Progression-free survival (PFS) rates were doubled in patients receiving sotorasib (Lumakras) for 

 G12C–mutated non–small cell lung cancer (NSCLC) compared with patients receiving docetaxel. In addition, patients receiving sotorasib also experienced a significant reduction in the risk of progression or death, according to data from the phase 3 CodeBreak 200 trial (NCT04303780), presented at the 2022 ESMO Congress.

At a median follow-up of 17.7 months, the 12-month PFS rate was 24.8% with sotorasib compared with 10.1% with docetaxel. Median PFS was 5.6 months (95% CI, 4.3-7.8) with sotorasib vs 4.5 months (95% CI, 3.0-5.7) with docetaxel (HR, 0.66; 95% CI, 0.51-0.86; 

 = .002). There were fewer grade 3 or greater treatment-related adverse effects (TRAEs) with the KRAS G12C inhibitor compared with chemotherapy (33.1% vs 40.4%, respectively). Additionally, serious adverse events were less common with sotorasib vs docetaxel (10.7% vs 22.5%).

“The PFS rate doubled and the PFS benefit was seen across all subgroups tested. Likewise, the secondary end points of objective response rate [ORR], disease control rate [DCR], time to response, and duration of response were all significantly improved in favor of sotorasib,” said study author Melissa L. Johnson, MD, director, Lung Cancer Research Program, Sarah Cannon Research Institute. “In my opinion, this supports sotorasib as a new second-line standard for patients with 

 (NCT03600883), the FDA granted sotorasib an 

 G12C–mutated locally advanced or metastatic NSCLC. In this study, the ORR was 36% (95% CI, 28%-45%) for a median duration of 10 months.

The global phase 3 CodeBreaK 200 study enrolled 345 patients with locally advanced, unresectable, or metastatic 

 G12C–mutated NSCLC. The study was originally designed to enroll 650 participants but was reduced to approximately 330, based on guidance from the FDA. The agency requested that patients on the docetaxel arm be able to crossover to receive sotorasib following disease progression. This shift maintained the statistical power for the primary end point of PFS but underpowered the trial to show a statistical difference in overall survival, which was a secondary end point.

“The trial was initially twice as big and when the CodeBreaK 100 data read out the FDA suggested strongly that the trial be amended to reduce the number of patients enrolled by half, so it would decrease the number of patients randomized to docetaxel,” Johnson said.

For the study, patients were randomized to receive either oral sotorasib at 960 mg per day (n = 171) or intravenous (IV) docetaxel at 75 mg/m2 every 3 weeks (n = 174). All patients had received prior platinum-based chemotherapy and a checkpoint inhibitor either concurrently or sequentially. Patients with active brain metastases were excluded from the study, although a history of brain metastases was allowed, Johnson noted.

The ORR with sotorasib was 28.1% (95% CI, 21.5%-35.4%) compared with 13.2% (95% CI, 8.6%-19.2%) with docetaxel (

 <.001). When also considering patients with stable disease, the overall DCR was 82.5% for sotorasib compared with 60.3% with docetaxel.

“Secondary end points were all significantly improved in favor of sotorasib,” said Johnson. “Response, disease control, time to response, and duration were all positive in favor of sotorasib.”

TRAEs leading to discontinuation were experienced by 9.5% of patients in the sotorasib arm compared with 11.3% with docetaxel. The most common any-grade TRAEs between sotorasib and docetaxel, respectively, were diarrhea (33.7% vs 18.5%), nausea (14.2% vs 19.9%), alanine aminotransferase (ALT) increase (10.1% vs 0%), aspartate aminotransferase (AST) increase (10.1% vs 0%), and fatigue (6.5% vs 25.2%). The most common grade 3 or greater TRAEs with sotorasib were diarrhea (11.8%), ALT increase (7.7%), and AST increase (5.3%).

“In CodeBreaK 100 as well as 200, the safety signals are pretty similar,” Johnson said. “There were 10% to 20% of patients who hit grade 3 [liver toxicity] but it was amenable to dose reduction and dose hold followed by restarting.”

Patient-reported outcomes were improved with sotorasib vs docetaxel, including time to deterioration in global health status, physical function, and cancer-related symptoms. For quality of life, global health status ratings were 6.6 with docetaxel vs 9.3 with sotorasib, representing a 31% reduction in the risk of quality-of-life deterioration with the targeted therapy (HR, 0.69; 95% CI, 0.53-0.91; 

 = .005). Sotorasib also delayed physical functioning deterioration by 31% vs docetaxel (9.4 vs 15.1; HR, 0.69; 95% CI, 0.52-0.92; 

 were also delayed significantly with sotorasib vs docetaxel. There was a 37% reduction in the risk of dyspnea (HR, 0.63; 95% CI, 0.48-0.83; 

 <.001) and the risk of cough worsening was delayed by 45% with sotorasib (HR, 0.55; 95% CI, 0.38-0.80;

 <.001). Chest pain deterioration was numerically delayed with sotorasib, with lower scores seen with docetaxel (27.3 vs 34.9); however, this finding was not statistically significant (HR, 0.84; 95% CI, 0.60-1.18; 

“Sotorasib is oral daily vs IV for docetaxel every 3 weeks. You lose your hair with docetaxel. Patients don’t lose their hair with sotorasib, for example,” Johnson said. “There are a lot of subtle ways this data shows how much better quality of life is for patients [with sotorasib vs docetaxel] and the patient-reported outcomes also show that.”

The phase 1/2 CodeBreaK 101 trial (NCT04185883) continues to enroll patients to explore potential sotorasib combination therapies for solid tumors with 

 G12C mutations. There are also several phase 1/2 studies exploring various sotorasib combinations across settings. Additionally, the phase 3 CodeBreaK 300 trial (NCT05198934) is exploring sotorasib with panitumumab (Vectibix) for patients with 

“We look at [CodeBreaK 200] as the first step. There are more studies ongoing adding other drugs to it,” Johnson said. “It is well tolerated, so it will pair nicely with other drugs inhibiting MAP kinase, EGFR, even PD-L1.”

Johnson ML, de Langen AJ, Waterhouse DM, et al. Sotorasib versus docetaxel for previously treated non-small cell lung cancer with KRAS G12C mutation: CodeBreaK 200 phase III study. 

. 2022;33(suppl 7):LBA10. doi:10.1016/j.annonc.2022.08.051

FDA grants accelerated approval to sotorasib for KRAS G12C mutated NSCLC. FDA. May 28, 2021. Accessed September 12, 2022. https://bit.ly/3De4CwM

Articles

Sotorasib doubled the progression-free survival rate in patients with KRAS G12C–mutated non–small cell lung cancer. 

