A post-hoc analysis of a phase 3 trial published in 

demonstrated that autologous hematopoietic stem-cell transplantation (HSCT) induced superior long-term benefit in patients with mantle cell lymphoma (MCL) in comparison with interferon alfa.

The sustained efficacy associated with HSCT supports its role as standard frontline treatment for this population, however, new targeted therapies may potentially challenge that role.

Data from an exploratory intention-to-treat analysis showed that the median progression-free survival (PFS) for those who underwent HSCT was 3.3 years (95% CI, 2.5-4.3) vs 1.5 years (95% CI, 1.2-2.0) for those who received interferon alfa maintenance (adjusted hazard ratio [aHR], 0.50; 95% CI, 0.36-0.69; 

 < .0001). Moreover, the median overall survival (OS) was 7.5 years (95% CI, 5.7-12.0) in the HSCT group compared with 4.8 years (95% CI, 4.0-6.6) in the interferon alfa group (aHR, 0.66; 95% CI, 0.46-0.95; 

Moreover, for patients who received induction therapy without rituximab (Rituxan), the aHR for PFS in the HSCT group vs interferon alfa group was 0.40 (95% CI, 0.26-0.61; 

< .0001), compared with 0.72 (95% CI, 0.42-1.24; 

= .087) in patients who did receive rituximab. The aHR for OS in the HSCT group vs interferon alfa group was 0.52 (95% CI, 0.33-0.82; 

= .016) without rituximab and 1.05 (95% CI, 0.55-1.99; 

= .680) for patients who received rituximab.

“Whether an autologous HSCT should be generally recommended despite the available additional therapeutic options cannot be appropriately addressed with this trial alone,” lead author Anna-Katharina Zoellner, MD, of Ludwig-Maximilians-University Hospital of Munich-Grosshadern, Munich, Germany, and colleagues, wrote. “However, the absence of any significant benefit of autologous HSCT for patients after rituximab-containing induction underlines the need to further explore the value of autologous HSCT in comparison with the most effective regimens available.”

Data from several studies done over the past 2 decades have demonstrated that HSCT results in high response and PFS rates. As such, this approach serves as the current standard of care for younger, fit patients with MCL in advanced stages.

This study, which was initiated in 1996 by the European Mantle Cell Lymphoma Network, was one of the first to establish the role of this modality. This was also the first to have an open-label, multicenter, randomized, phase 3 trial design that was conducted to specifically analyze the safety and efficacy of HSCT vs interferon alfa maintenance therapy following a cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP)–like induction therapy, without or with rituximab (R-CHOP), in patients with advanced-stage MCL who were younger than 65 years of age.

Primary results from the trial showed that although autologous HSCT significantly prolonged PFS over vs maintenance interferon alfa, the OS benefit with the former was not found to be statistically significant at a median follow-up of 25 months. In the 15 years since the primary publication of the study, treatment for this patient population has evolved substantially, with use of rituximab in induction therapy, as well as high-dose chemotherapy regimens, and targeted treatments.

For the current report, investigators sought to examine the long-term results from the trial, including OS, in patients with primary advanced-stage MCL treated with high-dose radiochemotherapy and autologous HSCT, or interferon alfa maintenance in remission following chemotherapy without or with rituximab. Additionally, the study authors assessed whether the efficacy of HSCT was modified by the addition of rituximab to frontline induction in this setting.

A total of 292 patients were registered to the European Mantle Cell Lymphoma Network trial. These patients were between the ages of 18 years and 65 years and had previously untreated advanced stage III and IV MCL. Those with a poor performance status, defined as an ECOG performance status of higher than 2, or who had severe cardiac, pulmonary, hepatic, or renal impairment, were excluded from the research.

Patients were randomized 1:1, prior to induction, to receive either myeloablative radiochemotherapy followed by autologous HSCT (n = 134) or interferon alfa maintenance afterinduction therapy was completed (n = 135).

Induction therapy consisted of 4 cycles of CHOP for those who experienced a complete remission (CR) following 4 cycles, or 6 cycles for all others; CHOP-like regimens; or a combination of IV rituximab at a dose of 375 mg/m2 on day 0 or 1 of each cycle plus CHOP. Those who were given CHOP received intravenous (IV) cyclophosphamide at a dose of 750 mg/m2 on day 1, IV doxorubicin at a dose of 50 mg/m2 on day 1, IV vincristine a dose of 1.4 mg/m2 on day 2, and oral prednisone at a dose of 100 mg/m2 on days 1 through 5; this was repeated every 21 days.

Per protocol, further treatment for patients who did not have a partial remission (PR) after 6 cycles of induction therapy was up to the discretion of the treating physician.

Additionally, patients randomized to the HSCT arm received intensified stem-cell mobilization chemotherapy. Myeloablative therapy was given within 2 months of mobilization and consisted of a total body irradiation and a high-dose cyclophosphamide regimen. The previously harvested peripheral blood stem cells were then reinfused on day 0 and granulocyte colony-stimulating factor was started on day 1.

Those randomized to the interferon alfa arm received 2 additional cycles of conventional chemotherapy to balance the mobilization scheme. Subcutaneous interferon alfa was thereafter given at a starting dose of 6 × 106 IU 3 times weekly until disease progression. The dose was adapted based on toxicity.

Patients were the followed until disease progression, through assessment history, physical examinations, ultrasound examinations of the abdomen, and a complete laboratory investigation every 3 months. Chest radiography was performed every 6 months, and survival follow-up until death was planned.

The primary outcome of the post-hoc analysis was PFS from the end of induction until disease progression or death among those who achieved a remission. The secondary outcome was OS from end of induction to death.

