February 01, 2021 - 02:02 pm 0 Comments
By Ted Bosworth
In early stage non-small cell lung cancer (NSCLC), one source of good news at the 2020 World Conference on Lung Cancer (WCLC 2020) was the efficacy of immune checkpoint inhibitor (ICI) as neoadjuvant therapy. In late stage disease, the news was mixed. In a phase 3 trial, the addition of a second ICI in previously untreated stage IV NSCLC did nothing but add toxicity. However, unique oral targeted agents, including the first KRAS inhibitor, are showing sufficient activity to change outcomes for many with advanced disease.
Neoadjuvant Atezolizumab Shrinks Tumors Prior to NSCLC Resection
In resectable, previously untreated stage IB to IIIA NSCLC, 66 (43%) of 155 patients who underwent subsequent pathologic stage evaluation were downsized after two cycles of neoadjuvant atezolizumab, according to results of the LCMC3 trial. Only 29 (19%) were upstaged. A major pathologic response, which was the primary endpoint, was achieved in 21%, and 7% achieved a pathologic complete response.
“The subsequent resection was achieved with a low rate of morbidity,” reported Jay M. Lee, MD, Chief, Division of Thoracic Surgery, University of California, Los Angeles.
Tumor-free (RO) margins were achieved in 92% of those who underwent surgery. After 1.5 years of followup, 79% of those with stage I or II NSCLC and 77% of those with stage III remained in disease-free survival (DFS). The rates of overall survival (OS) at this interval were 91% and 87%, respectively, which compare favorably to historical data.
There were 181 patients initially recruited for this single-arm study. Of the 159 who went onto surgery, 140 (88%) did so within the predefined protocol window of 30 to 50 days after initiating the first dose of atezolizumab. The median time from the end of cycle 2 of atezolizumab and surgery was 22 days.
Of the 14 surgeries (8%) without tumor-free margins at completion, 7 (4%) were R1. The remainder was R2.
Atezolizumab did not appear to complicate surgery, which was minimally invasive in the majority of cases. For example, the length of hospitalization was 7.5 days or about the same as that reported in previous series.
These data confirm that neoadjuvant ICI is feasible, according to Shinichi Toyooka, MD, Director, Department of General Thoracic Surgery, Okayama University Hospital, Japan. Invited as an expert discussant by the International Association for the Study of Lung Cancer (IASLC), which organized this World Conference, Dr. Toyooka advised ICI plus chemotherapy might still be preferable in those with stage III disease and good performance status.
Dual ICI Adds Nothing to Pembrolizumab Alone in Stage IV NSCLC
The hypothesis that adding a second ICI could improve outcomes over a single ICI in patients with stage IV NSCLC was not validated by the randomized KEYNOTE-598 trial. In a study that recruited patients with no prior systemic therapy but a high rate of PD-L1 expression, the addition of ipilimumab, an ICI targeting CTLA-4, plus pembrolizumab, which targets PD-1, did not achieve an advantage over pembrolizumab for any of the major study endpoints.
“The addition of ipilimumab did not improve efficacy but it did increase toxicity in first-line treatment for stage IV NSCLC,” reported Michael Boyer, MBBS, PhD, Chair of Thoracic Oncology, Chris O’Brien Lifehouse, Camperdown, Australia. He added, “This means that pembrolizumab remains the standard of care in this population.”
In this phase 3 study, patients were required to have PD-L1 expression of at least 50% tumor proportion score (TPS). The 568 enrolled patients were randomized to pembrolizumab at a dose of 200 mg every three weeks plus ipilimumab at a dose of 1 mg/kg every six weeks or to the same dose of pembrolizumab plus placebo. The co-primary endpoints were OS and progression-free survival (PFS).
The study was stopped when the lack of difference in the outcomes crossed previously defined boundaries of futility. At 12 months, survival was 63.6% in the patients on two ICIs versus 67.9% for those on pembrolizumab plus placebo. At the interim analysis the hazard ratio (HR) for the combination went the wrong way for OS (HR 1.08; P=0.74) and for PFS (HR 1.06; P=0.72).
