Gina Columbus

Adding the PD-L1 inhibitor durvalumab (Imfinzi) and the PARP inhibitor olaparib (Lynparza) to treatment with neoadjuvant paclitaxel led to better pathologic complete response (pCR) rates in patients with high-risk, HER2-negative stage II/III breast cancer compared with paclitaxel alone, according to investigators on the phase 2 I-SPY 2 study (NCT01042379). The findings were presented at the 2020 Annual American Association for Cancer Research Virtual Meeting.

Data showed that in all patients with HER2-negative breast cancer, the predicted probability of pCR with the combination compared with sin-gle-agent paclitaxel was 37% (95% CI, 27%-47%) and 22% (95% CI, 16%-25%), respectively. When broken down by subset, the respective pCR rates were 28% (95% CI, 08%-38%) versus 14% (95% CI, 09%-19%) in patients with hormone receptor (HR)–positive disease. In those with triple-negative breast cancer (TNBC), the pCR rate was 47% (95% CI, 29%-64%) with the combination and 27% (95% CI, 20%-34%) with chemotherapy alone (FIGURE).

Moreover, there were no unexpected safety signals; the adverse effects (AEs) were consistent with the known safety profiles of each agent alone.“Durvalumab and olaparib [given] concurrently with paclitaxel increased pCR rates in all 3 biomarker subsets where it was studied,” lead study author Lajos Pusztai, MD, DPhil, professor of medicine (medical oncology) and coleader of genetics, genomics, and epigenetics at Yale Cancer Center in New Haven, Connecticut, said in a virtual presentation during the meeting. “The estimated probability that the experimental arm is superior to chemotherapy alone is greater than 98% in all subsets.”

The rationale to combine checkpoint and PARP inhibition is biologic, Pusztai said, explaining that impaired nucleotide and base excision repair increase mutation and neoantigen load, and DNA fragments activate the intracellular STING pathway. Also, PARP inhibition upregulates PD-L1 expression in breast cell lines.

Previously, results of the open-label phase 1/2 bas-ket MEDIOLA (NCT02734004) trial showed that the combination of olaparib and durvalumab had clinical activity in a cohort of patients with germline 

 The objective response rate was 63.3% with the combination in this patient population. Another phase 2 trial (NCT03801369) of olaparib and durvalumab in patients with 

I-SPY 2 is an ongoing multicenter, neoadjuvant study that uses response-adaptive randomization with multiple concurrent experimental arms and a shared control arm. Overall, the design is based on Bayesian predictive probability that a biological regimen will be shown to be statistically superior to standard treatment in an equally randomized 300-patient confirmatory trial.

 Regimens that demonstrate a high Bayesian predictive probability of showing superiority in at least 1 of 10 predefined signatures graduate from the I-SPY 2 study.

Regimens are dropped for futility if they show a low predictive probability of showing superiority over standard therapy in all 10 signatures. Up to 120 patients can be assigned to each experimental regimen.

For this arm of I-SPY 2, investigators sought to determine whether the neoadjuvant combination of olaparib, durvalumab, and paclitaxel would increase pCR rates compared with chemotherapy alone in HER2-negative biomarker subgroups of patients with stage II/III breast cancer. The biomarker subsets included all patients with HER2-negative breast cancer, including those with HR-positive, HER2-negative disease and TNBC.

To be eligible, patients must have had a tumor size of at least 2.5 cm, adequate organ function, and an ECOG performance status of less than 2, as well as agree to undergo MRI and biopsy. If patients had HR-positive disease, they needed to have a high MammaPrint score.

Patients received either paclitaxel alone at 80 mg/m2 weekly for 12 cycles (n = 299) or combined with 1500 mg of durvalumab every 4 weeks for 3 cycles, plus olaparib at 100 mg twice daily for weeks 1 to 11 (n = 73). Prior to surgery, all patients received doxorubicin at 60 mg/m2 and cyclophosphamide at 600 mg/ m2 for 4 cycles, given every 2 or every 3 weeks.

The primary end point of the trial is pCR; gradby RCB-I (minimal burden), RCB-II (moderate burden), and RCB-III (extensive burden) “Durvalumab and olaparib not only increased the rate of pCR, it also shifted RCB categories toward lower values,” Pusztai said. “In other words, there were also fewer RCB-II and RCBIII patients in the experimental arm, indicating smaller residual cancers across the entire residual disease spectrum.” associated with higher pCR rates across both arms, and there was no significant marker-treatment interaction. Furthermore, in the HR-positive/HER2-negative subtype, patients with an ultrahigh MammaPrint score (MP2; n = 77) was found to have the most benefit from the combination, with an estimated pCR rate of 64% compared with 22% in the control arm. In patients with an MP1 score (n = 132), the estimated pCR rate was 9% with olaparib/ durvalumab versus 10% in the control arm. uation was based on the pCR rate for patients who underwent surgery and MRI response over time for those still on treatment. Investigators determined that for the combination regimen to be studied in a future phase 3 trial, the graduation for efficacy was an 85% or greater predicted probability of success with the combination over standard therapy. If the probability of success dropped below 10%, the trial was stopped for futility. The maximum accrual reached was 75 patients overall with HER2-negative breast cancer.

