Drug rechallenge and treatment beyond progression—
implications for drug resistance
Supplementary Text
Elizabeth A. Kuczynski, Daniel J. Sargent, Axel Grothey and Robert S. Kerbel
Additional rechallenge agents
Bortezomib
Bortezomib (Valcade) is a first-in-class proteasome inhibitor active in multiple myeloma and is
used alone or with chemotherapy and immunomodulating agents such as thalidomide.
Retrospective studies suggest that retreatment with bortezomib is effective in patients who
progressed after stopping bortezomib.1–3 In initially bortezomib-responsive but heavily pretreated patients, re-treatment with bortezomib yielded a similar TTP to initial treatment1,2 and
an ORR >60% at rechallenge.1–3 Initial response was also found to be predictive of secondary
response to bortezomib in a few studies.1,2 A follow-up of the VISTA (Valcade as Initial Standard
Therapy in Multiple Myeloma) phase III clinical trial compared second line therapies following
initial melphalan and prednisone with or without bortezomib.4 Response rates of 178 patients in
the bortezomib arm were similar (47% versus 41% versus 59% for bortezomib, thalidomide
and lenalidomide based therapies, respectively). Responses to bortezomib were relatively
similar when bortezomib was (ORR 47%) or was not used as first line therapy (ORR 59%). Two
prospective trials on bortezomib rechallenge have been reported. A single-arm communitybased phase IV trial of 32 heavily pre-treated patients found that although retreatment resulted
in decreased TTP, the ORR was favourable (50%).5 A phase II international open-label trial
‘RETRIEVE’ involved 130 patients that were retreated with bortezomib after ≥6 months TFI.6 An
ORR of 40% (plus 18% minimal response) was reported at retreatment, and a higher proportion
of patients who initially achieved a CR (63% of patients) versus a PR (52%) achieved greater
than a PR at rechallenge.
Generally, bortezomib retreatment is well tolerated with no new or cumulative (and
occasionally fewer2,4) toxicities.1,3,6 Both retrospective and prospective data suggest that in those
patients with a TFI ≥6 or 12 months, the ORR is significantly higher.1,2,4,5 The efficacy of
bortezomib retreatment suggests that relapsed patients are not intrinsically more resistant, and
that there is a lack of selection for truly resistant clones. The NCCN clinical practice guidelines
currently state that patients who relapse >6 months following induction of bortezomib may be
retreated with the same regimen if they have not received intervening therapies.
Alemtuzumab
Alemtuzumab, a humanized monoclonal antibody targeting the CD52 cell surface glycoprotein, is
approved as single agent for chronic lymphocytic leukemia (CLL). It is given until maximal
response or for a minimum of 12 weeks,7 but options at relapse are unclear.8 A handful of case
reports and case series have documented heavily pre-treated CLL patients re-achieving a PR
after relapse following a second course of alemtuzumab.9–13 Only one large retrospective
analysis has been published regarding alemtuzumab rechallenge.8 30 heavily pre-treated B-cell
CLL patients were identified who relapsed and were immediately rechallenged with
alemtuzumab. Of 29 evaluable patients, 14 achieved a PR and 6, SD. Importantly, 85% of those
who responded to initial alemtuzumab responded to rechallenge, and PFS at each exposure was
not significantly different. A third course of alemtuzumab was also active. Preliminary results in
26 patients by the same authors found that patients treated within 10.3 months after the last
dose of alemtuzumab had a significantly shorter median OS than if retreatment was later. 14
Current guidelines allow alemtuzumab retreatment but this strategy has yet to be tested in
prospective studies.7
Rituximab
Rituximab, a chimeric anti-CD20 monoclonal antibody, is used to treat B-cell lymphomas. Due to
high efficacy, rituximab is routinely re-administered over a 4 week course ( ± chemotherapy) in
first and sequential lines of therapy based on early phase II studies.15,16 In one trial, 57 initially
1
responding non-Hodgkin’s lymphoma patients were re-treated with rituximab after PD
(monotherapy in 61% initially and 49% subsequently).17 Estimates of time to progression (TTP)
at retreatment (17.8 months) were longer but not significantly different from initial TTP
(12.4 months; P = 0.224). In the second, 13 progressed patients were re-administered rituximab
leading to disease control in 84% and a second PFS of 5.1 months (versus 8.2 months at initial
treatment).18 Some patients also responded to greater than three courses of rituximab.17,18 In
other patient populations, retreatment with rituximab-based therapy following relapse or
refractoriness yields similar PFS and response rates to initial treatment.15,19 Monotherapy
rechallenges are reported in only a fraction of patients.20,21 Of 178 patients reintroducted to a
similar therapy, only 12 received monotherapy and, of these 3 patients achieved a CR and 7
patients a PR.15 A similar study observed that out of those retreated with rituximab
monotherapy (11 patients), 4 patients experienced a CR, 2 patients PR and 4 patients SD.19
‘Treat as needed’ rituximab has been compared head-to-head with rituximab maintenance
therapy. A phase II trial randomly assigned 90 indolent non-Hodgkin’s lymphoma patients on
induction rituximab to receive either re-introduction after relapse or maintenance rituximab.22
In the maintenance group, PFS and final overall and complete response rates were superior.