“Essentially every adverse events occurred more frequently in the arm that received both ipilimumab and pembrolizumab,” Dr. Boyer reported. Serious treatment-related adverse events (27.7% vs. 13.9%) and discontinuations due to adverse events (19.1% vs. 7.5%) were both higher in the group on the dual ICI.
Dual ICI therapy has shown an advantage over monotherapy in other cancers, such as melanoma, but the IASLC-invited discussant, Yun Fan, MD, PhD, Director of Thoracic Oncology, Zhejiang Cancer Hospital, Hangzhou, China, speculated that ipilimumab might be ineffective in tumors with a high rate of PD-L1 tumor expression. Dr. Fan noted that another NSCLC study that enrolled patients with ≥50% TPS also found this dual ICI combination ineffective.
New Uniquely Targeted Oral Therapies Are Exploding the Possibilities in Advanced NSCLC
Led by a first-in-class KRAS inhibitor, the most significant news for the control of advanced NSCLC might be the progress with oral targeted small molecule inhibitors. Based on a phase 2 study, the KRAS inhibitor sotorasib might offer the most immediate promise, but other drugs in earlier stages of development point to increasing individualization of therapy.
By inhibiting KRAS, sotorasib, has reached a target once thought undruggable, according to Bob T. Li, MD, Co-Director of the Thoracic Liquid Biopsy Program, Memorial Sloan Kettering Cancer Center, New York, New York. In advanced KRAS-mutated NSCLC, sotorasib was associated with “deep and durable responses” with little toxicity. He predicted a major role for this agent upon regulatory approval.
In this phase 2 study involving centers in 11 countries, called CodeBreaK 100, 126 previously treated patients with locally advanced or metastatic NSCLC with KRAS G12C mutation were enrolled. About 90% had received either an ICI or a platinum-based chemotherapy. Eighty-one percent had received both. The treatment was oral sotorasib once daily until disease progression.
For the primary endpoint, 34.7% achieved a partial response and 2.4% achieved a complete response. Disease control was observed in 86%, and some degree of tumor shrinkage was achieved in 81%. The median duration of response was 10 months. The median overall PFS was 6.8 months, but 43% remained on therapy without progression at the time of data cutoff, according to Dr. Li.
Diarrhea was the most common adverse event, occurring in 31%, but reached grade 3 severity in only 4%. Except for a blood alkaline phosphatase increase in one patient, the only other grade 3 events, occurring in less than 10% of patients, were liver enzyme elevations.
Due to the importance of KRAS mutations, which is the driver of progression in an estimated 13% of advanced NSCLC, Dean Fennell, MBBS, PhD, Chair of Thoracic Medical Oncology University of Leicester, UK, called these results “fabulous.” In his opinion, it means that characterization of KRAS status will now be an essential step to NSCLC management.
Due to the relative importance of the KRAS mutation, the sotorasib findings were featured in the President’s Symposium, but progress with other currently untreatable drivers of NSCLC suggest major progress in this field. Examples include mobocertinib, which targets epidermal growth factor receptor (EGFR) Exon20 insertions, and tepotinib, which targets MET exon14.
The objective response rate with mobocertinib in 96 patients with advanced EGFR Exon20+ advanced was 28% in a phase 1/2 trial presented by Caicun Zhou, MD, PhD, Director, Department of Oncology, Shanghai Pulmonary Hospital, China. This is impressive because the patients had all been treated previously with platinum-based chemotherapy, and the response was associated with durable disease control.
“The median duration of response was 17.5 months,” according to Dr. Zhou, who characterized this as a meaningful benefit in a group with highly limited treatment options.
In the phase II VISION study of tepotinib for treatment of METexon14 skipping advanced NSCLC, the overall response rate was 45.2%. The median duration of response was 11.1 months, according to Paul K. Paik, MD, Clinical Director, Thoracic Oncology Service, Memorial Sloan Kettering Cancer Center, New York City.
As in the experiences with sotorasib and mobocertinib, the activity with this highly targeted therapy was consistent across prior treatment experience. In the case of tepotinib, for example, responses were similar regardless of prior exposure to ICI, Dr. Paik reported.