Phase 3 Findings Showcase PFS Benefit with Sotorasib for Patients With KRAS G12C+ NSCLC

Phase 3 findings from the M14TIL trial (NCT02278887) showed a 50% reduction in the risk of progression or death among patients with stage IIIC/IV unresectable, treatment-refractory melanoma who received tumor-infiltrating lymphocyte (TIL) therapy compared with patients who received ipilimumab (Yervoy), according to a presentation at the 

2022 European Society for Medical Oncology Congress.

After a median follow-up of 33.0 months, median progression-free survival (PFS) with the TIL therapy was 7.2 months (95% CI, 4.2-13.1) compared with 3.1 months for ipilimumab (95% CI, 3.0-4.3), which was statistically significant (HR, 0.50; 95% CI, 0.35-0.72; 

 < .001). The 6-month PFS rate was 52.7% with the TIL therapy compared with 21.4% for ipilimumab.

“This is the first multicenter, randomized, controlled trial studying a T-cell therapy in solid cancer, in this case comparing TIL to ipilimumab as more or less a second-line treatment for metastatic melanoma. TIL significantly improved PFS,” lead investigator John Haanen, MD, PhD, Netherlands Cancer Institute in Amsterdam, said in a press conference at the meeting.

In the open-label study, which was initiated in 2014, 168 patients were randomized to receive TILs (n = 84) or ipilimumab (n = 84). Most patients were refractory to a prior anti-PD-1 therapy (86%). Patients were evenly stratified by 

 status, treatment line, and treatment center. LDH was 2 times or below the upper limit of normal, and all patients had a WHO performance status between 0 and 1.

For those in the TIL arm, the adoptive cell therapy was manufactured from a resected lesion of 2 to 3 cm in size. TILs were collected from the resected tissue and then expanded ex vivo using anti-CD3, feeder cells, and interleuken-2 (IL-2) until they reached at least 5 × 109 cells per infusion.

“The patients undergo surgery and the [TILs are grown] in the time needed for patients to recover from that, because we need a metastatic lesion to grow the TIL. If it is a subcutaneous nodule, it is easy, but if it is a lung nodule, it can be a bigger surgery. The time to grow the cells takes 5 to 6 weeks,” he said. “The total period of treatment consists of 8 weeks, more or less.”

Prior to infusion of the autologous T-cell product, patients received lymphodepleting cyclophosphamide for 2 days at 60 mg/kg/day and 5 days of fludarabine at 25 mg/m2/day. High-dose IL-2 (600,000 IU/kg/dose) was administered every 8 hours following infusion with the TILs to support proliferation. Hospitalization was required throughout this process. In the ipilimumab arm, the CTLA-4 inhibitor was administered at 3 mg/kg every 3 weeks for up to 4 doses.

The overall response rate was 48.8% with the TIL therapy (95% CI, 38%-60%) compared with 21.4% for ipilimumab (95% CI, 13%-32%). The complete response rate was 20.2% for patients treated with the TIL therapy (95% CI, 12%-30%) compared with 7.1% for ipilimumab (95% CI, 3%-15%). An additional 19.1% of patients experienced stable disease in the TIL arm compared with 17.9% in the ipilimumab group, bringing the clinical benefit rates to 67.9% and 39.3% in each arm, respectively.

The median OS was 25.8 months with TILs (95% CI, 18.2-not reached) vs 18.9 months with ipilimumab (95% CI, 13.8-32.6); however, these data were not yet statistically significant with follow-up ongoing (HR, 0.83; 95% CI, 0.54-1.27; 

Grade 3 or greater treatment-related adverse events were experienced by all patients in the TIL arm compared with 57% of patients in the ipilimumab group. Most of these events were related to IL-2 and the conditioning regimen, Haanen noted.

“There were no new safety concerns with TIL beyond what is known for this treatment. All of these toxicities are driven by the lymphodepleting regimen and the high-dose IL-2. Most of these side effects were already completely gone by the time the patients were released from the hospital and there were no long-term sequelae in patients treated with TILs,” he said. “There was also better health-related quality of life scores in patients treated with TIL.”

The study was conducted in collaboration with the Ministry of Health, Welfare, and Sport in the Netherlands. With this collaboration, it was agreed that if the study was positive, the treatment would become a standard of care in the Netherlands by January 2023, according to Haanen. Beyond that, EMA and FDA registration would be required, he said, which they are currently considering.

“If it gets EMA approval, the next question is how to roll it out,” he said. “At this point, you could involve pharma to do this or train other centers on the protocol to do point-of-care productions.”

Haanen JBAG, Rohaan M, Borch TH, et al. Treatment with tumor-infiltrating lymphocytes (TIL) versus ipilimumab for advanced melanoma: Results from a multicenter, randomized phase III trial. 

. 2022;33(suppl 7):LBA3. doi:10.1016/j.annonc.2022.08.036

At a median follow-up of 33.0 months, the median progression-free survival with tumor-infiltrating lymphocyte therapy was 7.2 months vs 3.1 months with ipilimumab. 

TIL Therapy Outperforms Ipilimumab in Extending Progression-Free Survival in Unresectable Melanoma

Patients with resectable stage IIIB to IVM1a melanoma may derive a clinical benefit from treatment with neoadjuvant talimogene laherparepvec (T-VEC; Imlygic), according to findings from a 5-year follow-up of a phase 2 trial (NCT02211131). The results, which were presented at the 

2022 European Society of Medical Oncology Congress

, indicate that the addition of neoadjuvant T-VEC may make surgery more effective for this patient population.

At the final 5-year analysis of the open-label study, the 5-year relapse-free survival (RFS) rate was 22.3% with the oncolytic virus T-VEC prior to surgery, compared with 15.2% for surgery alone (HR, 0.76; 80% CI, 0.60-0.97). At 5 years, 77.3% of patients treated with T-VEC prior to surgery were alive compared with 62.7% with surgery alone (HR, 0.54; 80% CI, 0.36-0.81). The event-free survival (EFS) rate at 5 years was 43.7% with T-VEC vs 62.7% with surgery alone (HR, 0.57; 80% CI, 0.43-0.76).

“The primary end point was relapse-free survival, and this was not the conventional relapse-free survival. It does not only count all the local, regional, and distant recurrences, [but] it also counts all the patients who withdrew to go to surgery and all the R1 and R2 resections,” lead investigator Reinhard Dummer, MD, University Hospital Zurich, Switzerland, said during a presentation of the results. “If the surgeon failed to completely resect the melanoma lesion, this is already counted as a relapse event.”

T-VEC is administered as a local injection directly to the tumor site. The therapy consists of herpes simplex 1 virus that has been genetically modified to secrete the cytokine GM-CSF, which causes cell lysis. Additionally, the lysis results in the release of tumor-derived antigens resulting in activation of an immune response. “There is both activation of T cells and natural killer cells with T-VEC,” Dummer said.

In the study, patients were randomized to surgery (n = 75) or 6 doses of intralesional T-VEC followed by surgery. Surgery was completed over a span of 6 weeks. T-VEC was administered as ≤4 ml x 106 plaque-forming units (PCU)/ml at week 1. After 3 weeks, it was administered at ≤4 ml x 108 PCU/ml over 2 weeks. Surgical resection in the T-VEC arm was completed from week 13 to week 18.

The baseline characteristics were balanced between arms for T-VEC plus surgery and surgery alone. In the T-VEC arm, the median age was 63.5 years and nearly two-thirds were male (64.5%). The most common ECOG score was 0 (88.2%) and the disease stages were well balanced, with the most common stage being IIIC. Most patients had received a prior surgery for melanoma (93.4%) and a minority had received radiotherapy (5.3%).

