Messersmith. Another agent, PF-06664178, also failed to elicit responses in this patient population, and its further development for this purpose was stopped.

RAS Pathway Signaling and Inhibition KRAS signaling can lead to multiple cellular-proliferation pathways, and this complexity and redundancy has made pathway targeting very complicated, according to Messersmith. Thus, many unsuccessful strategies have been reported over the past 15 years.

It is a very redundant and complex pathway to try to inhibit,” Messersmith said. “There was this idea that maybe we could just inhibit downstream effector signals, such as a MEK inhibitor…, but now we have more modern agents."

One of those agents is adagrasib (MRTX849), a covalent inhibitor of 

 G12C that irreversibly and selectively binds 

 G12C in its inactive, GDP-bound state. The agent was optimized for desired properties of 

 G12C inhibition, has high selectivity for the mutant 

, and has favorable pharmacokinetic properties; these include oral bioavailability, a long halflife, and extensive tissue distribution.

Investigators examined adagrasib as part of the phase 1 KRYSTAL-1 trial (NCT03785249). Previously reported data showed that adagrasib had clinical activity in patients with pretreated KRAS G12C–mutant CRC. For the trial, patients were treated on a standard-dose escalation, where they received up to 600 mg/kg of the agent twice daily. The median follow-up for patients with CRC was 4.3 months. The confi rmed ORR with the agent in patients with CRC was 17% (n = 3/18), and the disease control rate was 94% (n = 17/18). Patients tolerated the agent fairly well, with AEs that included nausea, diarrhea, and vomiting. These data are still very early; however, all patients enrolled to the study were still receiving treatment as of the August 2020 data cutoff.

The randomized, open-label, phase 3 KRYSTAL-10 trial (NCT04793958) will compare second-line adagrasib in combination with cetuximab (Erbitux) with chemotherapy in patients with metastatic, KRAS G12C–mutant CRC. The primary outcome measures for this study are PFS and OS, and secondary outcome measures include safety, ORR per RECIST 1.1 criteria, DOR, and patient-reported outcomes. To be eligible for enrollment, patients must have confirmed metastatic CRC and confirmed KRAS G12C mutation and have progressed on a first-line fluoropyrimidine-, oxaliplatin-, or irinotecan-based regimen.

TKI and Immune Checkpoint Inhibitor Combinations 

Combination regimens comprised of TKIs and immune checkpoint inhibitors have represented an interesting area of research in the GI cancer treatment paradigm, according to Messersmith.

Initially, promising results were reported from a phase 1 trial (NCT01988896) examining the combination of atezolizumab (Tecentriq) and cobimetinib (Cotellic) in patients with solid tumors, including those with metastatic CRC.

However, data from the phase 3 COTEZO IMblaze370 trial (NCT02788279), which looked at atezolizumab with or without cobimetinib vs regorafenib, showed that the response rate achieved with the combination had dropped.

The phase 2 LEAP-005 trial (NCT03797326) examined the combination of lenvatinib (Lenvima) plus pembrolizumab (Keytruda) in 30 patients with previously treated advanced solid tumors. Primary end points for this study were ORR and safety. The GI cohorts in the trial included patients with third-line gastric cancer, third-line CRC, and second-line biliary tract cancer.

Patients in the CRC cohort experienced an ORR of 21.9% (95% CI, 9.3-40.0) with the combination, whereas those in both the gastric cancer cohort and the biliary tract cancer cohort had an ORR of 9.7% (95% CI, 2.0-25.8).

“I have seen these patients in the clinic, and we have had multiple of these studies and investigator-initiated studies opened, and you definitely have patients who get these incredible responses,” Messersmith said.

“Unfortunately, however, it is not the majority, so trying to figure out which of these patients is going to benefit [from this approach] is a key challenge.”

The median PFS was 2.5 months (range, 1.8-4.2) in the gastric cancer cohort, 2.3 months (range, 2.0-5.2) in the CRC cohort, and 6.1 months (range, 2.1-6.4) in the biliary tract cancer cohort. “Two-thirds of the [patients with third-line CRC] are progressing at the 3-month interval, but if you make it out to 3 or 4 months, your chance of making it out to 9 months is actually pretty good,” Messersmith noted.

One of the challenges in the fi eld is to determine how to preclinically evaluate novel combinations, but different models are under exploration, Messersmith concluded.

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The heterogeneity of tumors in gastrointestinal cancers continues to pose a challenge, according to Wells Messersmith, MD.