Despite their early stage, these data predict increasing individualization of late stage NSCLC for very specific targets, allowing substantial hope for extending the lives of NSCLC patients with advanced disease regardless of the underlying driver.
December 14, 2020 - 07:12 pm Posted in ASH Conference Coverage Posted in Leukemia (includes ALL, AML, APL, CLL, CML, MDS, Myeloproliferative Disorders, Myelofibrosis) Posted in Lymphoma (includes NHL, HL, CNS Lymphoma) Posted in Multiple Myeloma 0 Comments
By Mary Ellen Schneider
This year’s annual meeting of the American Society of Hematology (ASH) featured new research on chimeric antigen receptor (CAR) T-cell therapy and bispecific T-cell engager (BiTE) molecules, along with trends toward treating cancer patients with immunotherapies earlier in the course of their disease.
The meeting, which was held virtually for the first time, also highlighted studies evaluating the extent and impact of racial and ethnic health disparities in hematology and oncology.
Health Disparities Highlighted
“As part of caring for patients and our citizens, ASH chose to have a significant light shine upon disparities in health care, or differences in outcomes between different groups of our patients,” Chancellor Donald, MD, an assistant professor of clinical medicine at Tulane University in New Orleans, told OBR.
Bringing attention to disparities in outcomes and access offers the potential for “immediate improvement in outcomes for those persons without a new diagnostic test, or without a new drug,” Dr. Donald said.
The ASH plenary session put the spotlight on poor treatment outcomes for Black patients younger than 60 years with acute myeloid leukemia (AML). In a study that looked both at Surveillance Epidemiology End Results (SEER) data and molecular features by race, researchers found that younger Black patients had a 27% higher likelihood of death than white patients. They also discovered that Black patients had a lower frequency of prognostically favorable NPM1 mutations (Abstract 6).
Another study that focused on health disparities identified a greater risk for cancer-associated thrombosis among Black patients, compared with their white counterparts. These disparities were especially prominent when the researchers looked only at pulmonary embolism (Abstract 203).
What is driving the disparities in cancer-associated thrombosis? The researchers acknowledged possible contributions from underlying biological traits. But they also pointed to the contribution of systemic racism, access to care, and the severity of underlying comorbidities.
“Since current risk prediction models for cancer-associated thrombosis do not include race and ethnicity as parameters, future studies should examine if incorporating these factors can improve predictive value,” said Alisa S. Wolberg, of the University of North Carolina at Chapel Hill and one of the ASH scientific program co-chairs. Dr. Wolberg highlighted the study as part her “Best of ASH” presentation.
Other health disparities research presented at this year’s ASH included a study exploring the impact of living in a socioeconomically disadvantaged neighborhood for Black and Hispanic people with AML. Researchers found that this “structural violence” led to worse survival for minority patients in the study (Abstract 217).
Latest Data in CAR T-Cell Therapy, BiTEs
The ASH annual meeting also included a variety of studies on CAR T-cell therapy, from clinical trials to real-world data.
“What strikes me now is that in the CD19 CAR T-cell space, you’re getting much more robust real-world data,” Catherine Bollard, MD, director of the Center for Cancer and Immunology Research at Children’s National Hospital in Washington, D.C., and a professor of pediatrics and immunology at George Washington University, told OBR.
Among the noteworthy research, Dr. Bollard pointed to a real-world study that investigated the tumor-specific factors driving inherent or acquired resistance to CAR T cells in large B-cell lymphoma (Abstract 556). The study, led by researchers at Stanford University, identified CD58 status as an important biomarker for durable response to CAR T cells in large B-cell lymphoma.
This type of real-world data will be even more important as CAR T-cell therapy moves earlier in the treatment of disease, Dr. Bollard said.
“As we continue to expand the reach of new targeted therapies, it is imperative that we deeply study our patients to determine the mechanisms that underscore success, and perhaps even more importantly, failure,” said Leslie S. Kean, MD, PhD, of Boston Children’s Hospital and Dana-Farber Cancer Institute and one of the ASH scientific program co-chairs. She highlighted Abstract 556 as part of her “Best of ASH” presentation.