There were more patients enrolled in this study with in-transit melanoma than other neoadjuvant studies, Dummer said. There were 21.1% of patients in the combination arm with in-transit disease and 23% in the surgery arm. Additionally, there were patients with nodal involvement and in-transit disease (22.4% vs 23%, respectively).

“One patient that I treated had extensive in-transit disease with multiple lesions, and there was a pronounced response in all of them and by histology this patient shows a complete remission,” said Dummer.

Following surgery, adjuvant therapy was determined by investigator's choice. In the T-VEC arm, 13.7% of patients received adjuvant therapy (n = 10), which most often consisted of immunotherapy (n = 8). More patients received adjuvant therapy in the surgery alone group (31.9%; n = 22), with immunotherapy being the top choice half of the time (n = 11). Approximately half of patients in the T-VEC arm received a subsequent therapy in any setting (54.8%) compared with over three-fourths in the surgery group (78.3%).

“In this final readout of the largest randomized neoadjuvant trial for an oncolytic virus in advanced melanoma, we report durable improvements in RFS, EFS, and overall survival at 5 years with neoadjuvant T-VEC plus surgery vs standard surgery,” said Dummer. “These results suggest that an intratumorally-administered oncolytic agent can elicit a meaningful long-term systemic effect and support neoadjuvant T-VEC plus surgery in advanced resectable melanoma.”

Caroline Robert, MD, PhD, head of the Dermatology Unit at Gustave Roussy, discussed the findings during the session at the ESMO meeting. She noted the results of the study favored T-VEC and that the low toxicity profile associated with the oncolytic virus gave it an advantage against more active but also more toxic regimens, like nivolumab (Opdivo) plus ipilimumab (Yervoy). However, she questioned the statistical plan used for the trial.

“There was potential bias in the randomization, a gap between the 2 arms in treatment timing, and an absence of visibility of the timing of events, especially in the combination arm,” she said. “The relaxed alpha error of 80% confidence interval means there's a 20% risk to conclude that the result is positive, whereas it is not, with the upper end of the confidence interval close to 1. Results may not have been significant if a more standard 95% CI had been chosen.”

Additional studies continue to assess T-VEC in the neoadjuvant setting for patients with melanoma, either as a single agent or in combination with other therapies. A study in the Netherlands is looking at T-VEC with nivolumab (NCT04330430) and another conducted at the University of California, Davis, is assessing it as a single agent (NCT04427306). Both studies are in phase 2 and currently recruiting participants.

Dummer R, Gyorki D, Hyngstrom J, et al. Final 5-year results of the phase II, multicenter, randomized, open-label trial of talimogene laherparepvec (T-VEC) neoadjuvant treatment (Tx) plus surgery vs immediate surgery in patients (pts) with resectable stage IIIB-IVM1a melanoma (MEL). 

. 2022;33(suppl 7).DOI:10.1016/j.annonc.2022.08.037.

The relapse-free survival rate was 22.3% among patients with resectable stage IIIB to IV M1a melanoma who received neoadjuvant talimogene laherparepvec versus 15.2% among those who received surgery alone.

5-Year Follow-Up Shows Neoadjuvant T-VEC Benefit in Patients with Resectable Melanoma

Data from the DESTINY-Breast04 (NCT03734029) showed that among patients with HER2-low, hormone receptor–positive metastatic breast cancer (MBC), treatment with the antibody-drug conjugate fam-trastuzumab deruxtecan-nxki (Enhertu) elicited a significant improvement in progression-free survival (PFS). Additionally, the agent improved overall survival and had a manageable safety profile according to presented at the 

In those with hormone receptor–positive, HER2-low MBC, which was the population explored for the primary end point of the study, trastuzumab deruxtecan elicited a median PFS of 10.1 months (95% CI, 9.5-11.5) compared with 5.4 months (95% CI, 4.4-7.1) for chemotherapy (HR, 0.51; 95% CI, 0.40-0.64; 

 < .0001). The median overall survival (OS) was 23.9 months (95% CI, 20.8-24.8) with trastuzumab deruxtecan compared with 17.5 months (95% CI, 15.2-22.4) for chemotherapy (HR, 0.64; 95% CI, 0.40-0.86; 

 = .003). Fewer grade 3 or greater adverse events (AEs) were reported with the antibody-drug conjugate trastuzumab deruxtecan compared with chemotherapy 52.6% and 67.4% of patients, respectively.

“Trastuzumab deruxtecan is the first HER2-targeted therapy to demonstrate statistically significant and clinically meaningful improvement in PFS and OS compared [with] standard chemotherapy for patients with HER2-low metastatic breast cancer,” said lead author Shanu Modi, MD, who is a medical oncologist at Memorial Sloan Kettering Cancer Center. “The benefits of trastuzumab deruxtecan were seen across subgroups, including the hormone receptor–positive and –negative patients and [immunohistochemistry] IHC 1+ and 2+ breast cancers.”

In the DESTINY-Breast04 study, 557 patients were randomly assigned 2:1 to receive trastuzumab deruxtecan at 5.4 mg/kg every 3 weeks (n = 373) or physician’s choice of chemotherapy at locally approved dosing (n = 184). Chemotherapy consisted of capecitabine (Xeloda; 20.1%), eribulin (Halaven; 51.1%), gemcitabine (10.3%), paclitaxel (8.2%), or nab-paclitaxel (Abraxane; 10.3%).

Low expression of HER2 was defined as an IHC score of 1+ or 2+ with a negative in situ hybridization (ISH) test, which represents approximately 65% of breast cancer diagnoses, Modi noted. Overall, 88.7% of patients were hormone receptor–positive and 11.3% were negative.

“Our currently available HER2-targeted therapies have not been effective for patients in this subgroup. We currently treat [patients with] HER2-low breast cancer as HER2-negative breast cancer, where therapy is really guided by hormone receptor status,” Modi said. “Ultimately, once we’ve exhausted endocrine therapy and a few lines of targeted agents, we have limited late-line options available for these patients, most commonly offering palliative single-agent chemotherapy, which has modest activity. We have a big unmet need for more effective therapies.”

Patient characteristics were balanced between each arm and representative of the overall population of patients with HER2-negative breast cancer. In the trastuzumab deruxtecan arm, the median age of patients was 57.5 years (range, 31.5-80.2) and 99.5% were female. HER2-low was IHC 1+ for 57.6% of patients and IHC 2+ and ISH-negative for 42.4%. ECOG performance status was split between 0 (53.6%) and 1 (46.4%). The primary locations of metastases were the brain (6.4%), liver (71.3%), and lung (35.6%). Patients had received a median of 3 (range, 1-9) prior lines of therapy, which consisted of targeted or immunotherapy (74.8%), endocrine therapy (93.0%), and chemotherapy (100%).