The median age of enrolled patients was 47 years; 79.5% were white, 12% were African American, 7.5% were Asian, and 0.5% were reported as other. Additionally, 62% of patients had HR-positive disease and 38% had HR-negative disease; specifically, in the combination arm, 71% and 29% of patients had HR-positive and HR-negative disease, respectively. The median tumor size was similar between the combination and control arms, at 3.7 cm and 3.8 cm, respectively. Overall, 32.5% of patients had palpable nodes.

Additional results also demonstrated the probability that the experimental regimen was superior to the control arm and the predicted probability of success in a 300-patient randomized trial. In all patients with HER2-negative breast cancer, the probability that olaparib/durvalumab plus chemotherapy was superior to the control arm was 99.9%, and the probability of success in a phase 3 trial was 81.4%.

In the TNBC subset, the probability rate that the combination was superior to the control arm was 98.4%, with an 80.6% rate that it will be successful in a phase 3 study. Finally, in the HR-positive/ HER2-negative group, the probability of success versus that of the control arm was 99.6%; the rate of succeeding in a phase 3 trial was 74.5%.

Moreover, the combination was found to: reduce values of residual cancer burden (RCB) across subtypes except RCB-III in patients with TNBC. RCB is categorized by RCB-I (minimal burden), RCB-II (moderate burden), and RCB-III (extensive burden).

“Durvalumab and olaparib not only increased the rate of pCR, it also shifted RCB categories toward lower values,” Pusztai said. “In other words, there were also fewer RCB-II and RCBIII patients in the experimental arm, indicating smaller residual cancers across the entire residual disease spectrum.”

Regarding safety, AEs were reported in 43 patients in the durvalumab/olaparib arm compared with 251 who received chemotherapy alone, as of March 15, 2020. The rate of grade 3/4 AEs occurred in 58% and 41% of patients in the experimental and control arms, respectively. The most frequent grade 3/4 AEs experienced in the combination arm and the paclitaxel-alone arm, respectively, included febrile neutropenia (16.3% vs 8.4%), colitis (7% vs 0.4%), adrenal insufficiency (7% vs 0%), increase in alanine aminotransferase levels (4.7% vs 2%), dehydration (4.7% vs 0.8%), and vaginal infection (4.7% vs 0%).

Immune-related AEs of special interest also occurred. Nineteen percent of patients receiving durvalumab/olaparib versus 1.6% of those on the chemotherapy-alone arm experienced grade 3 immune-related AEs, including colitis (n = 3), adrenal insufficiency (n = 3), pancreatitis (n =1), and thyroiditis (n = 1).

When exploring prespecified predictive markers, investigators also noted that higher expression of most immune markers was associated with higher pCR rates across both arms, and there was no significant marker-treatment interaction. Furthermore, in the HR-positive/HER2-negative subtype, patients with an ultrahigh MammaPrint score (MP2; n = 77) was found to have the most benefit from the combination, with an estimated pCR rate of 64% compared with 22% in the control arm. In patients with an MP1 score (n = 132), the estimated pCR rate was 9% with olaparib/ durvalumab versus 10% in the control arm.

In the TNBC subset, low CD3/CD8 gene signature ratio, high macrophage/T-cell–major histocompatibility complex class II ratio, and high proliferation signatures were associated with a higher pCR in the combination arm versus the control arm.

As a discussant during the presentation, Pamela Munster, MD, a professor in the Department of Medicine (Hematology/Oncology) at the University of California, San Francisco (UCSF), and director of the Early Phase Clinical Trials Unit, coleader of the Center for BRCA Research, and leader of the Experimental Therapeutics Program at UCSF Helen Diller Family Comprehensive Cancer Center, shared her insight on where this combination may fit best for this patient population.

“What we know so far in preoperative therapy for breast cancer is that pCR is associated with better outcomes,” Munster said. “What we learned from Dr. Pusztai’s presentation is that there may be promising activity with olaparib and durvalumab in addition to paclitaxel. This combination may be of particular interest to a subgroup of women with tumors expressing ultra-high MammaPrint. The toxicity, as presented today, appears incomplete, and one should consider the financial toxicity from this combination.”