Dr. Kean also highlighted findings from the primary analysis of the phase 2, Zuma-5 trial, which evaluated axicabtagene ciloleucel (axi-cel) in patients with follicular and marginal zone lymphoma (Abstract 700), noting that one of themes of the ASH meeting was an expansion of cellular therapies beyond their initial indications.
“The maturation of the field is evidenced by multiple commercial CARs now being investigated in these more indolent lymphoma patients,” Dr. Kean said.
Dr. Kean also pointed to an early study looking at the combination of the CAR T product lisocabtagene maraleucel (liso-cel) with the BTK inhibitor ibrutinib for the treatment of patients with relapsed/refractory chronic lymphocytic leukemia (CLL). In the phase 1 TRANSCEND CLL 004 study, researchers found promising efficacy and a manageable safety profile with the combination (Abstract 544).
Other immunotherapy studies presented at ASH were focused on the use of these treatments earlier in the course of therapy.
Dr. Kean pointed to a phase 3 trial in children with high-risk first relapse B-cell precursor acute lymphoblastic leukemia (ALL) that assessed the BiTE molecule blinatumomab, compared with high-risk consolidation chemotherapy before allogeneic hematopoietic stem cell transplant. Blinatumomab monotherapy achieved significantly better event-free survival, causing the trial’s data monitoring committee to recommend early termination of enrollment due to benefit (Abstract 268).
Another study focused on treatment with a BiTE molecule earlier in the course of therapy was a phase 2 study that examined the use of a hyper-CVAD chemotherapy regimen with sequential blinatumomab in adults with newly diagnosed Philadelphia chromosome-negative B-cell ALL (Abstract 464). The researchers found that the combination was effective in front-line treatment, with a high complete response rate and high percentage of patients achieving measurable residual disease negativity.
Potential New Treatments in Multiple Myeloma
Dr. Kean also highlighted two clinical studies of antibody-based and CAR T-cell therapies for the treatment of multiple myeloma.
The phase 1b/2 CARTITUDE-1 study looked at ciltacabtagene autoleucel (cilta-cel), a B-cell maturation antigen-directed CAR T-cell therapy, in the treatment of relapsed/refractory multiple myeloma (Abstract 177). Researchers reported an encouraging progression-free survival profile of at least a year. The safety and efficacy data indicate that larger studies of this agent are warranted, Dr. Kean said.
Along with CAR T-cell advances, Dr. Kean pointed to a new antibody-based therapy with potential in relapsed/refractory multiple myeloma. A phase 1, first-in-human study, evaluated talquetamab, a first-in-class bispecific antibody that binds to the G Protein-Coupled Receptor Family C Group 5 Member D (GPRC5D) and CD3 (Abstract 290). Researchers reported a manageable safety profile for the antibody treatment.
“This study suggests that there continue to be ‘new kids on the block’ for these otherwise difficult-to-treat patients,” Dr. Kean said.
by Chase Doyle
Day 4 of the 2020 San Antonio Breast Cancer Symposium (SABCS) virtual meeting featured advances in early treatment monitoring, a surprising setback for HDAC inhibition in endocrine-resistant disease, and better selection of patients for neoadjuvant chemotherapy in high-risk early breast cancer (EBC).
Circulating Tumor Cells Predict Overall Survival in Metastatic Breast Cancer
A simple blood test may be enough to predict survival in metastatic breast cancer less than one month after initiating treatment.
Results of a large, pooled analysis confirm that at a median of 29 days after treatment initiation, follow-up circulating tumor cell (CTC) assessments strongly predicted overall survival (OS) in patients with metastatic breast cancer (Abstract GS4-08).
Patients with evidence of CTC response had a significantly increased OS of 32.2 months compared with 17.9 months in patients without a treatment response (hazard ratio [HR] = 0.49).
Furthermore, early treatment monitoring of CTCs, which are shed from the primary tumor into the bloodstream, was predictive of survival in all tumor subtypes.