Across all patients enrolled in the study, the median PFS was 9.9 months (95% CI, 9.0-11.3) with trastuzumab deruxtecan compared with 5.1 months (95% CI, 4.2-6.8) with chemotherapy (HR, 0.50; 95% CI, 0.40-0.63). The median OS in this group was 23.4 months (95% CI, 20.0-24.8) with trastuzumab deruxtecan compared with 16.8 months (95% CI, 14.5-20.0) for chemotherapy, representing a 6.6-month improvement in survival with the agent (HR, 0.64; 95% CI, 0.49-0.84; 

In those with hormone receptor–negative disease, the median PFS was 8.5 months (95% CI, 4.3-11.7) with trastuzumab deruxtecan and 2.9 months (95% CI, 1.4-5.1) for chemotherapy (HR, 0.46; 95% CI, 0.24-0.89). The median OS in the hormone receptor–negative cohort was 18.2 months (95% CI, 13.2-not estimable) with trastuzumab deruxtecan vs 8.3 months (95% CI, 5.6-20.6) with chemotherapy (HR, 0.48; 95% CI, 0.24-0.95).

Across all patients, the overall response rate (ORR) was 52.3% (95% CI, 47.1%-57.4%) with trastuzumab deruxtecan (n = 331) compared with 16.3% (95% CI, 11.3%-22.5%) with chemotherapy (n = 163). In the hormone receptor–negative arm, the ORRs were 50.0% (95% CI, 33.8%-66.2%) and 16.7% (95% CI, 3.6%-41.4%) for trastuzumab deruxtecan (n = 40) and chemotherapy (n = 18), respectively.

In those with hormone receptor–positive disease, the ORR was 52.6% (95% CI, 47.0%-58.0%) for trastuzumab deruxtecan vs 16.3% (95% CI, 11.0%-22.8%) for chemotherapy. In this group, the median duration of response was 10.7 months with trastuzumab deruxtecan compared with 6.8 months for physician's choice.

Trastuzumab deruxtecan demonstrated a consistent improvement in PFS across subgroups. For patients with hormone receptor–positive disease, those with a HER2 IHC score of 1+ had a median PFS of 10.3 months (95% CI, 8.6-12.3) with trastuzumab deruxtecan compared with 5.3 months (95% CI, 4.1-7.8) with chemotherapy (HR, 0.48; 95% CI, 0.35-0.65). Among individuals with hormone receptor–positive HER2 IHC 2+ and ISH-negative disease, the median PFS was 10.1 months (95% CI, 8.2-12.2) for trastuzumab deruxtecan and 5.9 months (95% CI, 4.3-7.9) for chemotherapy (HR, 0.55; 95% CI, 0.38-0.80).

In patients with hormone receptor–positive disease who received prior treatment with a CDK4/6 inhibitor, the median PFS was 10.0 months (95% CI, 8.3-11.4) with trastuzumab deruxtecan compared with 5.4 months (95% CI, 4.0-7.8) for chemotherapy (HR, 0.55; 95% CI, 0.42-0.73). For those with hormone receptor–positive disease who did not receive a CDK4/6 inhibitor, the median PFS was 11.7 months (95% CI, 9.5-17.7) with trastuzumab deruxtecan compared with 5.9 months (95% CI, 4.3-8.2) for chemotherapy (HR, 0.42; 95% CI, 0.28-0.64).

“Overall, these results establish HER2-low metastatic breast cancer as a targetable population with trastuzumab deruxtecan as a new standard of care in this setting,” Modi said.

At the time of the cutoff, the median treatment duration was 8.2 months for trastuzumab deruxtecan and 3.5 months for chemotherapy. Adverse events led to treatment discontinuation for 16.2% of patients in the trastuzumab deruxtecan arm compared with 8.1% for chemotherapy. Dose reductions were required due to an AE for 22.6% of patients in the trastuzumab deruxtecan group vs 38.4% for chemotherapy.

Treatment-emergent adverse events (TEAE) were experienced by 99.5% of those in the trastuzumab deruxtecan arm compared with 98.3% of those treated with physician’s choice of therapy. Exposure adjusted AE rates were 1.30 per patient year for trastuzumab deruxtecan and 2.66 for physician’s choice of chemotherapy. Serious AEs occurred in 27.8% of patients treated with trastuzumab deruxtecan and for 25.0% with physician’s choice.

The most frequently observed treatment-related AEs for trastuzumab deruxtecan and chemotherapy, respectively, were nausea (73% vs 23.8%), fatigue (47.7% vs 42.4%), skin and subcutaneous tissue disorders, including alopecia (37.7% vs 32.6%), vomiting (34% vs 9.9%), neutropenia (33.2% vs 51.2%), and anemia (33.2% vs 22.7%).

There were 14 drug-related deaths with trastuzumab deruxtecan (3.8%) compared with 5 for physician’s choice of therapy (2.9%). Adjudicated interstitial lung disease (ILD)/pneumonitis occurred in 45 patients treated with trastuzumab deruxtecan (12.1%), with 5 patients having a grade 3 event and 3 having a grade 5 event.

“The drug has been in use now for a couple years and I think we have all gotten a little more comfortable, first responding to pulmonary symptoms more quickly and also how to manage it,” said Julie R. Gralow, MD, FACP, FASCO, chief medical officer and executive vice president of ASCO, and previously director of Breast Medical Oncology at the Seattle Cancer Care Alliance. “I think it was much more of a concern a couple of years ago and now we have learned how to be more aware and to act quickly.”

In December 2019, the FDA granted an accelerated approval to trastuzumab deruxtecan for adult patients with unresectable or metastatic HER2-positive breast cancer who have received 2 or more prior anti–HER2-based regimens in the metastatic setting. This accelerated approval was transitioned to a full regulatory approval on May 4, 2022. The prescribing information includes a box warning on the risk of ILD.

The efficacy of trastuzumab deruxtecan in HER2-low could be derived from the unique 8:1 ratio of antibody (trastuzumab) to toxic payload, which consists of a topoisomerase I inhibitor. “This is a new generation antibody-drug conjugate, and that is because it has some advanced pharmaceutical properties compared [with] other HER2 therapies,” Modi said. “The most unique thing is the high payload linked to each antibody. It is twice as much as T-DM1 [ado-trastuzumab emtansine; Kadcyla]. The payload itself is unique and novel, it is a topoisomerase I inhibitor, which is not a type of chemotherapy we usually use in breast cancer.”

“The linker technology is also very different from T-DM1, it is a cleavable linker,” she added. “When the linker is cleaved it releases the chemotherapy payload in a way that the chemotherapy retains memory permeability and now it can pass through the HER2-positive cell and into the microenvironment and has the ability to penetrate other cells in the neighboring area that may not express HER2. It offers a broader range of activity in heterogenous situations, and we know HER2 expression [in breast cancer] is very heterogenous. I think that is why, for the first time, we’re seeing activity for a HER-targeted agent.”

Several clinical trials are exploring trastuzumab deruxtecan for patients with breast cancer and other malignancies. The DESTINY-Breast05 study (NCT04622319) is comparing the agent with T-DM1 for those with residual invasive breast cancer following neoadjuvant therapy. Additionally, arm 6 of the BEGONIA study (NCT03742102) is exploring the treatment for patients with triple-negative breast cancer in combination with the PD-L1 inhibitor durvalumab (Imfinzi).