However, the total duration of rituximab benefit was similar across the groups (maintenance
31.3 months versus 27.4 months), in addition to 3 year survival. The randomized phase III
RESORT trial found a similar time to treatment failure in the maintenance (one infusion every
12 weeks) versus retreatment arms (3.9 and 3.6 years; not significant), suggesting that
retreatment improves benefit after an initial course of therapy. There was no difference in
health-related quality of life or anxiety between groups. Although maintenance groups received
more doses of rituximab,22,23 and retreatment required the development of progressive disease,
outcomes of the two dosing strategies were similar.
Trabectedin
Trabectedin is a DNA-damaging compound indicated for the treatment of soft tissue sarcomas.
Rechallenge after relapse has been reported in cohorts of 8 and 12 patients, with all patients
experiencing tumour control at re-exposure following a chemotherapy-free interval.24,25 A
Phase II trial (NCT01303094) currently recruiting participants will randomize sarcoma patients
to continuous or trabectedin with a drug holiday after 6 cycles of stable disease.26
Gemcitabine*
A multi-centre retrospective study on pancreatic adenocarcinoma patients compared survival
outcomes in 183 patients after first line gemcitabine-containing therapy. Of patients with initial
PFS ≥6 months, 6 patients that were rechallenged with single agent gemcitabine had significant
survival improvements compared to 16 treated with another drug.27 Additionally, there is a
single case report of gemcitabine rechallenge in clear cell ovarian carcinoma.28
Everolimus*
Inhibitors of mTOR are used sequentially with TKIs to stabilize RCC growth. To date, one case
report documented successful mTOR inhibitor rechallenge in an RCC patient.29 This patient
progressed on the mTOR inhibitor everolimus as well as two different anti-angiogenic TKIs.
Since everolimus achieved the best response (a PR; PFS 33 months), he was retreated with this
agent and once again achieved a PR lasting >5 months, with little toxicity.
Crizotinib*
The ALK inhibitor crizotinib is effective in ALK positive cases of NSCLC. A recent case report of
one NSCLC experienced 18 months of total disease control due to this agent.30 After progressing
on critozinib therapy (initial PFS 8 months), she received 16 months of intervening pemetrexed
then experienced initial tumour shrinkage following crizotinib rechallenge.
Pemetrexed‡
The anti-folate pemetrexed plus platinum has recently been established as first line treatment
for malignant pleural mesothelioma. This tumour is highly aggressive and second line agents are
currently undefined. Case reports and series and small retrospective studies have observed
favourable responses particularly in those with a prolonged intervening period31,32 or first line
PFS >12 months.33 Disease control rates reported range from 43–65% at retreatment.33–35 ‘True’
rechallenges have not been clearly reported since the platinum agent may vary (of be removed)
2
at rechallenge.32–35 The largest study to date, a multicentre survey of 423 malignant
mesothelioma patients, revealed that retreatment with platinum-based chemotherapy produced
improved responses when initial TTP ≥12 months, and compared to pemetrexed-naive patients,
retreatment improved both disease control rate and PFS.36 2009 guidelines for mesothelioma
treatment recommend retreatment in patients with a good initial response to first line
chemotherapy until other second line agents are established.37
Diethylstilbestrol§
Prostate cancer is initially dependent on intrinsic androgens for sustained growth necessitating
surgical or chemical castration consisting of anti-androgens and GnRH analogues. At progression
patients are termed castration resistant and further endocrine therapy (diethylstilbestrol or
corticosteroids which further manipulate the androgen pathway) and subsequently salvage
chemotherapy is initiated. Surprisingly, such patients have been observed to regain sensitivity to
hormonal therapy following (or not) chemotherapy, indicating that drugs targeting the
androgen pathway are still active.38–41 Sundar and Cox have observed that the same
phenomenon applies when exposure to diethylstilbestrol is repeated.42,43 For instance, in a
subset of androgen refractory patients who had received prior docetaxel and progressed on
prior diethylstilbestrol, 6 of 7 patients responded to rechallenge with diethylstilbestrol.42 In a
phase II trial, castrate patients who had failed diethylstilbestrol and dexamethasone, stopped
hormone therapy and then received chemotherapy, were retreated with this diethylstilbestrol
and dexamethasone post-progression.44 43% of 28 patients responded to rechallenge (both
castrate and non-castrate patients after chemotherapy), including 8 initial non-responders.
Obtaining a PSA response at rechallenge was associated with an increase in OS (16.5 versus
5.5 months). The same phenomenon has been observed in a case report of patients on the GnRH
agonist goserelin.45 Together, this work has challenged the notion of ‘castration resistance’ and
treatment options, and raises the question of whether rechallenge with an anti-androgen will be
similarly effective after a hormone-free interval.
Notes
*Studies not listed in Supplementary Tables.
‡
With the exception of a few case studies, studies regarding pemetrexed rechallenge rarely involve using the same drug
combination at each exposure. Data not in Supplementary Tables.
§
This data is provided for interest, as diethylstilbestrol represents an older example of rechallenge. Data not in Supplementary
Tables.
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