“With the increasing number of treatment options available to patients with metastatic breast cancer, being able to predict and monitor treatment responses rapidly will be critical to aiding treatment decisions,” said lead study author, Wolfgang Janni, Professor and Director of the Women’s Clinic at Ulm University Hospital, in Germany. “These data indicate that CTC dynamics can predict the trajectory of the disease a little more than four weeks after initiating treatment.”
For this study, the researchers analyzed global pooled datasets from peer-reviewed and published studies of 4,079 patients with metastatic breast cancer who had undergone baseline and follow-up CTC measurements using the CellSearch test.
According to Dr. Janni, “This provides an advantage over conventional imaging methods and can help physicians determine very early on whether a treatment should be continued,” said Dr. Janni. “It is also very reassuring that CTC dynamics predicted outcomes for all breast cancer subtypes.”
As precision medicine approaches continue to evolve, CTC dynamics combined with circulating tumor DNA may also be used to guide initial treatment decisions, concluded Dr. Janni.
Entinostat Disappoints in Endocrine-Resistant Breast Cancer
Despite recent treatment advances, resistance to endocrine therapy remains a significant clinical problem in breast cancer. Results of a randomized Phase 3 trial suggest that histone deacetylase (HDAC) inhibition is unlikely to be the solution (Abstract GS4-02).
Data from the E2112 study, which randomized 608 patients with hormone-receptor positive (HR+), HER2-negative advanced breast cancer to endocrine therapy plus entinostat, an HDAC inhibitor, versus endocrine therapy alone, showed no improvement in survival with the combination of exemestane and entinostat versus control.
“We were very disappointed in these results after so many years of work, but we’ve realized again the importance of confirmation of promising data,” said lead study author, Roisin M. Connolly, MD, of the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins.
The findings showed no significant difference in progression-free survival (PFS) with the addition of entinostat to endocrine therapy, and the overall response rate was low in both study arms (4.6% in the entinostat arm and 4.3% in the placebo arm).
With a median OS of 23.4 months in the intervention arm and 21.7 months in the placebo arm, no significant difference in OS was observed.
Subgroup analysis for both progression-free survival (PFS) and OS showed similar results in all subgroups, including prior CDK inhibitor exposure, said Dr. Connolly, who noted that these results differ from those of the multicenter ACE trial where a modest PFS advantage was observed with the addition of an HDAC inhibitor, chidamide or tucidinostat, to exemestane to a Chinese patient population.
“Although robust preclinical and clinical data supported the development of E2112, our results highlight the importance of Phase 3 confirmation of promising Phase 2 data,” said Dr. Connolly. “The short median PFS of approximately 3 months and low overall response rate observed with an endocrine-therapy backbone suggest that improved decision-making tools are required to help determine who may need chemotherapy versus alternative strategies in this setting.”
When asked to speculate on the future of HDAC inhibitors, Dr. Connolly noted several ongoing investigations of HDAC inhibitors in various combinations. After the results of this study, however, HDAC inhibitors “clearly do not have a role in this patient population,” she observed.
“HDAC inhibitors have been combined with chemotherapies and other targeted therapies over the years but have unfortunately not broken into the solid tumor space,” concluded Dr. Connolly. “Ongoing work will be required to see where they may fit in the future.”
Neoadjuvant Nab-Paclitaxel Improves pCR vs Dose-Dense Paclitaxel
Data from a large Phase 3 trial could help select patients for neoadjuvant chemotherapy in high-risk HR+, HER2-negative breast cancer.
Results from the neoadjuvant part of the ADAPT HR+/HER2– trial showed that patients randomized to nab-paclitaxel had improved rates of pathological complete response (pCR) compared with those receiving standard paclitaxel (Abstract GS4-03).
“Use of neoadjuvant nab-paclitaxel appears to be highly effective and well tolerated and was associated with a significantly higher pCR,” said lead study author, Sherko Kuemmel, MD, Director of the Breast Centre of the Essen-Mitte Clinics, in Germany. “We will have to wait for the final analysis of this huge trial to see if there’s a benefit in disease-free survival and overall survival, but these results are very promising.”