Participants included in the analysis had a median age of 55 years (range, 47-60), and the majority were male (78%), had stage IV disease (82%), and an ECOG performance status of 1 (53%). Moreover, 73% of patients had a low-risk disease, 29% had elevated serum lactate dehydrogenase concentration, and 40% had B symptoms present.

Regarding induction treatment, 51% received CHOP, 39% received CHOP with rituximab, and 10% received a CHOP-like chemotherapy regimen. By the end of induction, 29% achieved a CR and 71% experienced a PR.

Of the 114 patients with MCL enrolled to the interferon arm and the 118 patients enrolled to the HSCT arm, 81 and 93 patients, respectively, experienced remissions following induction treatment.

Results from an exploratory analysis of secondary malignancies revealed no clear effect of autologous HSCT vs maintenance interferon alfa on the risk of secondary myelodysplastic syndrome or leukemia (HR, 1.6; 95% CI, 0.31-8.3; 

Moreover, data from an exploratory subgroup analysis, showed that patients who achieved a CR after induction therapy experienced a median PFS of 3.9 years (95% CI, 3.0-7.5) in the HSCT group vs 1.9 years (95% CI, 1.06-3.00) in the interferon alfa group (

= .0003); those who achieved a PR had a median PFS of 2.5 years (95% CI, 2.3-4.3) and 1.4 years (95% CI, 1.1-2.0), respectively (

Patients who achieved a CR following induction therapy reported a median OS of 9.7 years (95% CI, 6.7–not reached [NR]) in the HSCT group vs 6.5 years (95% CI, 4.0-18.5) in the interferon alfa group (

= .15); those who achieved a PR had a median OS of 6.3 years (95% CI, 5.1-12.0) and 4.6 years (95% CI, 3.7-7.4), respectively (

Patients who received an induction regimen without rituximab experienced a significantly increased PFS and OS following HSCT compared with interferon alfa maintenance therapy, according to findings from further exploratory subgroup analyses.

Specifically, the median PFS was 3.1 years (95% CI, 2.5-4.3) in the HSCT group vs 1.2 years (95% CI, 1.0-1.9) in the interferon alfa group (

< .0001). The Cox regression analysis adjusted for MIPI score showed an aHR of 0.40 (95% CI, 0.26-0.61). Moreover, the median OS was 6.7 years (95% CI, 5.4-12.9) and 4.3 years (95% CI, 3.6-6.6), respectively (

= .016). The aHR was 0.52 (95% CI, 0.33-0.82).

For those treated with a rituximab-containing induction regimen, the median PFS survival was 3.4 years (95% CI, 2.4-6.8) in the HSCT group vs 1.7 years (95% CI, 1.4-5.9) n the interferon alfa group (

= .087). The aHR was 0.72 (95% CI, 0.42-1.24). Additionally, the median OS was 9.6 years (95% CI, 5.5-12.2) and 5.5 years (95% CI, 4.6–NR), respectively (

= .68). The Cox regression analysis adjusted to MIPI score gave an adjusted HR of 1.05 (95% CI, 0.55-1.99).

“On the basis of these mature data, the significantly improved PFS after autologous HSCT is independent of remission status after induction therapy, with OS showing the same trend,” study authors concluded. “Therefore, these data from the first randomized phase 3 trial of the European Mantle Cell Lymphoma Network underline the relevance of post-induction autologous HSCT in the context of a CHOP-like induction therapy.”

However, the treatment of the disease has changed since the start of this trial. As such, data from ongoing efforts like the phase 3 TRIANGLE trial (NCT02858258) could serve to challenge the future role of autologous HSCT in young patients with MCL.

Zoellner A-K, Unterhalt M, Stilgenbauer S, et al. Long-term survival of patients with mantle cell lymphoma after autologous haematopoietic stem-cell transplantation in first remission: a post-hoc analysis of an open-label, multicentre, randomised, phase 3 trial. 

. 2021;8(9):e648-e657. doi:10.1016/S2352-3026(21)00195-2

This article was originally published on OncLive as “Autologous HSCT Shows Sustained Long-Term Benefit in MCL, But Role May Be Rechallenged By Novel Approaches”

Articles

Autologous hematopoietic stem-cell transplantation, the standard frontline treatment in treating patients with mantel cell lymphoma, demonstrated superior long-term efficacy compared with interferon alfa in a recent trial. 

Autologous HSCT Continues to Show Sustained Benefit in MCL, But Targeted Therapies May Challenge its Role as Standard Frontline Treatment

indicate that 6 months following the second dose of the Pfizer-BioNTech COVID-19 vaccine, patients with solid tumors and individuals without cancer displayed similar levels of COVID-19 antibodies in their blood.

Results from the study showed that 79% of those with solid tumors were seropositive for the antibodies compared with 84% of healthy controls at 6 months after their second dose of the vaccine. However, antibody levels in both groups decreased significantly from the time of vaccination.

“In our study we saw that in all outcomes, including immunogenicity, infectivity rate throughout the 6-month period, and safety, patients with solid tumors depicted a similar trend as the general population,” said lead study author Irit Ben-Aharon, MD, PhD, director of the oncology division at Rambam Health Care Campus in Israel.

Though the available COVID-19 vaccines have shown high efficacy in the general population, their long-term safety and efficacy among patients with cancer had been underrepresented. Moreover, patients with cancer receiving cytotoxic therapy or immune modifying agents were not able to participate in other vaccine studies, and as such, there remains an unmet need to examine the efficacy of the vaccines in this group.

Although it had been suggested that all patients with cancer were at increased risk for COVID-19 infection, recent studies have shown that outcomes and manifestations differ significantly depending on the malignancy type and treatment. Furthermore, data on vaccine efficacy in patients with cancer have shown similar short-term efficacy and safety among patients with when compared with healthy controls.