Modi S, Jacot W, Yamashita T, et al. Trastuzumab deruxtecan (T-DXd) versus treatment of physician’s choice (TPC) in patients (pts) with HER2-low unresectable and/or metastatic breast cancer (mBC): results of DESTINY-Breast04, a randomized, phase 3 study. 

. 2022;40 (suppl 17):abstr LBA3. doi:10.1200/JCO.2022.40.17_suppl.LBA3

Modi S, Jacot W, Yamashita T, et al. Trastuzumab deruxtecan in previously treated HER2-low advanced breast cancer. 

. Published online June 5, 2022. doi:10.1056/NEJMoa2203690

Findings from DESTINY-Breast04 (NCT03734029) support the use of trastuzumab deruxtecan in patients with hormone receptor–positive, HER2-low metastatic breast cancer.

Trastuzumab Deruxtecan Is Effective Option for HER2-Low MBC

Fam-trastuzumab deruxtecan-nxki (Enhertu) continued to show a tolerable safety profile compared with ado-trastuzumab emtansine (T-DM1; Kadcyla) among patients with HER-positive metastatic breast cancer according to updated safety findings from the DESTINY-Breast03 trial (NCT03529110) presented at the 

No new safety signals were observed with trastuzumab deruxtecan for patients with HER2-positive unresectable or metastatic breast cancer, reinforcing the established risk-benefit profile of the agent.

“Most treatment-emergent adverse events [TEAEs] were grade 1 or 2, and exposure-adjusted incidence rates of grade 3 or greater, TEAEs, and serious TEAEs were lower with trastuzumab deruxtecan than T-DM1,” lead investigator Erika P. Hamilton, MD, from the Sarah Cannon Research Institute/Tennessee Oncology, said during a presentation of the safety results. “The risk of nausea, vomiting, fatigue, and alopecia was higher for trastuzumab deruxtecan and occurred in initial treatment cycles.”

At the time of the safety analysis, the median treatment duration was 16.1 months for trastuzumab deruxtecan vs 6.9 months for ado-trastuzumab emtansine, 54.9% of patients had discontinued trastuzumab deruxtecan (n = 257) and 85.1% had discontinued T-DM1 (n = 261). Any-grade TEAEs were experienced by 99.6% of those in the trastuzumab deruxtecan arm and by 95.4% treated with T-DM1, with grade 3 or greater TEAEs experienced by 53.3% and 49.8% for each treatment, respectively.

The label for trastuzumab deruxtecan was updated by the FDA in May 2022, based on superiority for the agent compared with ado-trastuzumab emtansine (T-DM1; Kadcyla) in the DESTINY-Breast03 study.

 In the primary analysis, the median progression-free survival (PFS) was not yet reached with trastuzumab deruxtecan compared with 6.8 months for T-DM1, which equated to a 72% reduction in the risk of progression or death with the novel antibody-drug conjugate (HR, 0.28; 95% CI, 0.22-0.37; 

 <.0001). The 12-month PFS rate was 75.8% with trastuzumab deruxtecan vs 34.1% with T-DM1.

In the DESTINY-Breast03 study, patients were randomized 1:1 to receive either trastuzumab deruxtecan or T-DM1. Efficacy data from the study was from a primary data cutoff of May 21, 2021, while the updated safety findings were from a cutoff of September 7, 2021. Findings from the initial analysis were published in the 

Patient characteristics were balanced between arms in the study. In the trastuzumab deruxtecan arm, the median age of patients was 54.3 years and the majority were Asian (58.2%). HER2 status was most commonly 3+ (89.7%) and the ECOG performance status was split between 0 (59%) and 1 (40.6%). The hormone receptor status was evenly positive (50.2%) and negative (49.8%) amongst patients in the trial. A quarter of patients (23.8%) had stable brain metastases and more than two-thirds had visceral disease (70.5%). The median number of prior lines of therapy was 1 (range, 0-16) for trastuzumab deruxtecan and 2 (range, 0-14) for T-DM1.

Additional data from the safety update showed that serious TEAEs of any grade were experienced by 21% of patients treated with trastuzumab deruxtecan and for 19.2% of those receiving T-DM1, with grade 3 or greater serious TEAEs seen in 15.2% and 14.6% of patients for each treatment, respectively.

TEAEs associated with drug discontinuation were experienced by 14.8% of those treated with trastuzumab deruxtecan and for 7.3% of those in the T-DM1arm. TEAEs led to a dose reduction for 23.0% and 13.8% of patients in the trastuzumab deruxtecan and the T-DM1arms, respectively.

“Rates of TEAEs both any grade, grade 3 or higher, or serious TEAEs were similar between arms,” said Hamilton. “The most common TEAE associated with drug discontinuation for trastuzumab deruxtecan was interstitial lung disease [ILD]/pneumonitis in approximately 8% of patients, and the most common TEAE associated with discontinuation for T-DM1 was thrombocytopenia."

The safety update analyzed exposure-adjusted incidence rates (EAIRs) for TEAEs. The treatment duration in each arm equated to 327.2 patient-years of exposure for trastuzumab deruxtecan and 186.3 patient-years of exposure for T-DM1. The EAIRs for trastuzumab deruxtecan and T-DM1 arms, respectively, were 0.42 and 0.70 for grade 3 or greater TEAEs, 0.17 and 0.27 for serious TEAEs of any grade, 0.12 and 0.20 for grade 3 or more serious TEAEs, 0.12 and 0.10 for TEAEs associated with drug discontinuation, and 0.18 and 0.19 for TEAEs associated with dose reduction.

“EAIRs are a commonly used measure to express risk in patients for studies with long-term follow-up where treatment duration between arms may differ,” said Hamilton. “EAIRs per patient-year were lower in the trastuzumab deruxtecan arm than the T-DM1 arm, except for TEAEs associated with drug discontinuation, which were primarily driven by the ILD and pneumonitis in the trastuzumab deruxtecan arm.”

The most common drug-related TEAEs of any grade for trastuzumab deruxtecan and T-DM1, respectively, were nausea (73.5% vs 27.6%), fatigue (45.9% vs 29.1%), vomiting (44.4% vs 5.7%), neutropenia (43.2% vs 11.5%), alopecia (37.7% vs 2.7%), anemia (31.9% vs 14.2%), leukopenia (30.7% vs 8.0%), decreased appetite (26.5% vs 13.0%), thrombocytopenia (25.3% vs 52.5%), diarrhea (23.7% vs 4.2%), and constipation (23.3% vs 9.6%). The most common grade 3 or greater drug-related TEAEs were neutropenia (19.8% vs 3.1%), thrombocytopenia (7.4% vs 24.9%), leukopenia (6.6% vs 0.8%), nausea (6.6% vs 0.4%), anemia (6.2% vs 4.2%), and fatigue (6.2% vs 0.8%).