Dr. Kuemmel noted that dose-dense chemotherapy is currently the standard of care in high-risk EBC. In some trials of HR+, HER2-negative EBC, however, neoadjuvant nab-paclitaxel has been shown to superior to solvent-based paclitaxel with respect to pCR and survival.
For the neoadjuvant part of this study, a total of 864 high-risk patients were randomized between 8x weekly nab-paclitaxel and a dose-dense regimen of paclitaxel. Results of the primary endpoint showed a pCR of 20.8% in the nab-paclitaxel arm compared with 12.9% in patients receiving paclitaxel (P=.002).
ADAPT is also the first large prospective study confirming recurrence score (RS) >25 as a predictive factor for pCR in patients treated with neoadjuvant chemotherapy, said Dr. Kuemmel, who noted that RS >25 and tumor size (<cT2) were shown to be independent predictive factors for pCR.
Ki67 as an additional dynamic marker further separates the high-risk group and identifies patients who may not benefit from intensive chemotherapy, reported Dr. Kuemmel.
Optimal therapy for these patients is being investigated in the ongoing ADAPTcYcle trial, which is evaluating a standard endocrine approach together with CDK4/6 inhibition versus chemotherapy in patients who are not candidates for chemotherapy alone in the adjuvant treatment setting.
When asked whether the improvement in pCR would translate into disease-free or OS benefit, Dr. Kuemmel noted results from the recent GeparSept trial.
“The difference in pCR in this subgroup of endocrine-positive disease translated to improved overall survival, so we will have to wait a few months to see just how many patients benefit with nab-paclitaxel instead of paclitaxel,” he concluded.
by Chase Doyle
Day 3 of the 2020 San Antonio Breast Cancer Symposium (SABCS) virtual meeting featured advances in how to optimally use adjuvant chemotherapy for early-stage breast cancer (EBC), a setback in the metastatic setting of triple-negative breast cancer (TNBC), and mixed news for survivors looking to conceive post-treatment.
No Adjuvant Chemo Needed for Postmenopausal Women with EBC and Low Recurrence Score
Many women with the most common form of breast cancer can safely avoid chemotherapy and still achieve similar outcomes with endocrine therapy alone, according to an interim analysis of the SWOG S1007 RxPONDER trial (Abstract GS3-00).
Findings from the study, which evaluated the role of chemotherapy in more than 5,000 women with hormone receptor (HR)-positive, HER2-negative breast cancer with 1 to 3 positive nodes and a recurrence score (RS) ≤25, suggest that postmenopausal women can forgo adjuvant chemotherapy without compromising invasive disease-free survival (iDFS).
“This will save tens of thousands of women the time, expense and potentially harmful side effects that can be associated with chemotherapy infusions,” said lead study author Kevin Kalinsky, MD, director of the Glenn Family Breast Center at Winship Cancer Institute of Emory University, Atlanta.
At 54% of the anticipated iDFS events in the overall population, the analysis showed that postmenopausal women with an RS score ≤25 did not benefit from adjuvant chemotherapy in any subgroup.
Conversely, investigators observed a five-year iDFS improvement with the addition of chemotherapy followed by endocrine therapy in all premenopausal subsets. Although the follow-up is still limited, investigators also identified a 5-year survival benefit of 1.3% favoring chemotherapy followed by endocrine therapy versus endocrine therapy alone in premenopausal women with positive nodes and an RS score ≤25.
Although the results of the study are clear, the explanation for the findings may be less so, according to Kent Osborne, MD, Dudley and Tina Sharp Chair for Cancer Research, Baylor College of Medicine, in Houston.
“The results clearly show no benefit to adding chemotherapy to standard endocrine therapy in post-menopausal patients, despite having positive nodes,” said Dr. Osborne. “This emphasizes that node positivity, while an important prognostic marker, is not a predictive marker of chemotherapy sensitivity. In premenopausal patients, a different result was obtained.”
Dr. Osborne explained the majority of premenopausal patients in this study received tamoxifen as endocrine therapy. The standard approach today, however, would be ovarian suppression plus either tamoxifen or an aromatase inhibitor, which would have been superior to tamoxifen alone in this subgroup.