In this study, investigators sought to examine the long-term safety and efficacy of the COVID-19 vaccine in this population at 6 months after vaccination.

The study enrolled patients with solid tumors receiving active anti-cancer therapy and followed their progress for 6 months after the administration of the second dose of the vaccine. Patients must have been receiving their cancer therapy throughout 6-month duration, as well.

In the study cohort overall, investigators enrolled 154 patients with solid tumors, in addition to 135 age-matched healthy controls. Of the original cohort, 88 patients were enrolled; 64 who met the inclusion criteria were subsequently added.

In the solid tumor cohort, the median age was 66 years (range, 32-87), and more than half of patients were male (55%). In the control cohort, 56% of individuals were women and the median age was 63 years old (range, 50-87).

Most of the patients with cancer enrolled presented with metastatic disease (84%), and the most common cancer types were gastrointestinal (36%), lung (23%), breast (17%), and genitourinary cancers (11%). Moreover, the most common anti-cancer treatment among patients was chemotherapy (62%), followed by biological agents (36%) and immunotherapy (30%).

Additional data showed that chemotherapy was more highly associated with seronegative serologic status vs other treatment modalities (27% vs 10%; odds ratio [OR], 0.31; 

 = .02), and women were more likely to be seropositive than men (93% vs 75%; OR, 0.21; 

Furthermore, there was 1 documented case of severe COVID-19 infection that required hospitalization in the cohort of patients with cancer.

In terms of safety, elevation of liver enzyme levels was reported in 10% of patients with cancer up to 6 weeks after receiving the first dose of the vaccine. Moreover, newly documented regional lymphadenopathy was reported on 5% of CT/PET scans. However, all adverse effects were resolved in all patients throughout the course of the study period.

Additionally, the vaccination led to anti-cancer treatment delays for 6% of patients with cancer, all of whom were receiving chemotherapy. Delays were most commonly due to neutropenia, mild thrombocytopenia, and neutropenia with herpes labialis.

“Our study indicates that the pattern of immunogenicity and efficacy of the [Pfizer-BioNTech COVID-19 vaccine] in patients with solid tumors on active intravenous anti-cancer treatment 6-months post vaccination resemble the pattern of the general population,” the study authors concluded. “Former subtle differences which were evident between the 2 cohorts shortly after vaccination disappeared throughout time. Nonetheless, due to uncertainty of the extended efficacy of the vaccine in the general population and recent reports on rising infection rates among vaccinated individuals, adherence to health care risk reduction recommendations is cardinal.”

Waldhorn I, Holland R, Goshen-Lago T, et al. Six month efficacy and toxicity profile of BNT162b2 vaccine in cancer patients with solid tumors. 

. Published online September 2, 2021. doi:10.1158/2159-8290.CD-21-1072

Six-month efficacy of Pfizer/BioNTech COVID-19 vaccine in patients with solid tumors similar to general population. News release. American Association for Cancer Research. September 2, 2021. Accessed September 2, 2021.

The Pfizer-BioNTech COVID-19 vaccine induces similar levels of COVID-19 antibodies in patients with solid cancer compared with people without cancer.



COVID-19 Vaccine Elicits Similar 6-Month Antibody Response in Both Patients with Solid Tumors and the General Population

High tumor mutational burden (TMB-H) was associated with high response rates to the single-agent dostarlimab-gxly (Jemperli) among patients with endometrial cancer. This response was consistent across mismatch repair (MMR) and microsatellite stability (MSI) status, suggest findings from a post-hoc analysis of the phase 1 GARNET trial (NCT02715284) presented during the 2021 ESMO Congress.

Dostarlimab elicited an overall response rate (ORR) of 44.9% (95% CI, 34.8%-55.3%) in patients with TMB-H status (n = 44/98) vs 13.0% (95% CI, 8.1%-19.3%) in those with TMB-low (TMB-L) status (n = 20/154).

In those with TMB-H and mismatch repair deficient (dMMR)/microsatellite instability­–high (MSI-H) status (n = 39/87), the ORR with the agent was 44.8% (95% CI, 34.1%-55.9%) vs 23.1% (95% CI, 5.0%-53.8%) in those with dMMR/MSI-H and TMB-low status (n = 3/13). In those with TMB-H status and mismatch repair proficient (MMRp)/microsatellite stable (MSS) disease, the ORR with the agent was 45.5% (95% CI, 16.7%-76.6%) vs just 12.1% (95% CI, 7.2%-18.6%) in those with TMB-L status and MMRp/MSS disease (n = 17/141).

“Notably, the ORR [experienced by] patients with MMRp and TMB-H endometrial cancer was comparable to the ORR of those with TMB-H and dMMR/MSI-H [disease],” lead study author Ana Oaknin MD, principal investigator of Vall d'Hebron Institute of Oncology’s Gynecological Malignancies Group, noted in a poster presentation on the data. “TMB-H status in patients with MMRp endometrial cancer was not due to MSI-H or POLe-mutated status.”

Dostarlimab is a humanized PD-1 monoclonal antibody that blocks interaction with the PD-1 ligands, PD-L1, and PD-L2. In April 2021, the FDA granted an accelerated approval to the agent for use as a monotherapy in adult patients with dMMR recurrent or advanced endometrial cancer that has progressed on or after a platinum-containing regimen.

 in the European Union to be used as a single agent in patients with dMMR/MSI-H endometrial cancer that has progressed on or following a platinum-containing regimen.

Both of the regulatory decisions were based on data from the single-arm phase 1 GARNET trial, which evaluated dostarlimab monotherapy in multiple tumor types, including 2 cohorts of patients with endometrial cancer.