The median time to a TEAE that was associated with treatment discontinuation was 224 days with trastuzumab deruxtecan compared with 147 days for T-DM1. The median time for a TEAE associated with first dose reduction was 96 days with trastuzumab deruxtecan vs 19 days with T-DM1. First event remained consistently later with trastuzumab deruxtecan vs T-DM1, except for fatigue (22 vs 24 days, respectively), leukopenia (74.5 vs 92.0 days), neutropenia (64.0 vs 105.0 days), nausea (2.0 vs 3.0 days), and alopecia (27.0 vs 43.0 days).

The risk of nausea, vomiting, and alopecia was significantly higher with trastuzumab deruxtecan compared with T-DM1 while the risk of fatigue was found to be similar between groups. The prevalence of fatigue and alopecia remained consistent in the study. Nausea and vomiting prevalence were both consistently higher with trastuzumab deruxtecan throughout the DESTINY-Breast03 study and were consistent over time. Most of the nausea and vomiting events were grade 1 or 2 in severity and resolved. One patient discontinued due to vomiting.

“At the time of DESTINY-Breast03 opening enrollment, there was no mandatory prophylaxis for nausea or vomiting on the study,” Hamilton said. “Anti-emetic prophylaxis recommendations were updated during the study, based on emerging data supporting the moderately emetogenic potential of trastuzumab deruxtecan. This is also now included in the drug's label.”

Adjudicated drug-related ILD or pneumonitis of any grade occurred in 10.9% and 1.9% of those treated with trastuzumab deruxtecan or T-DM1, respectively. These were primary low grade and there were no cases of grade 4 or 5 ILD/pneumonitis. The time to onset of ILD/pneumonitis was 181 days with trastuzumab deruxtecan and T-DM1. There was 1 fatal case of ILD/pneumonitis in the T-DM1arm and none with trastuzumab deruxtecan. There were 8 cases of unresolved ILD/pneumonitis in the trastuzumab deruxtecan arm and none with T-DM1. The remaining cases were recovering/resolving, resolved/recovered, or resolved/recovered with sequelae.

“There were no new grade 3 events observed in the safety update, with the rate remaining low at 0.8%. The only new case of adjudicated drug-related ILD/pneumonitis was 1 event that was grade 2 in the trastuzumab deruxtecan arm,” said Hamilton. “The majority of these cases resolved with ongoing follow-up.”

Hamilton EP, Bragaia VPH, Yeo W, et al. Trastuzumab deruxtecan (T-DXd) versus trastuzumab emtansine (T-DM1) in patients (pts) with HER2-positive (HER2+) unresectable and/or metastatic breast cancer (mBC): safety follow-up of the randomized, phase 3 study DESTINY-Breast03. 

. 2022;40(suppl 16):1000. doi:10.1200/JCO.2022.40.16_suppl.1000

FDA grants regular approval to fam-trastuzumab deruxtecan-nxki for breast cancer. FDA. May 4, 2022. Accessed June 4, 2022. https://bit.ly/3ybhZLL

Cortés J, Kim S-B, Chung W-P, et al. Trastuzumab deruxtecan versus trastuzumab emtansine for breast cancer. 

. 2022;386(12):1143-1154. doi:10.1056/NEJMoa211502

Updated safety findings from DESTINY-Breast03 showed that treatment with trastuzumab deruxtecan was safe and tolerable for patients with HER2-positive metastatic breast cancer.

Trastuzumab Deruxtecan Demonstrates Favorable Safety Profile in HER+ Metastatic Breast Cancer

Real-world findings revealed that eribulin (Halaven) yielded promising 2-year overall survival (OS) rates among pretreated patients with metastatic breast cancer (MBC). The findings, which were presented as a poster at the 

 Miami Breast Cancer Conference®, showed that patients who had already received either atezolizumab (Tecentriq) or sacituzumab govitecan- hziy (Trodelvy), experienced a 2-year OS rate of 53.6% (95% CI, 35.1%-68.9%).

“The treatment landscape for MBC has been rapidly evolving over the [past] few years with FDA approvals of multiple new therapies, including, for example, several immune checkpoint inhibitors and antibody-drug conjugates,” senior author Peter A. Kaufman, MD, said. “Eribulin is a unique chemotherapeutic agent [that is] FDA approved and widely used in the treatment of MBC in both the USA and worldwide. There has previously been very little data on the efficacy of eribulin in patients with MBC who have been previously treated with either of these classes of medications.” Kaufman is a professor of medicine in the Division of Hematology/Oncology at Larner College of Medicine at the University of Vermont in Burlington.

The retrospective, noninterventional study included de-identified electronic health record data for 91 patients with MBC, which predominantly was triple-negative breast cancer (TNBC; 74.7%). After a median follow-up of 11.7 months from time of eribulin initiation, 63.7% of patients were alive and the median OS was not reached. The estimated 1-year OS rate was 77.8% (95% CI, 67.3%-85.3%). The estimated 1-year progression-free survival (PFS) rate was 62%; the 2-year PFS rate from the time of eribulin initiation was 41.9%.

“This type of study design certainly has a number of limitations, that I think are generally acknowledged and understood. Additionally, we are reporting on a relatively modest sample size, with 91 patients in total,” Kaufman said. “[Although] this is a real-world analysis with data obtained from a medical chart review—with the limitations of these types of studies and the other limitations of this study design—we find these results to be quite intriguing and warrant further study.”

Patients selected for the analysis were treated between March 1, 2019, and September 30, 2020. The analysis included 53 patients treated with prior atezolizumab (Tecentriq) and 38 who had received sacituzumab govitecan-hziy (Trodelvy). Patients were enrolled across various geographic regions of the United States, with the majority being in the South (34.1%) and the Northeast (28.6%). Those who received eribulin as part of a clinical trial or who developed a second malignant neoplasm were excluded from the study.

The median age of patients was 63 years. The next most common status after TNBC was HER2-negative and hormone receptor–positive, which comprised 13.2% of patients. Most patients did not have visceral disease (84.6%) and the majority were ECOG performance status 0 (15.3%) or 1 (68.2%).

In 75.8% of cases, eribulin was administered as a second-line therapy. The agent was administered in the third line for 13.2% of patients and fourth line in 11.0% of individuals. At the time of the analysis, 36.3% of patients continued to received treatment with eribulin. For those who remained on treatment, the median treatment duration was 12.2 months. Patients who discontinued eribulin stopped therapy after a median treatment duration of 5.1 months.

“As we noted in our poster, approximately 75% of these patients had TNBC,” Kaufman said. “Interestingly as well, what was reported in this medical chart review was that [approximately] 75% of these patients overall were receiving eribulin in the second-line setting, and approximately 25% were receiving eribulin in the third-line or later setting, which we found somewhat surprising. Nonetheless, we believe our findings to be quite intriguing.”

There were 7.7% of patients with unknown status at the last follow-up (n = 7), which may have been a result of patients transferring care to another provider or center, the authors noted. Moreover, the data represent just the patterns of those willing to participate and may not be broadly applicable, they said.

“Importantly, it should be noted this study is a medical chart review, and not a prospective clinical trial,” Kaufman said. “It is a real-world analysis of patients who received treatment with eribulin in routine clinical practice in a mixture of practice settings, specifically after previously receiving therapy with either atezolizumab or sacituzumab.”