1. Pusztai L, Han HS, Yau C, et al. Durvalumab in combination with olaparib and paclitaxel in high-risk HER2 negative stage II/ III breast cancer: results from the I-SPY 2 trial. Presented at: 2020 American Association for Cancer Research Annual Virtual Meeting; April 27-28, 2020. Abstract CT011. https://bit.ly/3cdK2fK 

2. Domchek S, Postel-Vinay S, Im S, et al. Phase II study of olaparib (O) and durvalumab (D) (MEDIOLA): updated results in patients (pts) with germline BRCA-mutated (gBRCAm) metastatic breast cancer (MBC). Ann Oncol. 2019;30(suppl 5):v477. doi:10.1093/annonc/mdz253.017 

3. I-SPY2 trial demonstrates significant improvement in pCR with durvalumab and olaparib with paclitaxel, (compared to cheER, estrogen receptor; pCR, pathologic complete response; TNBC, triple-negative breast cancer. motherapy alone) in women with stage II/III high-risk, HER2-negative breast cancer, in HR+ and TNBC subsets [news release]. News release. Quantum Leap Healthcare Collaborative. April 27, 2020. Accessed April 27, 2020. prn.to/2yKj3cT

Articles

According to investigators on the phase 2 I-SPY 2 study, the addition durvalumab plus olaparib to treatment with neoadjuvant paclitaxel led to better pathologic complete response rates in patients with high-risk, HER2-negative stage II/III breast cancer compared with paclitaxel alone.

Neoadjuvant Therapy Impresses in I-SPY 2 Trial for Breast Cancer

The addition of the individualized neoantigen specific immunotherapy (iNEST) RO7198457 to atezolizumab (Tecentriq) induced neoantigen-specific T-cell responses, and was found to be well tolerated in patients with advanced solid malignancies, according to preliminary results from a phase 1b study presented during a press program ahead of the 2020 AACR Virtual Annual Meeting II.

Results showed that the combination led to ex vivo T-cell responses in nearly 73% (n = 46) of the 63 patients whose peripheral blood have been evaluated to date. The median number of neoantigen-specific responses per patient was 2.6 (range, 1-9), which were both CD4+ and CD8+ T-cell responses.

“We have established that RO7198457 in combination with atezolizumab was generally well tolerated,” said Juanita Lopez, MB BChir, PhD, a consultant medical oncologist at The Royal Marsden NHS Foundation Trust and The Institute of Cancer Research, London, during the press program. “RO7198457 in combination with atezolizumab induced immune responses in the majority of patients, including preliminary data demonstrating the detection of neoantigen-specific T-cell responses within the tumor. The combination of RO7198457 and a checkpoint inhibitor is currently under investigation in randomized phase 2 clinical studies.”

It is known that mutated neoantigens can be recognized by the immune system as foreign, making them attractive targets for therapies; RO7198457 was designed to induce strong T-cell responses against such neoantigens. Most mutated neoantigens are dissimilar between patients; therefore, the targeting of neoantigens requires an individualized approach, Lopez explained.

RO7198457 is a messenger RNA (mRNA)-based cancer vaccine, which is developed on a per-patient basis. As part of the manufacturing process, tumor-specific antigens are detected via next-generation sequencing. Once up to 20 neoantigens are selected, the corresponding mRNA is created as part of the vaccine. This is then encapsulated in a liposomal formulation, which is then delivered to patients as an intravenous injection.

“Its proposed dual mechanism of action is innate immune stimulation and [encoding of] neoantigens,” Lopez said. “First, patients receive an intravenous injection of RNA-LPX that include 2 messenger RNA molecules, each encoding up to 10 neoantigens, which is then preferentially delivered to antigen-presenting cells, including dendritic cells in the spleen.”

RO7198457 then activates the dendritic cells by binding to toll-like receptor 7/8 with the production of proinflammatory cytokines, which leads to the upregulation of costimulatory molecules. Then, the translation of RO7198457 into a polypeptide containing the neoantigens is processed into peptides that can be presented on MHC class I and II molecules, thereby activating CD4+ and CD8 T-cell responses.

The phase 1b trial (NCT03289962) includes a phase 1a dose-escalation phase in which investigators are evaluating RO7198457 at 5 dose levels: 25 μg 38 μg, 50 μg, 75 μg, and 100 μg. Three doses—25 μg, 38 μg, and 50 μg—were then tested in combination with 1200 mg of atezolizumab every 3 weeks. Eight doses of RO7198457 are administered in the induction phase in weekly and bi-weekly intervals, a boost in cycle 7, and followed by maintenance RO7198457 every 8 cycles thereafter. Atezolizumab is administered on day 1 of each 21-day cycle.
To be eligible for enrollment, patients must be at least 18 years of age, have advanced or recurrent solid tumors, a life expectancy of 12 weeks or longer, and an ECOG performance status of 0 or 1.

Patients are then enrolled onto indication-specific expansion cohorts, including non–small cell lung cancer and melanoma (separate cohorts for patients who previously received a checkpoint inhibitor and those who were immunotherapy–naïve), renal cell carcinoma, urothelial cancer, triple-negative breast cancer (TNBC), and serial biopsy select solid tumors. Patients across tumor types were enrolled on the dose-escalation phase regardless of PD-L1 expression or prior checkpoint inhibitor treatment.

The primary end point of the trial is safety and tolerability, and secondary outcome measures include maximum-tolerated dose, recommended phase 2 dose, pharmacodynamic activity, and preliminary antitumor activity. 

To date, 144 patients with advanced solid tumors have been enrolled. The median number of prior therapies was 3, and nearly 40% of patients previously received immunotherapy. The majority of patients had low levels of PD-L1 expression on both the tumor cells and the immune cells.