TMB has been previously studied as a predictor of response to anti–PD-1 therapy, but data in endometrial cancer are limited. As such, in the analysis, investigators sought to examine the antitumor activity of dostarlimab in patients with dMMR/MSI-H or MMRp/MSS endometrial cancer by TMB status.

The GARNET study was conducted in multiple parts, with part 1 serving as the dose-finding portion, and part 2A comprised of a fixed-dose safety run-in. Part 2B of the study included expansion cohorts of patients with dMMR/MSI-H (cohort A1; n = 129) and MMRp/MSS endometrial cancer (cohort A2; n = 161).

To be eligible for enrollment on cohorts A1 and A2, patients must have progressed on or after platinum doublet therapy, have received 2 or fewer prior lines of treatment for recurrent or advanced disease, and had measurable disease at baseline. Patients also needed to be naïve to anti–PD-L1 agents.

Patients could be screened based on local MMR/MSI testing results through the use of immunohistochemistry (IHC), polymerase chain reaction, or next-generation sequencing (NGS) performed in a certified local laboratory. However, patient cohort assignment was based on MMR IHC results.

Study participants received 500 mg of intravenous (IV) dostarlimab every 3 weeks for 4 cycles, and then 1000 mg every 6 weeks thereafter, until disease progression.

The primary end points of the study were ORR and duration of response per RECIST v1.1 criteria and blinded independent central review (BICR).

In the post-hoc analysis, and TMB status was an exploratory biomarker determined using the Foundation One test. TMB-H status was defined as having 10 or more mutations/megabase, and TMB-L status was defined as having less than 10 mutations/megabase.

As of a data cutoff date of March 1, 2020, a total of 129 patients with dMMR/MSI-H endometrial cancer and 161 patients with MMRp/MSS disease were enrolled and received treatment with dostarlimab. These populations comprise the safety populations of cohorts A1 and A2, respectively.

The primary efficacy population included those with 24 weeks or more of follow-up time in the study, and who had at least 1 measurable lesion at baseline, per BICR. Overall, 105 patients with dMMR/MSI-H disease and 156 patients with MMRp/MSS disease were evaluable for the analysis.

The median age of patients was 64 years (range, 30-86). Most patients with dMMR/MSI-H status had FIGO stage I or II disease at primary diagnosis (54.3%); the majority of those in the MMRp/MSS cohort had FIGO stage III or IV disease (62.8%). In terms of histology, most patients in cohort A1 presented with endometrioid carcinoma grade 1/2 (67.6%), and most patients in cohort A2 presented with serous disease (37.8%). In both cohorts A1 and A2, the majority of patients had a least 1 prior line of therapy (62.9% and 46.2%, respectively) and had received prior radiation (70.5% and 60.9%, respectively).

Among those with dMMR/MSI-H endometrial cancer (n = 105), 82.9% (n = 87) had TMB-H status, 12.4% (n = 13) had TMB-L status, and 4.8% (n = 5) had TMB status that could not be determined. For those with MMRp/MSS disease (n = 156), 90.4% (n = 141) had TMB-L status, 7.0% (n = 11) had TMB-H status, and 2.6% (n = 4) had TMB status that could not be determined.

The median number of mutations/megabase in patients with dMMR/MSI-H endometrial cancer (n = 100) was 20.17 (range, 2.52-428.69), compared with 3.78 (range, 0-83.22) in those with MMRp/MSS disease (n = 152).

The data cutoff date for the prespecified interim analysis was March 1, 2020, and additional data showed that TMB-high status and dMMR/MSI-H status had substantial overlap in the patient populations, and TMB-H endometrial cancers and dMMR/MSI-H endometrial cancers experienced similar response rates with dostarlimab, at 44.9% and 44.8% (n = 47/105; 95% CI, 35.0%-54.8%), respectively.

Moreover, the ORR achieved with the agent in patients with MMRp disease and TMB-H status was notably comparable to that ORR experienced by those with dMMR/MSI-H and TMB-H status, at 45.5% and 44.8%, respectively.

“Of the 11 patients with MMRp/TMB-H endometrial cancer, all had MSI and POLe test results available,” Oaknin said. “One patient was MSI-H, according to Foundation Medicine NGS testing, and 1 patient had an intermediate MSI score; 9 were MSS. None of the 11 patients had a POLe exonuclease domain mutation identified.”

The study was not powered to assess antitumor activity by TMB status, and interpretation is limited by the small number of patients in each subgroup, Oaknin concluded.

Oaknin A, Gilbert L, Tinker AV, et al. Analysis of antitumor activity of dostarlimab by tumor mutational burden (TMB) in patients (pts) with endometrial cancer (EC) in the GARNET trial. Presented at: 2021 ESMO Congress; September 16-21, 2021; Virtual. Abstract 76P.

FDA grants accelerated approval to dostarlimab-gxly for dMMR endometrial cancer. News release. FDA. April 22, 2021. Accessed September 16, 2021. 

European Commission approves GSK’s Jemperli (dostarlimab), the first anti-PD-1 therapy approved for recurrent or advanced endometrial cancer. News release. GlaxoSmithKline, April 23, 2021. Accessed September 16, 2021. 

Patients with endometrial cancer and high tumor mutational burden experienced superior overall response rates to the agent dostarlimab than patients with low mutational burden. 