Novel Approaches Address Tumor Heterogeneity in GI Malignancies

Despite questions about the potency and efficacy of tumor-infiltrating lymphocytes (TILs), ongoing research into their curative potential, especially in metastatic melanoma, continues to excite investigators. Inge Marie Svane, MD, PhD, a professor of clinical cancer immune therapy at the University of Copenhagen, and director of National Center for Cancer Immune Therapy at Herlev and Gentofte Hospital, highlighted TILs’ clinical responses when checkpoint inhibitors fail in melanoma during a presentation during the American Association for Cancer Research (AACR) Annual Meeting 2021 held virtually in May.

We don’t really know the whole truth about antigen specificity driving TIL efficacy. We know that some of the tumor-reactive TILs represent neoantigen-specific T cells, [whereas] some represent more shared or tumor-associated antigens and some may be viral antigens; however, there is also a population of these tumor-reactive T cells that are still unknown to us,” Svane explained. “We need to improve on how we can define TIL potency to document the efficacy of this therapy, and we need to clarify the role of CD4 T cells in the product. [Another] broad area of [interest is] to figure out how to increase the efficacy of TIL therapy in nonmelanoma cancers.”

TILs represent the most developed strategy for neoantigen-targeting immunotherapy, and it is well known that this therapy has shown efficacy in infiltrating tumors, Svane said. Additionally, efforts to expand, isolate, and stimulate TILs have been examined, according to Svane.

“We can show that a certain fraction of these expanded cells react toward the tumor,” Svane said. “In this subpopulation of tumor-reactive T cells, we find neoantigen-specific T cells as well as tumor-associated antigen-specific T cells and T cells reactive toward viral antigens [such as] human papillomavirus [HPV]. Then, the last fraction of these tumor-reactive T cells [is] of unknown specificity.”

Adoptive T-cell therapy is established by taking tumor tissue from the patient and driving out the T cells from the tumor lesion, followed by initial TIL expansion. TIL is rapidly expanded through the stimulation of anti-CD3 feeder cells and high doses of IL-2 to achieve 50 to 200 × 10

TILs for infusion, according to Svane. Patients are preconditioned with high-dose chemotherapy for 1 week prior to infusion with the TILs. Then the TILs are infused, and thereafter they are supported with high doses of IL-2.

This method for TIL infusion was established more than a decade ago, and published data showed response rates ranging from 50% to 70% in patients with metastatic melanoma.

Additionally, more than 20% of patients experienced long-term survival with this therapy. Twenty patients achieved a complete response (CR). Among these complete responders, the 3-year survival rate was 100% and the 5-year survival rate was 93%.

“With a long-term follow-up of more than 8 years, the National Cancer Institute has recently shown that this is an extremely durable response if the patients achieved CR and it is highly likely that they will be cured of their metastatic melanoma,” Svane said.

In another phase 1/2 study (NCT00937625), adoptive cell therapy with TILs was examined in patients with metastatic melanoma who had progressed on  prior treatment with high-dose IL-2 and ipilimumab (Yervoy). Overall, 25 patients were enrolled to the study and underwent a 3-step treatment comprised of high-dose chemotherapy, TIL infusion, and IL-2.

 The overall response rate (ORR) achieved with this regimen was 42%, and patients who achieved a CR demonstrated a long duration of response (DOR) to treatment, according to Svane.

Additionally, results from a meta-analysis that examined studies that administered adoptive cell therapy with TILs at treatment centers worldwide showed that durability of response can be experienced with this treatment if a CR is achieved.

Responses in PD-1–Resistant Melanoma With TILs 

Anti–PD-1 therapy is a main treatment strategy for patients with metastatic melanoma, according to Svane, and, as such, it was important for investigators to examine whether adoptive cell therapy with TILs can be utilized in patients who had progressed on this therapy.

“We showed in a small cohort of patients that we were, indeed, able to induce remission of metastatic lesions in patients progressing on anti–PD-1 [agents],” Svane said. “We also found tumor-reactive T cells in the product as well as in the peripheral blood after treatment. [However,] the durability of the treatment seems to be shorter lasting.”

This was also demonstrated in a study that examined clinical responses to TIL therapy in patients who were PD-1 naïve (n = 32) vs those who had progressed on previous PD-1 treatment (n = 23). Results showed a response rate of 42% in PD-1–naïve patients vs 32% in those who had progressed on PD-1 treatment.