Goyal RK, Zhang J, Dhuliawala S, Sluga-O'Callaghan M, Kaufman PA. Real-world treatment patterns and clinical outcomes in patients treated with eribulin after prior immunotherapy (IO) or antibody-drug conjugate (ADC) for metastatic breast cancer. Poster presented at: 

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

Real-world findings presented at the 39th Annual Miami Breast Cancer Conference showed that eribulin may be an effective agent for previously treated patients with metastatic breast cancer.

Eribulin Elicits Promising 2-Year Overall Survival in Pretreated Metastatic Breast Cancer

The novel coronavirus (COVID-19) spreading across the world represents a distinct challenge for all physicians, especially oncologists who commonly treat patients who have compromised immune systems. The spread of the virus was discussed by Scott Gottlieb, MD, during the keynote address at the 

At this point, the number of new confirmed cases of coronavirus infection seems to change every day, with more than 100,000 infections reported worldwide. When looking at epidemiology data, Gottlieb noted a distinct spike in reported respiratory illnesses across the United States. He partially credited this to additional hospital visits due to worry over the virus. However, given a lack of widespread testing, he added that it could also be from wider spread of the virus than estimated.

“I think we’re facing some difficult months ahead of this,” said Gottlieb. “Seeing what’s happening in some of the cities, there’s some speculation on just how bad this disease is. I think most of the modeling we’ve seen coming out, looking at South Korea, Italy, and certain parts of China, suggests the mortality rate will be about 1%, which is significantly more than the seasonal flu, which is about 0.1%.”

Gottlieb noted that each country seems to be handling the coronavirus outbreak differently. In China, he said there has been some success in containing the virus, but at significant social and human costs. On the opposite end of the spectrum, however, there seems to be very little effort on the part of Iran to slow the virus, allowing it to “burn through their population,” he said.

“We’re going to have to figure out what our American approach is to this and how we’re going to take more aggressive mitigation steps. We’re losing a pretty narrow window to step in,” Gottlieb said. “We really haven’t stepped in with the kind of mitigation step and social distancing in these hot spots that you’d want to see to break the chain of transmission. I think this week is going to be critical.”

Effective and widespread testing has represented another challenge facing the prevention of coronavirus spread. The initial step in the process, which was creation of a diagnostic by the Centers for Disease Control and Prevention (CDC), went as planned, he said; however, there was a shipment delay for reagents to public health labs, slowing down use of this test. Additionally, there was inadequate communication between the CDC and other testing organizations, such as LabCorp and Quest Diagnostics.

“In an ideal world, we would be doing what the Netherlands is doing. They’re testing their indeterminate cases of the flu. If someone shows up with the flu, gets swabbed, and shows up negative for the flu but still has a significant respiratory disease they’ll then get tested for the coronavirus,” said Gottlieb. “We announced that we’re going to start doing that in 5 cities, but that’s a small number.”

Each day, testing strategies continue to evolve and change, in response to the spread of the disease, with wider adoption of this testing strategy possible in the coming week. Additionally, several companies are now working to find treatments for the virus, including Gilead Sciences and Moderna.

Shifting topics in his keynote address, Gottlieb noted that innovation has been a mainstay in oncology for the past 2 decades, as new treatments have dramatically improved the long-term outcomes across several types of cancer. Innovation at the FDA has largely been driven by strategic changes made to endpoints, to allow for faster approval via surrogates. Looking solely for an improvement in overall survival has become steadily more difficult to achieve, he said, as treatments become more effective.

“The time required, and the large number of patients required, in the trial to demonstrate improvement or superiority over an otherwise effective regimen and in order to power that study it wouldn’t be practical, you couldn’t enroll it,” said Gottlieb. “We would potentially be denying effective drugs to patients who face life-threatening disease.”

Most of these changes were facilitated by a greater understanding of the biology that drives cancer, with a milestone approval seen with imatinib (Gleevec), which was the first targeted therapy approved by the agency. Other recent examples of innovation include immune checkpoint inhibitors and tumor agnostic approvals, he said.

Tissue-agnostic approvals were brought about following changes to the clinical trial designs, which was another key change at the FDA to foster greater innovation. FDA granted its first tissue-agnostic approval in 2017 for the PD-1 inhibitor pembrolizumab (Keytruda) for patients with unresectable or metastatic, microsatellite instability-high or mismatch repair deficient tumor tumors. This was followed by approvals for larotrectinib (Vitrakvi) and entrectinib (Rozlytrek) for patients with solid tumors harboring an NTRK fusion.

“We moved toward tissue-agnostic drug approvals, where you get the approval based on a molecular subtype rather than phenotype,” Gottlieb said. “You might be able to study multiple tumor types within one trial. The opportunity is forcing the agency to continue to evolve. It really was a palpable sense of real opportunity about what was happening.”

Hematology/Oncology (Cancer) Approvals & Safety Notifications. FDA Website. bit.ly/2EP6v4b. Accessed March 7, 2020.

This article was originally published on OncLive as, "

Gottlieb Addresses Coronavirus, Innovation in Keynote Address.

At this point, the number of new confirmed cases of coronavirus infection seems to change every day, with more than 100,000 infections reported worldwide.

Expert Addresses Coronavirus and Cancer Innovation

Frontline maintenance therapy with the combination of olaparib (Lynparza) and bevacizumab (Avastin) improved median progression-free survival (PFS) by 5.5 months compared with bevacizumab and placebo for patients with newly diagnosed, advanced ovarian cancer following prior treatment with a platinum-based chemotherapy plus bevacizumab, according findings from the phase III PAOLA-1 trial presented at the ESMO Congress 2019.

The median PFS in the olaparib arm was 22.1 months compared with 16.6 months in the placebo arm, representing a 41% reduction in the risk of progression or death with the addition of the PARP inhibitor (HR, 0.59; 95% CI, 0.49-0.72; 

 <.0001). This benefit was observed across all patient subsets but was more pronounced for those with tumors testing positive for 

m) and for those with a homologous recombination deficiency (HRD) score of ≥42 by the myChoice HRD Plus assay (HRD-positive).

“PAOLA-1 met its primary objective, demonstrating a statistically significant improvement in PFS in the intent-to-treat population when olaparib, compared with placebo, was added to first-line standard-of-care bevacizumab maintenance treatment,” said study author Isabelle Ray-Coquard, MD, PhD, from the Centre Leon Bérard, Université Claude Bernard, in Lyon, France. “This was the first randomized trial to explore the efficacy and the safety of the combination of olaparib and bevacizumab in patients with newly diagnosed ovarian cancer.”

The PAOLA-1 trial randomized patients to receive bevacizumab at 15 mg/kg every 3 weeks on day 1 with olaparib tablets at 300 mg twice daily (n = 537) or matched placebo (n = 269). All patients had newly diagnosed FIGO stage III or IV high-grade serous or endometroid ovarian, fallopian tube, or primary peritoneal cancer. Patients were enrolled regardless of the type or extent of surgery (upfront or interval). All patients had received prior platinum-based chemotherapy and bevacizumab for ≥3 cycles and had no evidence of disease, a complete response, or a partial response upon enrollment.