Dostarlimab Elicits Superior Responses in Patients with High Mutational Burden in Endometrial Cancer

Women between the ages of 25 and 42 years may be able to decrease their risk of developing early-onset colorectal cancer (CRC) by increasing their intake of vitamin D, according to results from a prospective cohort study published in 

Results showed that compared with women who consumed less than 300 IU of vitamin D daily, the HR was 0.51 (95% CI, 0.30-0.86) for those who consumed 300 IU to 450 IU daily, and 0.49 (95% CI, 0.26-0.93) for those who consumed 450 IU or more per day (

for trend = .01). No evidence of a nonlinear association was reported (

for nonlinearity = .50). Moreover, the HR per 400 IU/day increase was 0.46 (95% CI, 0.26-0.83).

“Vitamin D has known activity against CRC in laboratory studies. Because vitamin D deficiency has been steadily increasing over the past few years, we wondered whether this could be contributing to the rising rates of CRC in young individuals,” Kimmie Ng, MD, MPH, study author and director of the Young-Onset Colorectal Cancer Center at Dana-Farber Cancer Institute, stated in a press release.2 “We found that total vitamin D intake of 300 IU per day or more — roughly equivalent to three 8-oz. glasses of milk — was associated with an approximately 50% lower risk of developing young-onset CRC.”

Although the incidence of CRC has decreased in the United States and many other countries, the rate of adults younger than 50 years of age developing CRC has been on the rise. Due to delays in screening and other clinicopathologic features, cases of early-onset CRC tend to be is usually diagnosed at a more advanced stage. Moreover, although a large portion of early-onset cases do not have a family history of CRC, other known risk factors like obesity have been found to increase the risk of early-onset CRC.

Findings from previous studies have suggested that vitamin D intake may be a protective factor against CRC. However, it remains unknown whether vitamin D intake is linked with risk of early-onset CRC. With consumption of vitamin D–rich food, such as milk, fish, and eggs declining, investigators sought to examine whether vitamin D intake correlated with the risk of early-onset CRC.

To conduct this research, investigators analyzed data from the Nurses’ Health Study (NHS) II, a prospective cohort study of 116,429 female nurses between the ages of 25 years and 42 years. The trial began in 1989 and those enrolled on the NHS II study completed self-administered questionnaires every 2 years on demographics, lifestyle factors, and health-related information. These questionnaires were complemented by assessment of dietary intake through the use of food frequency questionnaires done every 4 years.

Those with inflammatory bowel disease, a previous diagnosis of CRC, implausible data for baseline energy intake or missing data for baseline vitamin D intake were not included in the analysis. Total vitamin D intake was calculated by adding dietary vitamin D intake and supplemental vitamin D intake from supplements or multivitamins.

Body mass index was calculated based on reported height and weight, with weight updated every 2 years. Investigators examined total energy, red meat, processed meat, fiber, calcium, folate, and alcohol. Smoking status was updated biennially for calculation of pack-years smoked. Physical activity was self-reported with questionnaires done every 2 to 4 years. Television viewing time was also used as a measure for sedentary behavior.

The primary end point for the study was the incidence of early-onset CRC, defined as CRC diagnosed before the age of 50 years.

“We also identified unreported lethal CRC cases through family members, the postal system, and the National Death Index. For all deaths due to CRC, we requested consent from the next of kin for acquisition of medical records,” the study authors wrote. “Physicians who were blinded to exposure status reviewed medical records to verify CRC diagnosis and recorded histopathologic findings and anatomic location.”

Of the 94,205 women studied, 111 cases of early-onset CRC during 1,250,560 person-years of follow-up were identified from 1991 to 2015, and the median vitamin D intake among them was 372 IU/day. Moreover, participants under the age of 50 years were less likely to have a high BMI, smoke cigarettes, consume alcohol, spend significant amounts of time watching television, or consume red meat. Additionally, these participants were more likely to consume more dietary fiber, folate, and calcium; use more aspirin and multivitamins; and be physically active and have healthy dietary habits.

Additional data showed that sources of vitamin D intake were inversely associated with reduced risk of early-onset CRC. A stronger association was observed for dietary vitamin D (HR per 400 IU/day increase, 0.34; 95% CI, 0.15-0.79) than supplemental vitamin D (HR per 400 IU/day increase, 0.77; 95% CI, 0.37-1.62). Moreover, vitamin D from dairy products was a significant contributor for this association (HR per 400 IU/day increase, 0.32; 95% CI, 0.12-0.84).

Investigators documented a total of 1,439 newly diagnosed conventional adenomas and 1,878 serrated polyps among participants younger than 50 years of age who had undergone a lower endoscopy from 1991 to 2011. Higher vitamin D intake was also associated with lower risk in this population. Compared with those who consumed less than 300 IU/day, the HR of any conventional adenoma was 0.71 (95% CI, 0.56-0.89) for those who consumed 600 IU/day or less, and the HR for any serrated polyp was 0.85 (95% CI, 0.70-1.03).

“Our results further support that avoiding low vitamin D status is important in younger adults for health and possibly CRC prevention,” study authors wrote. “If confirmed, our findings could potentially lead to recommendations for higher vitamin D intake as an inexpensive low-risk complement to CRC screening as CRC prevention strategy for adults younger than age 50.”

Kim H, Lipsyc-Sharf M, Zong X, et al. Total vitamin D intake and risks of early-onset colorectal cancer and precursors. 

. Published online July 7, 2021. doi:10.1053/j.gastro.2021.07.002

Shining new light on vitamin D and cancer. News release. Harvard University. August 17, 2021. Accessed August 20, 2021. 

This article was originally published on OncLive as “Increased Vitamin D Intake Associated With Lower Risk of Early-Onset CRC”

The data showed that a daily intake of around 300 IU of vitamin D — roughly the same as three 8-oz. glasses of milk — was linked to a nearly 50% decreased risk of early-onset colorectal cancer among women between the ages of 25 and 42 years.