Regarding safety, the combination was reported to be well tolerated; the majority of adverse events (AEs) were grade 1/2. While no dose-limiting toxicities were observed, 7 patients discontinued treatment due to treatment-related AEs.

Nine of 108 patients who had at least 1 tumor assessment responded to the combination, which demonstrated an 8% overall response rate. One complete response (CR) was reported in a patient with colorectal cancer; 53 patients (49%) had stable disease.

Preliminary data showed that the combination induces the production of cytokines that are detected post-infusion. Additionally, Lopez explained that there may be infiltration of RO7198457-stimulated T cells in the tumor, which was detected in 1 patient with rectal cancer who was treated with atezolizumab and RO7198457 at 38 μg. Induction and enhancement of 2 neoantigen immune responses by ex vivo were reported in 1 patient with TNBC.

“RO7198457 in combination with atezolizumab has modest activity in the heavily pretreated dose-escalation patient population with 1 CR observed in a [patient with] rectal cancer, and 1 partial response observed in a [patient with] triple-negative breast cancer,” said Lopez.

Ex-vivo data are not available for all vaccine targets due to limited material availability and T-cell fitness, Lopez explained.

AACR president Elaine R. Mardis, PhD, Nationwide Foundation Endowed Chair in Genomic Medicine, and co-executive director of the Institute for Genomic Medicine at Nationwide Children’s Hospital, commented on the study during the press program.

“The unique trial design that [the investigators] present combines dosing of the vaccine with dosing of the anti–PD-L1 antibody atezolizumab, and differs significantly from the handful of patients that have been described earlier in the peer-reviewed literature, wherein neoantigen vaccines of different types—including mRNA vaccines—were given to patients sometimes in combination with checkpoint blockade inhibitor therapy, but typically in the interval subsequent to the vaccine dosing, not [concurrent] vaccine dosing,” Mardis concluded.

Lopez JS, Camidge R, Iafolla M, et al. A phase Ib study to evaluate RO7198457, an individualized Neoantigen Specific immunoTherapy (iNeST), in combination with atezolizumabin patients with locally advanced or metastatic solid tumors. Presented at: 2020 AACR Virtual Annual Meeting II, June 22-24, 2020; Virtual. Abstract CT301.

Personalized Cancer Vaccine Plus Atezolizumab Shows Clinical Activity in Patients With Advanced Solid Tumors [news release]: Philadelphia, PA. AACR. Published June 22, 2020. Accessed June 22, 2020.

“RO7198457 in combination with atezolizumab induced immune responses in the majority of patients, including preliminary data demonstrating the detection of neoantigen-specific T-cell responses within the tumor."

iNEST/Atezolizumab Combo Induces Neoantigen-Specific T-Cell Responses in Advanced Solid Tumors 

Heterogenous populations with ovarian cancer r treated in both the frontline and recurrent settings will require varying treatment strategies involving PARP inhibitors in combination with other classes of agents to reach optimal therapy benefit. These strategies were reviewed during a virtual presentation of the 11th Annual International Symposium on Ovarian Cancer and Other Gynecologic Malignancies™ and hosted by Physicians' Education Resource®, LLC (PER®).

In the up-front settings, the use of PARP inhibitors is designed to improve progression-free survival (PFS), objective response rates (ORRs), and overall survival (OS). In the recurrent space, the goal with this type of therapy is to improve efficacy, overcome resistance, improve immunogenic response, target multiple oncogenic pathways, and provide options for all patients with ovarian cancer, regardless of their homologous recombination deficiency (HRD) status.

“Even though we have trials with different stratifications, eligibility, and designs, we certainly have a heterogeneous patient population,” said Susana M. Campos, MD, MPH, who presented the data. “We are starting to see more and more patients with recurrent ovarian cancer, we’re treating them much more aggressively in the up-front setting, and we have to face PARP [inhibitor] resistance in the future.”

Investigators have explored the combination of the PARP inhibitor olaparib (Lynparza) and the angiogenesis inhibitor bevacizumab (Avastin) in the frontline maintenance setting for patients with advanced ovarian cancer who are in complete or partial response to first-line platinum-based chemotherapy with bevacizumab. In the double-blind, placebo-controlled, phase 3 PAOLA-1 trial (NCT02477644), patients with newly diagnosed, stage III to IV, high-grade, serous or endometroid ovarian, fallopian tube, or peritoneal cancer were randomized 2:1 to receive olaparib in combination with bevacizumab (n = 537) or bevacizumab with placebo (n = 269) as a f irst-line maintenance treatment.

Eligible patients had a complete or partial response to frontline platinum-based chemotherapy and bevacizumab, regardless of genetic biomarker status or their outcome with prior surgery. Findings showed that the combination led to a 41% reduction in the risk of disease progression or death compared with bevacizumab alone in this patient population, based on an investigator assessment (HR, 0.59; 95% CI, 0.490.72; 

 Additionally, after a median follow-up of 22.9 months, the median progression-free survival (PFS) was 22.1 versus 16.6 months with the combination and bevacizumab alone, respectively. When stratified by somatic 

 status, the PFS favored the tumors that were 

 mutant (HR, 0.31; 95% CI, 0.20-0.47) versus those that were not (HR, 0.71; 95% CI, 0.58-0.88).