 The median overall survival (OS) in these 2 cohorts was 19.6 months and 14.0 months, respectively, and the median progression-free survival (PFS) was 3.9 months and 2.8 months, respectively. Additionally, the DOR for patients who achieved a CR and partial response was 32.2 months for PD-1–naïve patients vs 7.6 months for those who had progressed on PD-1 treatment.

“The number of patients who had a response [was] lower when they had previously progressed on a checkpoint inhibitor, and the durability of responses was far shorter [in those who were] refractory to PD-1 therapy,” Svane noted.

Additionally, data from a study presented during the 2020 American Society of Clinical Oncology (ASCO) Virtual Scientific Program demonstrated that when the cryopreserved TIL product lifileucel (LN-144) was used in patients with PD-1–resistant melanoma, the ORR was 36.4%.

Moreover, 80.6% of patients treated in this study (n = 50/62) experienced a reduction in tumor burden with the treatment (

Only a small number of studies examining TIL therapy in patients with other cancers beyond melanoma have been published, and very few trial results have been finalized, according to Svane.

However, 1 of the published studies examined treatment with HPV-targeted TILs in 9 patients with metastatic cervical cancer. Results showed durable complete regression with the approach, with 3 patients experiencing objective tumor responses to treatment.

 Additionally, a phase 1 study (NCT03215810) examined adoptive cell transfer with TILs in 13 patients with non–small cell lung cancer (NSCLC), and durable CRs were reported in some of these patients.

Notably, TIL therapy also led to a durable CR in a patient with metastatic breast cancer, according to a patient report published in Nature Medicine.

 “The treatment that they offered this patient was very complex, as they aimed to increase the number of new antigens between T cells in the TIL product,” Svane explained.

To do this, the investigators sequenced the tumor from the patient and predicted different neoepitopes. Based on that prediction, investigators prepared minigenes, which were transduced into dendritic cells established from the patients. This was so the dendritic cell could then present the neoantigen epitopes to the TILs during the outgrowth and then increase the fraction of neoantigen-specific T cells in the infusion product.

“Indeed, they saw very impressive responses, with multiple lesions disappearing after therapy,” Svane noted.

Additionally, an ongoing phase 1/2 trial (NCT03296137) is examining TIL therapy in 25 patients with advanced cancer who have been heavily pretreated, including with anti–PD-1 therapy. Of the patients treated on this study, 7 have gastrointestinal cancers (28%), 6 have melanoma (24%), 3 have cholangiocarcinoma (12%), 2 have squamous cell carcinoma (8%), 2 have sarcoma (8%), and 5 have other carcinomas (20%).

On this study, investigators sought to take advantage of treatment with checkpoint inhibitors at different points throughout treatment, according to Svane. Patients were pretreated with 1 dose of ipilimumab to recruit more TILs into the tumor lesion as well as to expand the repertoire of the TILs prior to tumor resection. After conditioning with chemotherapy, patients were then infused with the TILs and received treatment with 4 doses of nivolumab (Opdivo). Additionally, patients received treatment with low-dose IL-2 for 14 days.

Results from this study showed that some patients did achieve regressive disease with this therapy and 5 out of 25 patients demonstrated substantial tumor regression, according to Svane. However, the durability of these responses was short.

Treatment with TIL therapy also has been examined in several pilot studies in patients with ovarian cancer. In a study that examined TIL therapy without the addition of checkpoint inhibitors, results showed that patients only achieved disease stabilization, according to Svane.

 However, in another study, which utilized ipilimumab and nivolumab to increase TIL efficacy, responses deepened, Svane explained.

Future Directions Toward Standard of Care 

Currently, an ongoing, randomized phase 3 trial is comparing TIL-based adoptive cell therapy vs standard ipilimumab treatment in patients with PD-1–resistant melanoma, according to Svane. The goal is to enroll 168 patients with metastatic melanoma who have progressed on prior anti–PD-1 therapy. 

Patients will be randomized 1:1 to receive ipilimumab at a daily dose of 3 mg/kg every 3 weeks for 4 cycles (arm A) or nonmyeloablative chemotherapy comprised of cyclophosphamide plus fludarabine followed by intravenous adoptive transfer of at least 5 × 10

 TIL followed by high-dose IL-2 (arm B). Patients will be stratified by 

 V600 mutational status (yes vs no), line of treatment (first vs second), and treatment center.

The primary end point of the study is 6-month PFS, and secondary end points include PFS per immune-related response criteria (irRC), ORR per RECIST v1.1 criteria and irRC, CR, OS, and safety.