Vitamin D Intake May Be Protective Against Early-Onset Colorectal Cancer

The phase 3 CheckMate-73L trial (NCT04026412) will evaluate the potential benefit of adding more immunotherapy in the treatment of patients with stage III non–small cell lung cancer (NSCLC) by examining nivolumab  plus chemoradiation followed by nivolumab and ipilimumab (Yervoy).The study will build upon the understanding gleaned from the pivotal phase 3 PACIFIC trial (NCT02125461) of durvalumab (Imfinzi) following chemoradiation in an effort to provide more mature data, explained Nagla F. Abdel Karim, MD.

“It is good that we have [seen] success with including immunotherapy in the consolidation phase, but we need more mature data,” Karim said. “Is the addition of more drugs better? Or does it just come [at the cost of] more financial and autoimmune toxicity?”

®, a sister publication of Oncology Nursing News®, Karim, a medical oncologist at Augusta University Medical Center, further discussed the ongoing CheckMate-73L trial in patients with stage III NSCLC, the potential impact of the research on the paradigm, and future areas of exploration.

®: What was the rationale for the CheckMate-73L trial?

: Stage III NSCLC has been a very difficult disease [to treat], and until recently, we just did concomitant chemoradiation [for these patients]. Additionally, we had used consolidation chemotherapy following the chemoradiation, but this has been proven to be not beneficial, and in fact, even harmful. As such, [we stopped doing that].

Then, the PACIFIC trial examined the initiation of immunotherapy after the chemoradiation for all comers, and [that approach resulted in an increase in] median progression-free survival from 5.6 months to 17.2 months; this was significant. Additionally, the median overall survival for patients who received 1 year of immunotherapy with durvalumab had not been reached vs 28.7 months for those who received standard-of-care chemoradiation alone.

This is [a great option], and we do offer that to our patients. However, we know that [patients with a lower PD-L1 expression did not [experience] the benefit that those with a higher PD-L1 expression did [from that approach]. We also know that administering durvalumab less than 14 days [after] the chemoradiation yielded the highest benefits. However, we still have patients who do not do as well [with this approach], with an 18-month PFS rate of just 44%. That means that more than half of patients are going to ultimately progress. We have to improve on that.

In the CheckMate-73L trial, we are examining the combination of 2 types of immunotherapy that have different mechanisms of action. [By using them in] the consolidation phase, [we] should ultimately [see a] synergistic antitumor response. The 2 agents that are being used are ipilimumab and nivolumab. Ipilimumab blocks the interaction between the CTLA-4 on T cells, and the CD80 and CD86 on those presenting cells; this is in addition to the anti–PD-1 inhibitor which is nivolumab. Having this combination should lead to a stronger or synergistic mechanism in the consolidation [phase], and [we hypothesize that] this will subsequently [result in] a better clinical outcome in terms of progression-free survival [PFS] and overall survival [OS].

What was the design of the trial, and what were some of the eligibility criteria?

The eligibility criteria are straightforward: patients with stage III NSCLC who are not candidates for surgery. Eligible patients should not have received any prior chemotherapy or other anticancer treatments and should be newly diagnosed with stage III disease. They should not have [any underlying conditions, such as] acute infections, a history of transplant, or other conditions that might make them sick from the chemotherapy or from this approach.

In terms of stratification, we have learned so much from melanomas and other tumor types [in terms of how to] use immunotherapies. Patients in arm A will receive chemotherapy, which is [comprised of] carboplatin and paclitaxel and is standard of care. However, the only difference in this trial is that [the chemotherapy] will be given for 1 day every 3 weeks; it is not [given] weekly as we used to do. The chemotherapy will be given in addition to nivolumab. Again, this is given 1 time every 3 weeks, plus the radiation therapy. Then this arm will continue with the consolidation after finishing chemoradiation, using ipilimumab plus nivolumab for 1 year. The reason I mention that we learned from other diseases is because we are using a 1-mg/kg dose of ipilimumab [that is given] every 6 weeks. [We know this dose] is not as toxic and is supposed to be better tolerated with this combination.

The only difference in arm B is that consolidation will not include ipilimumab; it is just going to be nivolumab, given every 4 weeks for 1 year. Arm C is just the standard of care, with just chemotherapy plus radiotherapy, and that will be followed by 1 year of durvalumab.

What do you anticipate seeing in terms of safety with this approach?

We do not yet have a standard of care of immunotherapy plus chemotherapy given at the same time as radiation. This is something also that we are looking into with this trial. However, prior trials have shown that these treatments are safe to combine with radiation therapy. Of course, this is a larger-scale clinical trial, so we are going to ensure that our patients are safe and closely monitored.

With chemotherapy plus radiation, we are aware that patients can have inflammation of the esophagus or some difficulty swallowing. [With AEs like] nausea and vomiting, the best supportive care works well to control those toxicities. In addition, if we are adding immunotherapy during that period, or later in the consolidation [phase], we pay attention to autoimmune AEs. That is why we monitor thyroid functions, we monitor if patients get diarrhea, if there are signs of colitis or pneumonitis, if they have inflammation of the lungs, if they experience shortness of breath. [We have ways to stay] on top of those AEs.

Is there anything that you would like to add about this research?

The trial started in August 2019 and is anticipated to conclude between 2022 and 2024. Notably, trial is being conducted at 175 study sites in 26 countries; this is important because we will have information on diverse populations [who reside in] different areas of the world. This will [allow us to determine whether there are] any vulnerable populations in terms of autoimmune adverse effects [AEs] experienced with the approach, or [whether any] efficacy differences [exist between] the sites.

If this trial proves to be positive, how might this research impact the paradigm for this population?