Results also showed that the benefit with olaparib was most pronounced in patients with tumors positive for HRD, which included tumors with 

 mutations (HR, 0.33; 95% CI, 0.25-0.45). In this subgroup, the median PFS was 37.2 months with the olaparib combination and 17.7 months with bevacizumab alone, respectively.

Based on the PAOLA-1 data, the FDA expanded the indication of olaparib to include its combination with bevacizumab for the maintenance treatment of patients with advanced ovarian cancer who are in complete or partial response to first-line platinum-based chemotherapy.

“The PAOLA-1 study did not have an olaparib-only arm,” Campos, a physician at the Dana-Farber Cancer Institute and an assistant professor of medicine at Harvard Medical School, both in Boston, Massachusetts, said of PAOLA-1. “This draws us into the question, ‘What patient population is this combination most appropriate for?’ I bring myself back to, ‘Who would I have put on bevacizumab? What are the data that surround GOG-0218 or ICON7?’”

The phase 3 VELIA trial (NCT02470585), which looked at the investigational agent veliparib, evaluated the addition of a PARP inhibitor to chemotherapy in patients with high-grade serous ovarian cancer. The trial randomized patients evenly among 3 arms: The first arm (control) consisted of carboplatin and paclitaxel with placebo followed by placebo as maintenance (n = 375). The second arm examined the addition of veliparib to carboplatin/paclitaxel as induction therapy, followed by placebo maintenance (n = 383). In the third arm, investigators added veliparib at 150 mg twice daily to carboplatin/paclitaxel followed by veliparib alone at 400 mg twice daily as maintenance (n = 382).

Results showed that the arm of veliparib plus carboplatin/paclitaxel followed by maintenance veliparib led to a 32% reduction in the risk of progression or death versus placebo/chemotherapy with placebo maintenance in the intentionto-treat (ITT) population.4 The median PFS was 23.5 months versus 17.3 months in the placebo arm (HR, 0.68; 95% CI, 0.56-0.83; 

The benefit was more pronounced in those with 

 mutations. In this group, the median PFS was 34.7 months compared with 22.0 months for veliparib and placebo, respectively (HR, 0.44; 95% CI, 0.28-0.68; 

 <.001). In a subset of patients with both 

 mutations and HRD positivity, the median PFS was 31.9 months with the addition of veliparib and 20.5 months for the control arm (HR, 0.57; 95% CI, 0.43-0.76; 

 wild-type patients, the addition of the PARP inhibitor did not demonstrate a PFS benefit versus the control arm, at 18.2 months and 15.1 months, respectively (HR, 0.80; 95% CI, 0.64-0.997). Investigators observed a similar effect in patients with 

 wild-type/ HRD positivity (HR, 0.74; 95% CI, 0.52-1.06) and HRD negativity (HR, 0.81; 95% CI, 0.60-1.09).

“It draws some questions in terms of the second arm,” said Campos. “If you combine chemotherapy with a PARP inhibitor, do you just add toxicity? Can you, at that point in time, abbreviate the backbone of therapy, which is carboplatin/paclitaxel? We have many different patients; [the combinations in PAOLA-1 and VELIA] may have utility in a particular patient group.”

Trials are also evaluating combination strategies using PARP inhibition in the recurrent setting of both patients with platinum-sensitive and platinum-resistant disease. Although Campos explained that combining PARP inhibitors and other agents can present challenges, such as dose-limiting toxicities, she added that opportunities do exist to overcome PARP inhibitor resistance mechanisms and enhance tumor mutational load and immunogenicity.

Some of these studies, which include PARP inhibitors plus antiangiogenic agents, immunotherapy, or chemotherapy, have already reported data showcasing their efficacy, and others are expected to read out in the near future. For example, investigators explored olaparib plus the investigational antiangiogenic agent cediranib in a small phase 2 trial (NCT01116648) of 90 patients with platinum-sensitive, relapsed, high-grade serous or endometrioid ovarian, fallopian tube, or primary peritoneal cancer, as well as other histologies with deleterious germline 

 mutations. Updated findings showed that in the ITT population, the median PFS was 16.5 versus 8.2 months with the combination and olaparib alone, respectively (HR, 0.50; 95% CI, 0.30-0.83; 

 = .007).5 The median OS was also improved with the combination, at 44.2 versus 33.3 months with olaparib alone (HR, 0.64; 95% CI, 0.36-1.11; 

 mutation status, the median PFS was 23.7 months with olaparib/cediranib and 5.7 months with olaparib alone in those who did not harbor somatic 

 mutations (HR, 0.32; 95% CI, 0.16-0.66; 

 = .002). However, this improvement was not mirrored in the somatic 

-mutant carrier subgroup (median PFS, 16.4 months and 16.5 months, respectively; HR, 0.75; 95% CI, 0.38-1.49; 