“Accrual has been moving along and has been successful for the past couple of years. We aim to have the full recruitment of the trial within the next year,” Svane said.

Predictors of ResponseIn terms of which patients could be the best candidates to receive TIL therapy as a potential standard of care, a lot of information has been gathered from past studies, according to Svane. Ideal patients are younger than 70 years, have at least 1 resectable metastatic lesion of sufficient size, and have a good clinical performance status. Additionally, patients with metastatic melanoma who have progressed after standard therapy, have no brain metastases, and have sufficient organ function have demonstrated the best responses with this approach.

However, questions regarding predictive factors and markers of response remain, Svane noted. It has been suggested that mutational load and inflammation may be potential biomarkers.

“Indeed, mutational load correlates with clinical benefit, and it also correlates with PFS as well as OS for patients treated with T-cell therapy,” Svane said. Moreover, immune system activation profile has been shown to be a hallmark of responding tumors.

Moreover, immunology has been found to correlate with tumor regression, with the number of T cells in the infusion product reacting toward the tumor playing a key role in efficacy, according to Svane. As such, the patients with the best reduction of tumor lesions had the highest number of tumor-reactive TILs in the infusion product.

 This also was seen in blood samples collected months after treatment.

Additionally, a qualitative analysis of expandedTILs across multiple tumor types showed significantly more tumor-reactive T cells were found in the products for patients with melanoma compared with those with other types of cancer, according to Svane.

“This is, indeed, [the case] for both the CD8 cells as well as the CD4 cells,” Svane said. “If you look at the total percentage of tumor-reactive T cells, we have generally more CD8 tumor-reactive T cells than CD4s, but these 2 fractions do correlate.”

Moreover, stem-cell–like CD8 T cells in TIL infusion products also were found to be associated with clinical responses and survival. These T cells, CD39-negative and CD69-negative, correlated with complete cancer regression, according to Svane. Although most antitumor neoantigen-reactive TILs were found in a differentiated CD39-positive state, patients who responded to treatment also maintained CD39-negative neoantigen-specific TILs.

1. Svane IM. Targeting neoantigens by adoptive cell therapy. Presented at: AACR Annual Meeting 2021; May 17-21, 2021; virtual. Session ED071.

2. Donia M, Junker N, Ellebaek E, Andersen MH, Straten PT, Svane IM. Characterization and comparison of ‘standard’ and ‘young’ tumor-infiltrating lymphocytes for adoptive cell therapy at a Danish translational research institution. 

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

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4. Andersen R, Donia M, Ellebaek E, et al. Long-lasting complete responses in patients with metastatic melanoma after adoptive cell therapy with tumor-infiltrating lymphocytes and an attenuated IL2 regimen. 

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5. Dafni U, Michielin O, Lluesma SM, et al. Efficacy of adoptive therapy with tumor-infiltrating lymphocytes and recombinant interleukin-2 in advanced cutaneous melanoma: a systematic review and meta-analysis. 

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6. Borch TH, Andersen R, Ellebaek E, Met O, Donia M, Svane IM. Future role for adoptive T-cell therapy in checkpoint inhibitor-resistant metastatic melanoma. 

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

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8. Stevonavíc S, Draper LM, Langhan MM, et al. Complete regression of metastatic cervical cancer after treatment with human papillomavirus–targeted tumor-infiltrating T cells. 

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11. Kverneland AH, Borch TH, Chamberlain C, et al. Clinical potential of adoptive cell therapy with tumour infiltrating lymphocytes therapy in combination with checkpoint inhibitors in non-melanoma patients. 

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14. Andersen R, Donia M, Ellebaek E, et al. Long-lasting complete responses in patients with metastatic melanoma after adoptive cell therapy with tumor-infi ltrating lymphocytes and an attenuated IL2 regimen. 

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According to Inge Marie Svane, MD, PhD, the truth about what drives tumor-infiltrating lymphocyte efficacy is not yet known, and more research is needed.

More Research on Potency,  Efficacy of  TILs Is Needed in Melanoma

Encouraging findings from the phase 1 TROPION-PanTumor01 trial revealed a positive response and safety profile for the antibody-drug conjugate (ADC) datopotamab deruxtecan (DS-1062a) in patients with triple-negative breast cancer (TNBC). The preliminary findings were presented during the European Society for Medical Oncology (ESMO) Breast Cancer Virtual Congress 2021.