There was a median of 6 weeks from the last cycle of chemotherapy to randomization in the study, Ray-Coquard noted. “It is an important point to consider when comparing the results to other data,” she said. The median time from first cycle of chemotherapy to randomization was 7 months.

“Patient selection was not restricted by surgical outcome or 

 mutation status, so participants represent the general population of women with advanced ovarian cancer,” Ray-Coquard said. “Previous studies of relapse have suggested benefits from combining anti-angiogenic agents and PARP inhibitors and today’s results appear to support this. In addition, olaparib did not increase side effects compared to placebo.”

m subgroup, the median PFS was 37.2 months with olaparib and bevacizumab compared with 21.7 months for placebo and bevacizumab (HR, 0.31; 95% CI, 0.20-0.47). The 24-month PFS rate was 76% in the olaparib group versus 39% for placebo. In the HRD-positive group, which included those with t

m, the median PFS was 37.2 months compared with 17.7 months (HR, 0.33; 95% CI, 0.25-0.45). In HRD-positive patients who did not have a 

 mutation, the median PFS was 28.1 months with olaparib and 16.6 months with placebo (HR, 0.43; 95% CI, 0.28-0.66).

“Prespecified subgroup analyses showed that patients with tumor 

 mutations and patients with a positive HRD status had the greatest PFS benefits,” said Ray-Coquard. “The results reveal a patient population beyond t

m patients, who are HRD-positive, that experiences substantial benefit from maintenance treatment with olaparib and bevacizumab.”

There were more grade ≥3 adverse events (AEs) in the olaparib arm compared with the placebo group; however, there was no clinically meaningful difference in health-related quality of life between the arms. Dose interruptions were required for 54% of those in the olaparib group compared with 24% in the placebo arm. Dose reductions were required for 41% and 7% of patients and dose discontinuations were needed for 20% and 6% of patients, in the olaparib and placebo groups, respectively.

The most common grade ≥3 AEs in the olaparib group and placebo arms, respectively, were hypertension (19% vs 30%) and anemia (17% vs <1%). There were 4 treatment-emergent deaths in the placebo group and 1 in the olaparib arm.

“The main goal in ovarian cancer is to avoid relapse after first-line therapy because otherwise, the probability of cure is quite low,” ESMO discussant Ana Oaknin, MD, PhD, from the Vall d´Hebron Institute of Oncology, said in a statement. Based on this goal, she added that “the combination of bevacizumab and olaparib as maintenance therapy should become a new standard of care for patients with advanced ovarian cancer...this trial is a significant step forward in treatment for these women.”

In December 2018, the FDA approved olaparib monotherapy as a frontline maintenance treatment for patients with deleterious or suspected deleterious germline or somatic 

-mutated advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in complete or partial response to frontline platinum-based chemotherapy.

This approval was based on findings from the phase III SOLO-1 trial,

 in which olaparib monotherapy reduced the risk of disease progression or death by 70% compared with placebo in patients with 

-mutant advanced ovarian cancer who were in complete or partial response to platinum-based chemotherapy (HR, 0.30; 95% CI, 0.23-0.41; 

 <.0001). The median PFS had not yet been reached in the olaparib arm and was 13.8 months with placebo.

Comparing the SOLO-1 results to the PAOLA-1 findings, Ray-Coquard noted that “in 

-mutated patients, the HR is 0.31 in favor of the combination of olaparib and bevacizumab [in PAOLA-1]. This is similar to what we observed in the SOLO-1 trial, where olaparib monotherapy was compared with placebo. The PFS in the control arm is longer in PAOLA-1 than the SOLO-1 trial, which is due to the use of bevacizumab.”

A version of this article originally appeared on OncLive

Frontline Olaparib/Bevacizumab Maintenance Combo Extends PFS in Ovarian Cancer

Ray-Coquard IL, Pautier P, Pignata S, et al. Phase III PAOLA-1/ENGOT-ov25 trial: Olaparib plus bevacizumab (bev) as maintenance therapy in patients (pts) with newly diagnosed, advanced ovarian cancer (OC) treated with platinum-based chemotherapy (PCh) plus bev. Presented at: ESMO Congress 2019, Barcelona, Spain, September 27 to October 1, 2019. LBA2_PR.

Moore K, Colombo N, Scambia G, et al. Maintenance olaparib in patients with newly diagnosed advanced ovarian cancer. 

. 2018;379(26):2495-2505. doi: 10.1056/NEJMoa1810858.

At the 2019 European Society for Medical Oncology, new study results showed promise for a frontline combination therapy for patients with newly diagnosed, advanced ovarian cancer. 

Frontline Combo Therapy Shows Improved Results for Ovarian Cancer Treatment

Optimizing the methods for preclinical research with an emphasis on patient-derived models, may help speed up the translation of new treatment advances from the laboratory to the clinic, according to a presentation by Charles M. Rudin, MD, PhD, at the 2019 International Lung Cancer Congress.

"Bench to beside is not a one-way street. It is there and back again. It is how can we do discovery research in the laboratory and turn it rapidly into clinical development and patient care but then really, also, in the reverse direction, it's using patient data to try to inform which research questions are relevant," said Rudin, chief, Thoracic Oncology, Memorial Sloan Kettering Cancer Center (MSK). "Optimizing preclinical models could enhance both discovery science and clinical translation."

There are many available models for preclinical research, all of which have limitations for immediate applicability to the clinical setting. The two most common models are cancer cell lines and human cell line xenografts. Both of these options allow for rapid and affordable research; however, there is poor correlation with clinical outcomes. With the growth of genetic manipulation, genetically engineered mouse models have grown in popularity, although these models are restricted by a lack of heterogeneity and complexity.

Two of the more clinically relevant models are patient-derived xenografts (PDX) and circulating tumor cell-derived xenografts, Rudin said. These models have the heterogeneity and complexity that is reflective of human disease; however, they are often not susceptible to genetic engineering and may represent an immunosuppressed microenvironment. Overcoming some of these liabilities could permit for more rapid development, he noted.

To this end, Rudin said that MSK has devoted extensive resources to developing a PDX library for various types of thoracic malignancies, with more than 250 banked samples. These PDX lines were subjected to extensive sequencing using MSK-IMPACT to characterize genetic alterations. As an early example of the success of this approach, Rudin described a study looking at resistance to cisplatin and etoposide in small cell lung cancer (SCLC).

In this preclinical study, molecular characteristics were examined between the mice models with an initial complete response to cisplatin and etoposide and those with a partial response. These findings were then compared with their human counterparts from which the cells were derived, uncovering a strong correlation between the response in mice and those seen in humans.

The next step for the research was to determine why sensitivity to cisplatin and etoposide was lost after 6 months of treatment. From this, the gene SLFN11 was identified as a potential mechanism for resistance. Those with SLFN11 expression were chemosensitive whereas those with SLFN11-low expression were more chemoresistant. Moreover, expression of this gene typically diminished following initial treatment with cisplatin and etoposide.

Silas Inman