We want to look into PFS and OS. If these patients are going to live longer, with less AEs [or a similar] toxicity [profile] compared with [what has been seen with] durvalumab, then this [new approach] could be the standard of care. If patients can tolerate the dual-immunotherapy combination, and they have a better outcome with less toxicity, then we would recommend that our patients [receive this treatment].

Having mentioned that, we like to personalize treatment for our patients with lung cancer. Our patients are not all the same; some might have more problems with specific treatments. As such, we will benefit so much from knowing more about markers or translational components. In this trial, we are looking into molecular markers, and other markers that can help us identify which patients are going to benefit the most [from this kind of approach], as well as which patients might experience more AEs. We still [have a lot to] learn, but certainly this is a very important trial.

This article was originally published on OncLive as 

“CheckMate-73L to Examine Nivolumab/Ipilimumab Following Nivolumab/Chemoradiation in NSCLC”

The ongoing CheckMate-73L trial seeks to determine if nivolumab plus ipilimumab following nivolumab plus chemoradiation could become the new standard of care in treating non-small cell lung cancer, says Nagla F. Abdel Karim, MD.

CheckMate-73L To Explore Ipilimumab and Nivolumab Combo in Non-Small Cell Lung Cancer Treatment

Ongoing research seeks to determine which biomarker-selected cohorts of patients with lung cancer might respond to PARP inhibitors, shared Sandip Patel, MD, said in a presentation during the 

 International Lung Cancer Congress®, a program hosted by Physicians’ Education Resource®, LLC.1

While PARP inhibitors have been successfully utilized across various subspecies of oncology, including breast cancer, ovarian cancer, and prostate cancer, they have not yet proved to be effective in treating thoracic malignancies such as non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC).

The way in which PARP inhibitors work can be defined by 2 distinct mechanisms: synthetic lethality and PARP trapping. The former leads to chromosomal catastrophe in the cancer cells, which makes them unable to survive or replicate.2 With PARP trapping, although this is more nuanced and varied amongst the different inhibitors, DNA strands are trapped and the replication of cancer cells is blocked, according to Patel.

“Predictive biomarkers for PARP inhibition sensitivity often involves having a baseline mutation that already effects ability to conduct DNA repair” Patel, an associate professor in the Department of Medicine at UC San Diego Health, explained. “These drugs were FDA approved initially for [those with] germline mutations in 

, followed by some somatic mutations initially in breast and ovarian cancers. There have been data in pancreatic and prostate cancer, as well. As such, the idea that this can be a pan-histology biomarker was initially met with enthusiasm. However, over time, it looks like some of these efficacy changes are context specific.”

In terms of genomic correlates of response to these agents, certain pathways have been found to be more strongly associated with synthetic lethality than others.3 Those pathways include:

 pathway, which repairs single- and double-strand breaks in DNA

The SLFN11 pathway, which results in the killing of cells undergoing replication stress

The loss of heterozygosity (LOH), which is an assay that can be used to look for homologous recombination deficiency (HRD)

“There are multiple mechanisms by which you can have an underlying issue in terms of DNA repair in cancer cells, for which a PARP inhibitor can be that second ‘key’ on the nuclear summary to lead to chromosomal catastrophe,” Patel noted.

Rationale for PARP in Thoracic Malignancies

 mutations have been found to be present in approximately 14% of patients with NSCLC, and 12% of those with SCLC.4 As such, if these mutations prove to be viable therapeutic targets as they have in other cancer types, PARP inhibition could have potential as the third leading targeted treatment in thoracic malignancies, after 

In the phase 1/2 ATF-07 trial (NCT02412371) the PARP inhibitor veliparib (ABT-888) was examined in combination with concurrent chemoradiotherapy to induce DNA damage in patients with stage III NSCLC.5 The regimen yielded some activity, with an objective response rate (ORR) of 64.3%. “These are reasonable rates of activity but nothing that substantially moved the needle to want to incorporate [this into practice], and there was toxicity that was predominantly related to cytopenias,” Patel said.

Similarly, the Lung-MAP SWOG S1400G trial (NCT02154490) examined talazoparib (Talzenna) in patients with advanced, refractory squamous cell lung cancer whose tumors harbor 

 mutations. The agent yielded an ORR of just 4%.6

“The most elite responder was HRD negative, and so the biomarker was not exactly predicting the limited biologic effect we saw here,” Patel noted.

Modest efficacy was observed, however, in the Lung-MAP SWOG S1900A trial (NCT03845296) that examined rucaparib in the second-line treatment of patients with 

-mutant, LOH advanced NSCLC.7 Results from the study demonstrated a potential benefit in patients with homozygous 

 mutations, although the overall efficacy was muted, according to Patel.

Efforts to Incorporate PARP Inhibition in SCLC

SCLC remains a disease where targeted therapeutic approaches have yet to be established, despite the disease being characterized by mutations in DNA repair.8 Due to this, ongoing studies are examining the potential for PARP inhibition in this patient population.

“The thought has been to combine temozolomide [Temodar], a drug commonly used in glioblastoma but that can also be used in SCLC, in combination with PARP inhibitors as a rational, biologically-designed approach in patients with refractory SCLC,” Patel said.9 “However, although some patients had benefit, overall, the response rates were limited.”

In a multicenter phase 2 clinical trial (NCT01638546), investigators compared the use of temozolomide plus veliparib or placebo in the second- or third-line treatment of patients with relapsed SCLC.9 Results indicated a significant difference in ORRs between those who received veliparib/temozolomide vs those who were given temozolomide alone, at 39% and 14%, respectively (

= .016). However, no significant difference was observed with regard to the 4-month progression-free survival rates in the investigative and control arms, at 36% and 27%, respectively (

Similarly, temozolomide was examined in combiantion with olaparib (Lynparza) in patients with refractory SCLC, and although some responses were observed, the durability of those responses was limited, Patel said. Additionally, the toxicity associated with this treatment was prohibitive to some patients, according to Patel.10

What’s Next with PARP Inhibition in Lung Cancer?