Among 21 evaluable patients in the trial (NCT03401385), the objective response rate with datopotamab deruxtecan was 43% (n = 9) per blinded independent central review (BICR); this included a confirmed complete response/ partial response (CR/PR) rate of 24%; 19% of patients had a CR/PR that was pending confirmation. The disease control rate was 95% by BICR. Moreover, only 1 patient experienced disease progression, and no patients discontinued treatment due to adverse events (AEs).

“Further study [of this agent] in breast cancer is needed, and the hormone receptor [HR]-positive cohort [of this trial] is now enrolling,” said lead study author Aditya Bardia, MD, MPH, director of precision medicine at the Center for Breast Cancer and founding director of the Molecular and Precision Medicine Metastatic Breast Cancer Clinic at Massachusetts General Hospital Cancer Center, during an oral presentation.

Patients with relapsed/refractory advanced or metastatic TNBC continue to have poor clinical outcomes. Datopotamab deruxtecan is a TROP2-directed ADC with 3 components: a humanized anti-TROP2 IgG1 monoclonal antibody, a topoisomerase 1 inhibitor payload, and a tetrapeptide-based cleavable linker.

Previously, the ADC demonstrated encouraging antitumor activity with acceptable safety in the non–small cell lung cancer (NSCLC) cohort of this trial. Based on those efficacy results, 6 mg/kg has been selected as the dose for expansion in other advanced tumor types.

TROPION-PanTumor01 is an ongoing, phase 1, first-in-human basket trial with multiple cohorts, including NSCLC, TNBC, and soon, HR-positive breast cancer. At the ESMO congress, Bardia shared results from the TNBC cohort.

To be eligible for enrollment to the cohort, patients had to have advanced or metastatic HR-negative/human epidermal growth factor receptor 2 (HER2)-negative TNBC and have relapsed or progressed on at least 1 standard treatment. Measurable disease per RECIST 1.1 criteria was required, and patients needed to be unselected for TROP2 expression.

In the TNBC cohort, investigators treated 24 patients with intravenous datopotamab deruxtecan every 3 weeks; 22 received the 6-mg/kg dose and 2 received an 8-mg/kg dose. Of those patients, 18 remain on treatment and 6 have discontinued due to disease progression.

The primary end point of the study is safety and tolerability, and secondary end points include efficacy and pharmacokinetics.

The median age of study participants was 57 years (range, 32-82), and the majority were from the United States (75%). Most patients had an ECOG performance status of 1 (67%), and 38% presented with de novo metastatic disease. Additionally, this was a heavily pretreated population who had received a median of 4 prior lines of therapy (range, 1-9), with 88% having received at least 2 prior therapies. Previous treatment included taxanes (83%), platinum-based chemotherapy (50%), immunotherapy (33%), sacituzumab govitecan (Trodelvy; 8%), and a PARP inhibitor (4%).

In terms of safety, all patients experienced treatment-emergent AEs (TEAEs) of any grade, whereas grade 3 or higher TEAEs were reported in only 8 patients (33%). Seventeen percent of patients (n = 4) experienced treatment-related toxicities that were grade 3 or higher in severity. Serious TEAEs occurred in 3 patients (13%), but none were determined to be associated with the study drug.

Additionally, 6 patients (25%) needed dose reductions due to AEs, which were mostly due to stomatitis (13%; n = 3) or mucosal inflammation (8%; n = 2). The trial investigators reported no fatal TEAEs.

Most of the AEs reported were grade 1 or 2, the most common of which included stomatitis (63%), nausea (63%), fatigue (42%), vomiting (42%), and alopecia (25%). Grade 3 or higher TEAEs included stomatitis (13%), fatigue (4%), and anemia (4%). Investigators observed no cases of grade 3 or higher diarrhea or neutropenia, and reported no cases determined as drug-related interstitial lung disease.

1. Bardia A, Juric D, Shimizu T, et al. Datopotamab deruxtecan (Dato-DXd), a TROP2-directed antibody-drug conjugate (ADC), for triple-negative breast cancer (TNBC): preliminary results from an ongoing phase 1 trial. 

l. 2021;32(suppl 2):S60. doi:10.1016/j.annonc.2021.03.213

Encouraging findings from theTROPION-PanTumor01 trial revealed a positive response and safety profile for the antibody-drug conjugate datopotamab deruxtecan in patients with triple-negative breast cancer.

Courtney Marabella | Authors

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More Research on Potency, Efficacy of TILs Is Needed in Melanoma

Promising Antitumor Activity for Datopotamab Deruxtecan in TNBC