Similarly, the AVANOVA study investigated the PARP inhibitor niraparib (Zejula) in combination with bevacizumab versus niraparib alone (NCT02354131). The regimen was tested in patients with high-grade serous, endometrioid, platinum-sensitive recurrent ovarian cancer who could have received any number of prior therapies. Data showed that the median PFS was 11.9 months with niraparib/bevacizumab and 5.5 months with single-agent niraparib (adjusted HR, 0.35; 95% CI, 0.21-0.57; 

 <.0001).6 The combination improved PFS regardless of HRD positivity (HR, 0.38; 95% CI, 0.20-0.72; 

 = .0019) or negativity (HR, 0.40; 95% CI, 0.19-0.85; 

Although response rates and PFS with single-agent immunotherapy in ovarian cancer have historically been “less than exciting,” said Campos, intriguing research has demonstrated synergy when PD-1/PD-L1 inhibitors are partnered with PARP inhibitors.

Results of smaller studies have shown preliminary efficacy with these types of regimens in different ovarian cancer populations. In the phase 2 MEDIOLA trial (NCT02734004), for example, durvalumab (Imfinzi) plus olaparib led to a 71.9% ORR in a germline BRCA-mutant, platinum-sensitive population (n = 35).7 Yet the phase 1/2 TOPACIO trial (n = 60) of pembrolizumab (Keytruda) and niraparib had a more modest ORR at 25%, with a median duration of response of 9.3 months (NCT02657889).8 Results of another small trial of durvalumab plus olaparib (n = 35) showed that the combination had a modest ORR in a population with mostly platinum-resistant recurrent ovarian cancer.

Beyond doublet regimens, investigators are also beginning to evaluate triplet therapies with all 3 classes of agents, as in the phase 2 OPAL study (NCT03574779) with niraparib, TSR-042, a PD-1 inhibitor, and bevacizumab in patients with recurrent, platinum-resistant, ovarian, fallopian tube, or peritoneal cancer.

There has been a “tremendous amount of interest” in looking at other emerging combinations in terms of DNA damage–repair targets and other agents, Campos explained, citing Wee-1, PI3K/Akt/mTOR, ATR, Chk1, and MEK all as targets that a number of trials are exploring.

For example, investigators are exploring the Wee-1 inhibitor adavosertib (AZD1775) with and without olaparib in the phase 2 EFFORT trial (NCT03579316) of patients with recurrent ovarian, primary peritoneal, or fallopian tube cancer. Activated Wee-1 phosphorylates CDK1, Campos said, and therefore results in G2-M arrest.

Additionally, the MEK inhibitor selumetinib (Koselugo) is also being combined with olaparib in a phase 1 trial (NCT03162627) of patients with recurrent solid tumors, including ovarian cancer. The addition of MEK inhibitors to PARP could decrease homologous recombination repair gene expression, Campos said. 

“In a short period of time, there is a tremendous amount of work,” Campos concluded. “

1. Campos S. Incorporating combination therapy in an evolving treatment landscape. Presented at: 

 International Symposium on Ovarian Cancer and Other Gynecologic Malignancies™; May 2, 2020.

2. Ray-Coquard I, Pautier P, Pignata S, et al; 

. Olaparib plus bevacizumab as first-line maintenance in ovarian cancer. 

. 2019;381(25):2416-2428. doi:10.1056/NEJMoa1911361

3. FDA approves olaparib plus bevacizumab as maintenance treatment for ovarian, fallopian tube, or primary peritoneal cancers. FDA. Updated May 11, 2020. Accessed May 12, 2020. https://bit.ly/3dGTQiv

4. Coleman RL, Fleming GF, Brady MF, et al. Veliparib with first-line chemotherapy and as maintenance therapy in ovarian cancer. 

. 2019;381(25):2403-2415. doi:10.1056/NEJMoa1909707

5. Liu JF, Barry WT, Birrer MJ, et al. Overall survival and updated progression-free survival results from a randomized phase 2 trial comparing the combination of olaparib and cediranib against olaparib alone in recurrent platinum-sensitive ovarian cancer. 

. 2017;35(suppl 15):5535. doi:10.1200/JCO.2017.35.15_suppl.5535

6. Mirza MR, Åvall Lundqvist E, Birrer MJ, et al. Niraparib plus bevacizumab versus niraparib alone for platinum-sensitive recurrent ovarian cancer (NSGO-AVANOVA2/ENGOT-ov24): a randomised, phase 2, superiority trial. 

. 2019;20(10):1409-1419. doi:10.1016/S1470-2045(19)30515-7

7. Drew Y, Kaufman B, Banerjee S, et al. Phase II study of olaparib + durvalumab (MEDIOLA): updated results in germline BRCA-mutated platinum-sensitive relapsed (PSR) ovarian cancer (OC). 

. 2019;30(suppl 5):v485-v486. doi: 10.1093/annonc/mdz253.016

8. Konstantinopoulos PA, Waggoner SE, Vidal GA, et al. TOPACIO/Keynote-162 (NCT02657889): a phase 1/2 study of niraparib + pembrolizumab in patients (pts) with advanced triple-negative breast cancer or recurrent ovarian cancer (ROC)—results from ROC cohort. 