An area of research that has yielded promising outcomes in other disease types, such as ovarian cancer, is the combination of immunotherapeutic agents with PARP inhibitors, Patel said. In fact, recent data have shown that even those patients with 

 wild-type mutations are experiencing responses to PARP inhibition combined with PD-1 inhibition, that would be expected with either therapy alone.

“This is an area of potential interest across other tumor types,” Patel concluded. “The mechanism by which this biology leads to benefit, and potentially durable benefit, for patients is still unclear, but it is an exciting avenue of research.”

Patel S. Incorporation of PARP inhibitors. Presented at: 

 International Lung Cancer Congress; July 29-31, 2021; Huntington Beach, CA. Accessed July 29, 2021.

Lord CJ, Ashworth A. PARP inhibitors: synthetic lethality in the clinic. 

. 2017;355(6330):1152-1158. doi:10.1126/science.aam7344

Murai J, Tang S-W, Leo E, et al. SLFN11 blocks stressed replication forks independently of ATR. 

. 2018;69(3):371-384. doi:10.1016/j.molcel.2018.01.012

Ji W, Weng X, Xu D, et al. Non-small cell lung cancer cells with deficiencies in homologous recombination genes are sensitive to PARP inhibitors. 

. 2020;522(1):121-126. doi:10.1016/j.bbrc.2019.11.050

Kozono DE, Stinchcombe T, Salama JK, et al. Veliparib (Vel) in combination with chemoradiotherapy (CRT) of carboplatin/paclitaxel (C/P) plus radiation in patients (pts) with stage III non-small cell lung cancer (NSCLC) (M14-360/AFT-07). 

. 2019;37(suppl 15):8510. doi:0.1200/JCO.2019.37.15_suppl.8510

Owonikoko TK, Redman MW, Byers LA, et al. Phase 2 study of talazoparib in patients with homologous recombination repair-deficient squamous cell lung cancer: Lung-MAP substudy S1400G. 

. 2021;22(3):187-194. doi:10.1016/j.cllc.2021.01.001

Reiss JW, Redman MW, Wheatley-Price P, et al. A phase II study of rucaparib in patients with high genomic LOH and/or BRCA 1/2 mutated stage IV non-small cell lung cancer (Lung-MAP Sub-Study, S1900A). 

. 2021;39(suppl 15):9024. doi:10.1200/JCO.2021.39.15_suppl.9024

Knelson EH, Patel SA, Sands JM. PARP inhibitors in small-cell lung cancer: rational combinations to improve responses. 

. 2021;13(4):727. doi:10.3390/cancers13040727

Pietanza MC, Waqar SN, Krug LM, et al. Randomized, double-blind, phase II study of temozolomide in combination with either veliparib or placebo in patients with relapsed-sensitive or refractory small-cell lung cancer. 

. 2018;36(23):2386-2394. doi:10.1200/JCO.2018.77.7672

Farago AF, Yeap BY, Stanzione M, et al. Combination olaparib and temozolomide in relapsed small-cell lung cancer. 

. 2019;9(10):1372-1387. doi:10.1158/2159-8290.CD-19-0582

This article was originally published on OncLive as “

Research Efforts Seek to Unlock the Potential of PARP Inhibition in Thoracic Malignancies”


Researchers are using biomarker-testing to determine which patients with lung cancer might benefit from PARP inhibitors. 


New Research Aims to Incorporate PARP Inhibitors in Lung Cancer Treatment

Multicancer early detection (MCED) tests demonstrated a strong capacity for delivering accurate and specific cancer signal origin (CSO) predictions across various tumor types. These results suggest that MCED tests should be included as a complement to existing single-cancer screening tests.

Specifically, data from The Circulating Cell-Free Genome Atlas Study (CCGA; NCT02889978), published in 

 showed that cancer signals were detected across more than 50 tumor types and that the MCED tests demonstrated a specificity for cancer signal detection of 99.5% (95% CI, 99.0%-99.8%). The overall sensitivity for cancer signal detection was 51.5% (n = 1453/2823; 95% CI, 49.6%-53.3%) and the sensitivity of the tests increased with disease stage; sensitivity for stage I disease was 16.8% (95% CI, 14.5%-19.5%), 40.4% (95% CI, 36.8%-44.1%) for stage II, 77.0% (95% CI, 73.4%-80.3%) for stage III, and 90.1% (95% CI, 87.5%-92.2%) for stage IV.

Overall, the accuracy of CSO prediction in true positives was 88.7% (95% CI, 87.0%-90.2%).

Investigators also reported that the MCED test demonstrated a cancer signal detection sensitivity of 40.7% (95% CI, 38.7%-42.9%) in an analysis was conducted in a cohort of patients with 12 prespecified cancers which account for approximately 66% of annual cancer deaths annually in the United States. Specifically, this cohort included patients with either anal, esophageal, lung, pancreatic, bladder, head and neck, stomach, ovarian, liver/bile duct, and colorectal cancers, as well as lymphoma and plasma cell neoplasms.

Further, an analysis of patients with stage I-III disease showed that the sensitivity of cancer signal detection with the MCED tests was 67.6% (95% CI, 64.4%-70.6%).

Multicancer early detection tests provided specified and accurate cancer signal origin detection across more than 50 tumor types. 

Courtney Marabella

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