“Since adjuvant chemotherapy causes ovarian suppression in many premenopausal patients, the patients in this study actually received ovarian suppression plus tamoxifen, while tamoxifen alone was the endocrine therapy for the no-chemotherapy arm,” he concluded. “We may never know whether the difference in outcome in this subset is due to the endocrine effects of chemotherapy.”
Ipatasertib Shows No PFS Benefit in Advanced TNBC
Findings of a Phase 3 study could cast doubt on the future of AKT and PI3K inhibition in triple-negative breast cancer (TNBC).
The addition of AKT inhibitor ipatasertib to paclitaxel in patients who harbored PIK3CA, AKT1, or PTEN alterations did not significantly improve progression-free survival (PFS) in the first-line setting of advanced TNBC, according to primary results from IPATunity130 Cohort A (Abstract GS3-04).
With a median follow-up of 8.3 months, data from the double-blind, placebo-controlled, randomized Phase 3 trial showed a PFS of 6.1 months in patients receiving paclitaxel alone versus 7.4 months with ipatasertib. However, the stratified PFS hazard ratio of 1 was not statistically significant, said Rebecca Dent, MD, associated professor at the National Cancer Center Singapore, in Singapore.
Confirmed overall response showed a slight improvement from 35% with paclitaxel compared to 39% with the addition of ipatasertib, and similar rates of clinical benefit.
Safety was consistent with previously reported results for this combination, which showed higher rates of diarrhea in the ipatasertib combination arm.
Dr. Dent highlighted the surprising differences in results between this Phase 3 study and the randomized Phase 2 LOTUS trial of ipatasertib, which showed “impressive improvement in overall survival and a modest improvement in PFS.”
“The question on everybody’s mind is, ‘Why after such amazing data from both randomized Phase 2 trials with AKT inhibition in advanced TNBC have we gotten these [negative] results?’” said Dr. Dent. “I think it’s important to recognize that TNBC is very heterogeneous. It’s really just an overarching term to describe a breast cancer that has several different pathways that are upregulated.”
As for the future of AKT or PI3K inhibitors in TNBC, Dr. Dent noted that translational work exploring potential biomarkers of benefit from ipatasertib is ongoing as researchers continue to learn about this disease.
“I don’t think the story is over yet,” said Dr. Dent. “I think it’s only just beginning.”
Meta-Analysis Finds Significantly Reduced Odds of Pregnancy after Breast Cancer
New research highlights the significant impact of breast cancer and its treatment on subsequent chance of pregnancy.
Results of the systematic review and meta-analysis of 39 studies that identified women who had been pregnant after a breast cancer diagnosis and included data on 114,573 breast cancer patients showed a 60% lower chance of getting pregnant post-treatment in breast cancer survivors compared with the general population (Abstract GS3-09). In fact, only survivors of cervical cancer had lower odds of subsequent pregnancy.
“While results of this meta-analysis provide reassuring evidence on the feasibility and safety of conceiving in women with prior history of breast cancer, the reduced chances of future conception among breast cancer survivors should raise awareness about the importance of offering complete oncofertility counseling,” said Lead study author, Eva Blondeaux, MD, a medical fellow in oncology at IRCCS Policlinico San Martino Hospital.
Dr. Blondeaux and colleagues also identified higher risk of delivery and fetal complications, particularly in women exposed to prior chemotherapy. Compared with women in the general population, breast cancer survivors had 50% higher risk of having a baby with low birth weight, 16% higher risk of having a baby that was small for gestational age, a 45% higher risk of preterm labor, and a 14% higher risk of having a caesarean section.
Importantly, however, the researchers found no significant increased risk of congenital abnormalities or other delivery complications. Although there is a need for closer monitoring of these pregnancies, said Dr. Blondeaux, the lack of negative effects on survival indicate that many women can successfully go through pregnancy after breast cancer.
“Returning to a normal life after cancer should be considered a crucial ambition in cancer care in the 21st century,” said Dr. Blondeaux. “This study shows the need for deeper consideration of patients’ pregnancy desire as a crucial component of their survivorship care plan and wish to return to a normal life.”