. 2018;36(suppl 15):106. doi:10.1200/JCO.2018.36.15_suppl.106

9. Lee J-M, Annunziata CM, Houston N, et al. A phase 2 study of durvalumab, a PD-L1 inhibitor and olaparib in recurrent ovarian cancer (ovca). 

. 2018;29(suppl 8):viii332-viii358. doi:10.1093/annonc/mdy285

“We are starting to see more and more patients with recurrent ovarian  cancer, we’re  treating them much more aggressively in the up-front setting, and we have to face PARP inhibitor resistance in the future.”

Diverse Populations  Necessitate Innovative Combinations in Ovarian Cancer

In a retrospective analysis, clinical activity was demonstrated with infigratinib in patients with metastatic urothelial carcinoma, regardless of which line of therapy patient were on when the drug was administered. The data were presented at the 2020 ASCO Virtual Scientific Program.

Results showed that the overall confirmed objective response (complete response [CR] or partial response [PR]) was 30.8% (95% CI, 9.1%-61.4%) in patients who received infigratinib as a first-line therapy and was 24.1% (95% CI, 13.5%-37.6%) in those who received it as a second- or later-line treatment, leading to a total confirmed objective response of 25.4% (95% CI, 15.5-37.5).

Notably, the activity was most significant in a subset of patients with upper tract urothelial cancer, which is enriched for 

-driven disease. In this subset, the confirmed objective response rate (ORR) was 50% (95% CI, 15.7%-84.3%) and the disease control rate (DCR) was 100% for those who received infigratinib as second- or later-line treatment.

"Our data suggests similar activity of infigratinib in patients receiving it in the first-line setting versus subsequent lines for advanced urothelial carcinoma," lead study author Yung Lyou, MD, PhD, an assistant clinical professor in the Department of Medical Oncology and Therapeutics Research at City of Hope, said in a poster presentation during the virtual meeting. "These results suggest that infigratinib has activity in patients with advanced urothelial carcinoma, regardless of the line of treatment."

Advanced urothelial carcinoma continues to be an incurable disease for many patients. Platinum-based chemotherapy continues to serve as the foundation for treatment; only approximately 15% to 40% of patients respond to checkpoint inhibitors. Moreover, an estimated 20% of patients with lower tract disease, and 40% to 75% of those with upper tract disease have 

 activating mutations, suggesting it to be a potential new target for novel therapies.

Infigratinib is a potent, oral, selective ATP-competitive FGFR1/2/3 inhibitor that has previously reported to have significant clinical activity in patients with advanced urothelial cancer whose tumors harbor 

 In the retrospective analysis of this phase 1b trial, investigators sought to determine whether differences existed with regard to infigratinib activity based on the number of prior lines of therapy that patients could have received.

In the trial, 67 patients with advanced or metastatic urothelial cancer that harbored 

 alterations were treated with oral infigratinib at 125 mg once daily on days 1 to 21 every 28 days until disease progression or unacceptable toxicity. Dose reductions to 100 mg daily, followed by 75 mg daily, were permitted and further reductions were permitted on an individualized basis.

To be eligible for enrollment, patients must have progressed on, or were intolerant to, platinum-based chemotherapy, unless contraindicated. Patients also had to undergo baseline imaging, including CT of the chest, abdomen, and pelvis, as well as brain MRI or CT and technetium bone scan. Follow-up serial imaging comprised the same baseline CT imaging, along with bone scan if indicated, at 8-week intervals thereafter.

The primary end point of the trial was to compare the ORR via RECIST v1.0 criteria in patients receiving infigratinib up front (n = 13) versus those receiving the agent in a later-line setting (n = 54). Secondary outcome measures included a comparison of DCR and PFS in both arms, as well as best overall response, overall survival (OS), safety, and pharmacokinetics.

For responses, investigators used the chi-square test and utilized; additionally, they used the Kaplan-Meier method with log-rank test to compare PFS outcomes. Moreover, comparisons were also made across individual lines of therapy with the use of descriptive statistics to optimally fit the number of patients in each subgroup. Tissue and blood specimens were also genomically assessed.

Slightly more than half (56.7%) of patients were younger than 65 years, and 68.7% of patients were male. Additionally, 31.3% of patients had a World Health Organization performance status of 0, 53.7% had a status of 1, and 14.9% of patients had a performance status of 2. Furthermore, 17.9%, 40.3%, 37.3%, and 4.5% of patients had Bellmunt Criteria risk scores of 0, 1, 2, and 3, respectively. Most patients had urothelial bladder cancer (88.1%) versus upper tract urothelial cancer (11.9%), and nearly two-thirds of patients overall (61.2%) had visceral lung disease, while 37.3% had visceral liver metastases. Additionally, 41.8% of patients had lymph node metastases and 61.2% had bony metastases. Notably, 19.4% of patients received prior immunotherapy.

In the response assessment, data in the overall population showed that there was 1 CR, which occurred in the later-line arm and translated to a 1.5% CR rate. Four PRs (30.8%) and 12 PRs (22.2%) were reported in the frontline and later-line arms, respectively, which translated to a 23.9% total PR rate. The stable disease (SD) rate was 15.4% and 44.4%, respectively, leading to an overall 38.8% SD rate. Progressive disease (PD) was reported in 46.2% of patients on frontline infigratinib and 22.2% of those on later-line treatment for a 26.9% overall PD rate; 1 patient on frontline treatment had an unknown response versus 5 patients who received infigratinib later on.

The best overall response (BOR) was 38.5% (95% CI, 13.9%-68.4%) with up-front infigratinib and 42.6% (95% CI, 29.2%-56.8%) with later-line infigratinib, leading to a total BOR of 41.8% (95% CI, 29.8%-54.5%); the DCR was 46.2% (95% CI, 19.2%-74.9%) and 68.5% (95% CI, 54.4%-80.5%), respectively, which led to a total 64.2% DCR (95% CI, 51.5%-75.5%).

When stratified by patients with urothelial bladder cancer, no CRs were reported in either group; however, 4 PRs (30.8%) were observed in those who received up-front infigratinib and 9 PRs (19.6%) were reported in those who received later-line therapy, leading to a total PR rate of 22%. SD was reported in 15.4% and 43.5% of patients with frontline and later-line infigratinib, respectively, leading to an overall SD rate of 37.3%. The PD rates were 46.2% and 26.1% in the first- and later-line settings, respectively, with a total PD rate of 30.5%. The confirmed objective response was 30.8% with frontline infigratinib and 19.6% with later-line treatment, leading to an overall confirmed objective response of 22.0%.

The BOR in this population was 38.5% (95% CI, 13.9%-68.4%) and 39.1% (95% CI, 25.1%-54.6%) for up-front and later-line infigratinib, respectively, leading to an overall BOR of 39.0% (95% CI, 26.5%-52.6%). Finally, the DCR was 46.2% (95% CI, 19.2%-74.9%) with frontline infigratinib and 63.0% (95% CI, 47.5%-76.8%) with second- or later-line therapy, which translated to a 59.3% BOR (95% CI, 45.7%-71.9%).

In the overall population, the median PFS was similar between arms, with a median 3.65 months (95% CI, 0.95-7.43) in the first-line infigratinib arm compared with 3.75 months in the second- or later-line group (95% CI, 3.09-5.42). The findings were similar with regard to OS; the median OS was 7.93 months (95% CI, 2.40–not evaluable) and 7.75 months (95% CI, 5.72-13.67), respectively, and were not found to be statistically significantly different from one another.

Regarding safety, all-grade and grade 3/4 adverse events (AEs) occurred in 98.5% and 68.7% of patients, respectively. Grade 3/4 AEs comprised of hyperphosphatemia (1.5%), fatigue (7.5%), anemia (7.5%), decreased appetite (4.5%), dry mouth (1.5%), nausea (4.5%), stomatitis (3.0%), vomiting (4.5%), diarrhea (3.0%), abdominal pain (1.5%), dyspepsia (1.5%), and arthralgia (3.0%).

All-grade hyperphosphatemia, which was reported in 46.3% of patients, is known to be a commonly associated AE with FGFR inhibition, Lyou explained. Fatigue and constipation (37.3% each) were also commonly reported AEs.

The investigators did note in the presentation that the study had limitations, such as that a relatively small proportion of patients received infigratinib in the first-line setting, and that the current data also reflect an unplanned subset analysis.

The results support the ongoing PROOF 302 study (NCT04197986), which is comparing adjuvant infigratinib with placebo in patients with resected disease, and in an upper tract urothelial carcinoma–enriched population, according to the investigators. In this research, disease-free survival (DFS) via central review will serve as the primary end point and secondary end points will include investigator-reviewed DFS, metastasis-free survival, OS, and safety/tolerability.

1. Lyou Y, Grivas P, Rosenberg JE, et al. Infigratinib and treatment response in advanced/unresectable or metastatic urothelial carcinoma in first-line and later-line treatment settings. 

. 2020;38(suppl 15; abstr 5038). doi:10.1200/JCO.2020.38.15_suppl.5038

2. Pal SK, Rosenberg JE, Hoffman-Censits JH, et al. Efficacy of BGJ398, a fibroblast growth factor receptor 1–3 inhibitor, in patients with previously treated advanced urothelial carcinoma with FGFR3 alterations. 

. 2018;8(7):812-821. doi:10.1158/2159-8290.CD-18-0229

3. Pal SK, Bajorin D, Dizman N, et al. Infigratinib in upper tract urothelial carcinoma versus urothelial carcinoma of the bladder and its association with comprehensive genomic profiling and/or cell-free DNA results. 

. 2020;126(11):2597-2606. doi:10.1002/cncr.32806

"Our data suggests similar activity of infigratinib in patients receiving it in the first-line setting versus subsequent lines for advanced urothelial carcinoma."

Gina Columbus | Authors

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